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  • 151. Mahajan, Anubha
    et al.
    Sim, Xueling
    Ng, Hui Jin
    Manning, Alisa
    Rivas, Manuel A
    Highland, Heather M
    Locke, Adam E
    Grarup, Niels
    Im, Hae Kyung
    Cingolani, Pablo
    Flannick, Jason
    Fontanillas, Pierre
    Fuchsberger, Christian
    Gaulton, Kyle J
    Teslovich, Tanya M
    Rayner, N William
    Robertson, Neil R
    Beer, Nicola L
    Rundle, Jana K
    Bork-Jensen, Jette
    Ladenvall, Claes
    Blancher, Christine
    Buck, David
    Buck, Gemma
    Burtt, Noël P
    Gabriel, Stacey
    Gjesing, Anette P
    Groves, Christopher J
    Hollensted, Mette
    Huyghe, Jeroen R
    Jackson, Anne U
    Jun, Goo
    Justesen, Johanne Marie
    Mangino, Massimo
    Murphy, Jacquelyn
    Neville, Matt
    Onofrio, Robert
    Small, Kerrin S
    Stringham, Heather M
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Trakalo, Joseph
    Abecasis, Goncalo
    Bell, Graeme I
    Blangero, John
    Cox, Nancy J
    Duggirala, Ravindranath
    Hanis, Craig L
    Seielstad, Mark
    Wilson, James G
    Christensen, Cramer
    Brandslund, Ivan
    Rauramaa, Rainer
    Surdulescu, Gabriela L
    Doney, Alex S F
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Linneberg, Allan
    Isomaa, Bo
    Tuomi, Tiinamaija
    Jørgensen, Marit E
    Jørgensen, Torben
    Kuusisto, Johanna
    Uusitupa, Matti
    Salomaa, Veikko
    Spector, Timothy D
    Morris, Andrew D
    Palmer, Colin N A
    Collins, Francis S
    Mohlke, Karen L
    Bergman, Richard N
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Tuomilehto, Jaakko
    Hansen, Torben
    Watanabe, Richard M
    Prokopenko, Inga
    Dupuis, Josee
    Karpe, Fredrik
    Groop, Leif
    Laakso, Markku
    Pedersen, Oluf
    Florez, Jose C
    Morris, Andrew P
    Altshuler, David
    Meigs, James B
    Boehnke, Michael
    McCarthy, Mark I
    Lindgren, Cecilia M
    Gloyn, Anna L
    Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus2015Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, nr 1, artikkel-id e1004876Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.

  • 152.
    Manning, Alisa
    et al.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA..
    Highland, Heather M.
    Univ Texas MD Anderson Canc Ctr, Human Genet Ctr, Houston, TX 77030 USA.;Univ Texas Hlth Sci Ctr Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA.;Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA..
    Gasser, Jessica
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Sim, Xueling
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Tukiainen, Taru
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Dept Genet, Boston, MA USA..
    Fontanillas, Pierre
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;23andMe, Mountain View, CA USA..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Rivas, Manuel A.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Mahajan, Anubha
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Locke, Adam E.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Cingolani, Pablo
    McGill Univ, Sch Comp Sci, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Pers, Tune H.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark.;Boston Childrens Hosp, Div Endocrinol & Genet, Boston, MA USA.;Boston Childrens Hosp, Div Genom, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes, Boston, MA USA.;Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark..
    Vinuela, Ana
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland.;Univ Geneva, Inst Genet & Genom Geneva, Geneva, Switzerland..
    Brown, Andrew A.
    Wellcome Trust Sanger Inst, Hinxton, England.;Oslo Univ Hosp, Norwegian Ctr Mental Disorders Res, Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Ctr Psychosis Res, Div Mental Hlth & Addict, Oslo, Norway..
    Wu, Ying
    Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC USA..
    Flannick, Jason
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA..
    Fuchsberger, Christian
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Gamazon, Eric R.
    Univ Chicago, Dept Med, Sect Genet Med, 5841 S Maryland Ave, Chicago, IL 60637 USA.;Univ Amsterdam, Acad Med Ctr, Amsterdam, Netherlands..
    Gaulton, Kyle J.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA..
    Im, Hae Kyung
    Univ Chicago, Dept Med, Sect Genet Med, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Teslovich, Tanya M.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Blackwell, Thomas W.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Bork-Jensen, Jette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Burtt, Noel P.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Chen, Yuhui
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Green, Todd
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Hartl, Christopher
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Kang, Hyun Min
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Kumar, Ashish
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Basel, Swiss Trop & Publ Hlth Inst, Chron Dis Epidemiol Unit, Basel, Switzerland..
    Ladenvall, Claes
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Ma, Clement
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Moutsianas, Loukas
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Pearson, Richard D.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Perry, John R. B.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England.;Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Rayner, N. William
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England..
    Robertson, Neil R.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Scott, Laura J.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    van de Bunt, Martijn
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Eriksson, Johan G.
    Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.;Univ Helsinki, Unit Gen Practice, Cent Hosp, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Vaasa Cent Hosp, Vaasa, Finland.;Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Tampere, Dept Clin Chem, Fimlab Labs, Sch Med, Tampere, Finland..
    Jula, Antti
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Koskinen, Seppo
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Lehtimaki, Terho
    Palotie, Aarno
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland..
    Jacobs, Suzanne B. R.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Wessel, Jennifer
    Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN USA.;Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA..
    Chu, Audrey Y.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Scott, Robert A.
    Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Goodarzi, Mark O.
    Cedars Sinai Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA.;Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA..
    Blancher, Christine
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Buck, Gemma
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Buck, David
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Chines, Peter S.
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Gabriel, Stacey
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Gjesing, Anette P.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Groves, Christopher J.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Hollensted, Mette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Huyghe, Jeroen R.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Jackson, Anne U.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Jun, Goo
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Justesen, Johanne Marie
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Murphy, Jacquelyn
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Neville, Matt
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Onofrio, Robert
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Small, Kerrin S.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Stringham, Heather M.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Trakalo, Joseph
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Banks, Eric
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Carey, Jason
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Carneiro, Mauricio O.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    DePristo, Mark
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Farjoun, Yossi
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Fennell, Timothy
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Goldstein, Jacqueline I.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Grant, George
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    de Angelis, Martin Hrabe
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Expt Genet, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Tech Univ Munich, Sch Life Sci Weihenstephan, Inst Expt Genet, Freising Weihenstephan, Germany..
    Maguire, Jared
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Neale, Benjamin M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Poplin, Ryan
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Purcell, Shaun
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Psychiat, New York, NY 10029 USA..
    Schwarzmayr, Thomas
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Shakir, Khalid
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Smith, Joshua D.
    Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA..
    Strom, Tim M.
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Neuherberg, Germany..
    Wieland, Thomas
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Lindstrom, Jaana
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland..
    Brandslund, Ivan
    Univ Southern Denmark, Dept Reg Hlth Res, Odense, Denmark.;Vejle Hosp, Dept Clin Biochem, Vejle, Denmark..
    Christensen, Cramer
    Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark..
    Surdulescu, Gabriela L.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Lakka, Timo A.
    Univ Eastern FinIand, Inst Biomed, Dept Physiol, Kuopio, Finland.;Kuopio Res Inst Exercise Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Doney, Alex S. F.
    Ninewells Hosp & Med Sch, Med Res Inst, Div Cardiovasc & Diabet Med, Dundee, Scotland..
    Nilsson, Peter
    Lund Univ, Fac Med, Dept Clin Sci, Malmo, Sweden..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Varga, Tibor V.
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmo, Sweden.;Lund Univ, Genet & Mol Epidemiol Unit, Malmo, Sweden..
    Franks, Paul W.
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmo, Sweden.;Lund Univ, Genet & Mol Epidemiol Unit, Malmo, Sweden.;Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Rolandsson, Olov
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Rosengren, Anders H.
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Farook, Vidya S.
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Thameem, Farook
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Puppala, Sobha
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Kumar, Satish
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Lehman, Donna M.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Jenkinson, Christopher P.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA.;South Texas Vet Hlth Care Syst, Res & Dev Serv, San Antonio, TX USA..
    Curran, Joanne E.
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Hale, Daniel Esten
    Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA..
    Fowler, Sharon P.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Arya, Rector
    Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA..
    DeFronzo, Ralph A.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Abboud, Hanna E.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hicks, Pamela J.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Palmer, Nicholette D.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Ng, Maggie C. Y.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA..
    Bowden, Donald W.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Freedman, Barry I.
    Wake Forest Sch Med, Dept Internal Med, Sect Nephrol, Winston Salem, NC USA..
    Esko, Tonu
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Narisu, Narisu
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Kinnunen, Leena
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Bonnycastle, Lori L.
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Swift, Amy
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Pasko, Dorota
    Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England..
    Wood, Andrew R.
    Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England..
    Fadista, Joao
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Pollin, Toni I.
    Univ Maryland, Dept Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA..
    Barzilai, Nir
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA..
    Atzmon, Gil
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA.;Univ Haifa, Fac Nat Sci, Haifa, Israel..
    Glaser, Benjamin
    Hadassah Hebrew Univ, Endocrinol & Metab Serv, Med Ctr, Jerusalem, Israel..
    Thorand, Barbara
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Dept Genet Epidemiol, Munich, Germany..
    Peters, Annette
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Partner Site Munich Heart Alliance, Herz Kreislauf Forsch DZHK, Deutsch Zentrum, Munich, Germany..
    Roden, Michael
    Heinrich Heine Univ, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;Partner Dusseldorf, German Ctr Diabet Res, Dusseldorf, Germany..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Dept Genet Epidemiol, Munich, Germany.;Partner Site Munich Heart Alliance, Herz Kreislauf Forsch DZHK, Deutsch Zentrum, Munich, Germany.;Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany..
    Liang, Liming
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Kriebel, Jennifer
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany.;German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Illig, Thomas
    German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany.;Hannover Med Sch, Inst Human Genet, Hannover, Germany..
    Grallert, Harald
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany.;German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Gieger, Christian
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Meisinger, Christa
    German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Lannfelt, L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Musani, Solomon K.
    Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS 39216 USA..
    Griswold, Michael
    Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA..
    Taylor, Herman A., Jr.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Wilson, Gregory, Sr.
    Jackson State Univ, Coll Publ Serv, Jackson, MS USA..
    Correa, Adolfo
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Oksa, Heikki
    Pirkanmaa Hosp Dist, Tampere, Finland..
    Scott, William R.
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Afzal, Uzma
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Tan, Sian-Tsung
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Loh, Marie
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Univ Oulu, Inst Hlth Sci, Oulu, Finland.;ASTAR, Translat Lab Genet Med, Singapore, Singapore..
    Chambers, John C.
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll London, Imperial Coll Healthcare NHS Trust, London, England..
    Sehmi, Jobanpreet
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Kooner, Jaspal Singh
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England..
    Lehne, Benjamin
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Cho, Yoon Shin
    Hallym Univ, Dept Biomed Sci, Chunchon, South Korea..
    Lee, Jong-Young
    Minist Hlth & Welf, Seoul, South Korea..
    Han, Bok-Ghee
    Korea Natl Res Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea..
    Karajamaki, Annemari
    Vaasa Hlth Care Ctr, Vaasa, Finland.;Vaasa Cent Hosp, Dept Primary Hlth Care, Vaasa, Finland..
    Qi, Qibin
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA..
    Qi, Lu
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Huang, Jinyan
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Hu, Frank B.
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Melander, Olle
    Lund Univ, Dept Clin Sci, Hypertens & Cardiovasc Dis, Malmo, Sweden..
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci, Diabet & Cardiovasc Dis Genet Epidemiol, Malmo, Sweden..
    Below, Jennifer E.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Aguilar, David
    Baylor Coll Med, Cardiovasc Div, Houston, TX 77030 USA..
    Wong, Tien Yin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Liu, Jianjun
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;ASTAR, Genome Inst Singapore, Div Human Genet, Singapore, Singapore..
    Khor, Chiea-Chuen
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;ASTAR, Genome Inst Singapore, Div Human Genet, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Paediat, Singapore, Singapore..
    Chia, Kee Seng
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Lim, Wei Yen
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Cheng, Ching-Yu
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Duke NUS Grad Med Sch Singapore, Ctr Quantitat Med, Off Clin Sci, Singapore, Singapore..
    Chan, Edmund
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore..
    Tai, E. Shyong
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore.;Duke NUS Grad Med Sch Singapore, Cardiovasc Metab Disorders Program, Singapore, Singapore..
    Aung, Tin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Linneberg, Allan
    Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Isomaa, Bo
    Folkhalsan Res Ctr, Helsinki, Finland.;Dept Social Serv & Hlth Care, Pietarsaari, Finland..
    Meitinger, Thomas
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Neuherberg, Germany.;Partner Site Munich Heart Alliance, Herz Kreislauf Forsch DZHK, Deutsch Zentrum, Munich, Germany..
    Tuomi, Tiinamaija
    Folkhalsan Res Ctr, Helsinki, Finland.;Helsinki Univ Cent Hosp, Dept Endocrinol, Helsinki, Finland..
    Hakaste, Liisa
    Folkhalsan Res Ctr, Helsinki, Finland..
    Kravic, Jasmina
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Lauritzen, Torsten
    Aarhus Univ, Dept Publ Hlth, Sect Gen Practice, Aarhus, Denmark..
    Deloukas, Panos
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England..
    Stirrups, Kathleen E.
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Univ Cambridge, Dept Haematol, Cambridge, England..
    Owen, Katharine R.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Farmer, Andrew J.
    Univ Oxford, Dept Primary Care Hlth Sci, Oxford, England..
    Frayling, Timothy M.
    Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England..
    O'Rahilly, Stephen P.
    Univ Cambridge, Inst Metab Sci, Med Res Labs, Cambridge, England..
    Walker, Mark
    Univ Newcastle, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England..
    Levy, Jonathan C.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Hodgkiss, Dylan
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Hattersley, Andrew T.
    Univ Exeter, Sch Med, Exeter, Devon, England..
    Kuulasmaa, Teemu
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland..
    Stancakova, Alena
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England.;Univ Cambridge, Inst Metab Sci, Med Res Labs, Cambridge, England..
    Bharadwaj, Dwaipayan
    CSIR Inst Genom & Integrat Biol, Funct Genom Unit, New Delhi, India..
    Chan, Juliana
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China..
    Chandak, Giriraj R.
    CSIR Ctr Cellular Mol Biol, Hyderabad, Andhra Pradesh, India..
    Daly, Mark J.
    Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Donnelly, Peter J.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Dept Stat, Oxford, England..
    Ebrahim, Shah B.
    Ctr Chron Dis Control, New Delhi, India. Imperial Coll London, MRC, PHE Ctr Environm & Hlth, London, England..
    Elliott, Paul
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Fingerlin, Tasha
    Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA..
    Froguel, Philippe
    CNRS, Inst Biol Lille, Genom & Mol Physiol, Lille, France..
    Hu, Cheng
    Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Diabet Inst, Dept Endocrinol & Metab, Shanghai, Peoples R China..
    Jia, Weiping
    Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Diabet Inst, Dept Endocrinol & Metab, Shanghai, Peoples R China..
    Ma, Ronald C. W.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China..
    McVean, Gilean
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Park, Taesung
    Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea.;Seoul Natl Univ, Dept Stat, Seoul, South Korea.;Univ Cambridge, Dept Publ Hlth & Primary Care, Inst Publ Hlth, Cambridge, England..
    Prabhakaran, Dorairaj
    Ctr Chron Dis Control, New Delhi, India. Imperial Coll London, MRC, PHE Ctr Environm & Hlth, London, England..
    Sandhu, Manjinder
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Inst Publ Hlth, Cambridge, England..
    Scott, James
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England..
    Sladek, Rob
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Dept Med, Div Endocrinol & Metab, Montreal, PQ, Canada..
    Tandon, Nikhil
    All India Inst Med Sci, Dept Endocrinol & Metab, New Delhi, India..
    Teo, Yik Ying
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Inst Life Sci, Singapore, Singapore.;Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England..
    Watanabe, Richard M.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Diabet & Obes Res Inst, Los Angeles, CA USA..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Dept Med, Helsinki, Finland.;Univ Helsinki, Abdominal Ctr, Endocrinol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Minerva Fdn, Inst Med Res, Helsinki, Finland..
    Kesaniemi, Y. Antero
    Univ Oulu, Inst Clin Med, Fac Med, Oulu, Finland..
    Uusitupa, Matti
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland..
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Rauramaa, Rainer
    Fdn Res Hlth Exercise & Nutr, Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Palmer, Colin N. A.
    Ninewells Hosp & Med Sch, Med Res Inst, Pat Macpherson Ctr Pharmacogenet & Pharmacogenom, Dundee, Scotland..
    Prokopenko, Inga
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Morris, Andrew D.
    Ninewells Hosp & Med Sch, Clin Res Ctr, Div Mol Med, Dundee, Scotland..
    Bergman, Richard N.
    Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA..
    Collins, Francis S.
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden.;Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia.;Dasman Diabet Inst, Dasman, Kuwait..
    Karpe, Fredrik
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Groop, Leif
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Jorgensen, Torben
    Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Aalborg Univ, Fac Med, Aalborg, Denmark..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Kuusisto, Johanna
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Abecasis, GonOalo
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Bell, Graeme I.
    Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA.;Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA..
    Blangero, John
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Cox, Nancy J.
    Univ Chicago, Dept Med, Sect Genet Med, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Duggirala, Ravindranath
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Seielstad, Mark
    Univ Calif San Francisco, Dept Lab Med, Inst Human Genet, San Francisco, CA 94143 USA.;Blood Syst Res Inst, San Francisco, CA USA..
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA..
    Dupuis, Josee
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;NHLBI, Framingham Heart Study, Framingham, MA USA..
    Ripatti, Samuli
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Univ Helsinki, Hjelt Inst, Helsinki, Finland..
    Hanis, Craig L.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Florez, Jose C.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA..
    Mohlke, Karen L.
    Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC USA..
    Meigs, James B.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA..
    Laakso, Markku
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Morris, Andrew P.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Boehnke, Michael
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Altshuler, David
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Harvard Med Sch, Dept Genet, Boston, MA USA.;Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA.;MIT, Dept Biol, Cambridge, MA USA..
    McCarthy, Mark I.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Gloyn, Anna L.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Lindgren, Cecilia M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Li Ka Shing Ctr Hlth Informat & Discovery, Big Data Inst, Oxford, England..
    A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk2017Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 7, s. 2019-2032Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

  • 153.
    Marincevic-Zuniga, Yanara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahlberg, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nilsson, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Raine, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nystedt, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindqvist, Carl Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Berglund, Eva C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Abrahamsson, Jonas
    Univ Gothenburg, Sahlgrenska Acad, Dept Pediat, Inst Clin Sci, Gothenburg, Sweden..
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Forestier, Erik
    Univ Umea, Dept Med Biosci, Umea, Sweden..
    Heyman, Mats
    Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Childhood Canc Res Unit, Karolinska Inst, Stockholm, Sweden..
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Nordlund, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles2017Inngår i: Journal of Hematology & Oncology, ISSN 1756-8722, E-ISSN 1756-8722, Vol. 10, artikkel-id 148Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). In this study, we performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts. Methods: We combined fusion gene detection with genome-wide DNA methylation analysis, gene expression profiling, and targeted sequencing to determine molecular signatures of emerging ALL subtypes. Results: We identified 64 unique fusion events distributed among 80 individual patients, of which over 50% have not previously been reported in ALL. Although the majority of the fusion genes were found only in a single patient, we identified several recurrent fusion gene families defined by promiscuous fusion gene partners, such as ETV6, RUNX1, PAX5, and ZNF384, or recurrent fusion genes, such as DUX4-IGH. Our data show that patients harboring these fusion genes displayed characteristic genome-wide DNA methylation and gene expression signatures in addition to distinct patterns in single nucleotide variants and recurrent copy number alterations. Conclusion: Our study delineates the fusion gene landscape in pediatric ALL, including both known and novel fusion genes, and highlights fusion gene families with shared molecular etiologies, which may provide additional information for prognosis and therapeutic options in the future.

  • 154.
    Marincevic-Zuniga, Yanara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Zachariadis, Vasilios
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Castor, Anders
    Skane Univ Hosp, Pediat Oncol Hematol, Lund, Sweden.
    Barbany, Gisela
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Forestier, Erik
    Umea Univ, Dept Med Biosci, S-90187 Umea, Sweden.
    Fogelstrand, Linda
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Clin Chem & Transfus Med, Gothenburg, Sweden; Sahlgrens Univ Hosp, Clin Chem Lab, Gothenburg, Sweden.
    Heyman, Mats
    Karolinska Inst, Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Childhood Canc Res Unit, Stockholm, Sweden.
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Dept Pediat, Gothenburg, Sweden.
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Nordgren, Ann
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    PAX5-ESRRB is a recurrent fusion gene in B-cell precursor pediatric acute lymphoblastic leukemia2016Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, nr 1, s. e20-e23Artikkel i tidsskrift (Fagfellevurdert)
  • 155.
    Marzouka, Nour-al-dain
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Nordlund, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Bäcklin, Christofer L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Almlöf, Jonas Carlsson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    CopyNumber450kCancer: baseline correction for accurate copy number calling from the 450k methylation array2016Inngår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 32, nr 7, s. 1080-1082Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Illumina Infinium HumanMethylation450 BeadChip (450k) is widely used for the evaluation of DNA methylation levels in large-scale datasets, particularly in cancer. The 450k design allows copy number variant (CNV) calling using existing bioinformatics tools. However, in cancer samples, numerous large-scale aberrations cause shifting in the probe intensities and thereby may result in erroneous CNV calling. Therefore, a baseline correction process is needed. We suggest the maximum peak of probe segment density to correct the shift in the intensities in cancer samples.

  • 156.
    Mauro, D.
    et al.
    Queen Mary Univ London, Expt Med & Rheumatol, London, England..
    Lewis, M. J.
    Queen Mary Univ London, Expt Med & Rheumatol, London, England..
    Pullabhatla, V.
    Kings Coll London, Dept Med & Mol Genet, London, England..
    Vyse, S.
    Queen Mary Univ London, Expt Med & Rheumatol, London, England..
    Simpson, M.
    Kings Coll London, Dept Med & Mol Genet, London, England..
    Cunninghame-Graham, D.
    Kings Coll London, Dept Med & Mol Genet, London, England..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Pitzalis, C.
    Queen Mary Univ London, Expt Med & Rheumatol, London, England..
    de Rinaldis, E.
    Kings Coll London, Dept Med & Mol Genet, London, England..
    Vyse, T. J.
    Kings Coll London, Dept Med & Mol Genet, London, England..
    C1qtnf4 Mutation Identified by Exome Sequencing Is Associated with Systemic Lupus Erythematosus and Dysregulation of Tnf-Induced Apoptosis2016Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, s. 145-154Artikkel i tidsskrift (Annet vitenskapelig)
  • 157. McEvoy, Brian P.
    et al.
    Montgomery, W
    McRae, F
    Ripatti, Samuli
    Perola, Markus
    Spector, D
    Cherkas, Lynn
    Ahmadi, R
    Boomsma, Dorret
    Willemsen, Gonneke
    Hottenga, J
    Pedersen, L
    Magnusson, E
    Kyvik, Ohm
    Christensen, Kaare
    Kaprio, Jaakko
    Heikkila, Kauko
    Palotie, Aarno
    Widen, Elisabeth
    Muilu, Juha
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Hardiman, Orla
    Cronin, Simon
    Peltonen, Leena
    Martin, G
    Visscher, Peter M.
    Geographical structure and differential natural selection among North European populations2009Inngår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, nr 5, s. 804-814Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Population structure can provide novel insight into the human past, and recognizing and correcting for such stratification is a practical concern in gene mapping by many association methodologies. We investigate these patterns, primarily through principal component (PC) analysis of whole genome SNP polymorphism, in 2099 individuals from populations of Northern European origin (Ireland, United Kingdom, Netherlands, Denmark, Sweden, Finland, Australia, and HapMap European-American). The major trends (PC1 and PC2) demonstrate an ability to detect geographic substructure, even over a small area like the British Isles, and this information can then be applied to finely dissect the ancestry of the European-Australian and European-American samples. They simultaneously point to the importance of considering population stratification in what might be considered a small homogeneous region. There is evidence from FST-based analysis of genic and nongenic SNPs that differential positive selection has operated across these populations despite their short divergence time and relatively similar geographic and environmental range. The pressure appears to have been focused on genes involved in immunity, perhaps reflecting response to infectious disease epidemic. Such an event may explain a striking selective sweep centered on the rs2508049-G allele, close to the HLA-G gene on chromosome 6. Evidence of the sweep extends over a 8-Mb/3.5-cM region. Overall, the results illustrate the power of dense genotype and sample data to explore regional population variation, the events that have crafted it, and their implications in both explaining disease prevalence and mapping these genes by association.

  • 158.
    Milani, Lili
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Gupta, Manu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Andersen, M.
    Dhar, Sumeer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Isaksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Syvänen, Ann Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells2007Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 35, nr 5, s. e34-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Using the relative expression levels of two SNP alleles of a gene in the same sample is an effective approach for identifying cis-acting regulatory SNPs (rSNPs). In the current study, we established a process for systematic screening for cis-acting rSNPs using experimental detection of AI as an initial approach. We selected 160 expressed candidate genes that are involved in cancer and anticancer drug resistance for analysis of AI in a panel of cell lines that represent different types of cancers and have been well characterized for their response patterns against anticancer drugs. Of these genes, 60 contained heterozygous SNPs in their coding regions, and 41 of the genes displayed imbalanced expression of the two cSNP alleles. Genes that displayed AI were subjected to bioinformatics-assisted identification of rSNPs that alter the strength of transcription factor binding. rSNPs in 15 genes were subjected to electrophoretic mobility shift assay, and in eight of these genes (APC, BCL2, CCND2, MLH1, PARP1, SLIT2, YES1, XRCC1) we identified differential protein binding from a nuclear extract between the SNP alleles. The screening process allowed us to zoom in from 160 candidate genes to eight genes that may contain functional rSNPs in their promoter regions.

  • 159.
    Milani, Lili
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Lundmark, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Kiialainen, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Nordlund, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Flaegstad, Trond
    Forestier, Erik
    Heyman, Mats
    Jonmundsson, Gudmundur
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Söderhäll, Stefan
    Gustafsson, Mats G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia2010Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, nr 6, s. 1214-1225Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite improvements in the prognosis of childhood acute lymphoblastic leukemia (ALL), subgroups of patients would benefit from alternative treatment approaches. Our aim was to identify genes with DNA methylation profiles that could identify such groups. We determined the methylation levels of 1320 CpG sites in regulatory regions of 416 genes in cells from 401 children diagnosed with ALL. Hierarchical clustering of 300 CpG sites distinguished between T-lineage ALL and B-cell precursor (BCP) ALL and between the main cytogenetic subtypes of BCP ALL. It also stratified patients with high hyperdiploidy and t(12;21) ALL into 2 subgroups with different probability of relapse. By using supervised learning, we constructed multivariate classifiers by external cross-validation procedures. We identified 40 genes that consistently contributed to accurate discrimination between the main subtypes of BCP ALL and gene sets that discriminated between subtypes of ALL and between ALL and controls in pairwise classification analyses. We also identified 20 individual genes with DNA methylation levels that predicted relapse of leukemia. Thus, methylation analysis should be explored as a method to improve stratification of ALL patients. The genes highlighted in our study are not enriched to specific pathways, but the gene expression levels are inversely correlated to the methylation levels.

  • 160.
    Milani, Lili
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Lundmark, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Nordlund, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Kiialainen, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Flaegstad, Trond
    Jonmundsson, Gudmundur
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Gunderson, Kevin L.
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation2009Inngår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, nr 1, s. 1-11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To identify genes that are regulated by cis-acting functional elements in acute lymphoblastic leukemia (ALL) we determined the allele-specific expression (ASE) levels of 2, 529 genes by genotyping a genome-wide panel of single nucleotide polymorphisms in RNA and DNA from bone marrow and blood samples of 197 children with ALL. Using a reproducible, quantitative genotyping method and stringent criteria for scoring ASE, we found that 16% of the analyzed genes display ASE in multiple ALL cell samples. For most of the genes, the level of ASE varied largely between the samples, from 1.4-fold overexpression of one allele to apparent monoallelic expression. For genes exhibiting ASE, 55% displayed bidirectional ASE in which overexpression of either of the two SNP alleles occurred. For bidirectional ASE we also observed overall higher levels of ASE and correlation with the methylation level of these sites. Our results demonstrate that CpG site methylation is one of the factors that regulates gene expression in ALL cells.

  • 161.
    Morin, Andreanne
    et al.
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada;McGill Univ, Montreal, PQ, Canada;Genome Quebec Innovat Ctr, Montreal, PQ, Canada;Univ Quebec Chicoutimi, Dept Sci Fondamentales, Saguenay, PQ, Canada.
    Madore, Anne-Marie
    Univ Quebec Chicoutimi, Dept Sci Fondamentales, Saguenay, PQ, Canada.
    Kwan, Tony
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada;McGill Univ, Montreal, PQ, Canada;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.
    Ban, Maria
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England.
    Partanen, Jukka
    Finnish Red Cross Blood Serv, Res & Dev, Helsinki, Finland.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sawcer, Stephen
    Univ Cambridge, Dept Clin Neurosci, Cambridge, England.
    Stunnenberg, Hendrik
    Radboud Univ Nijmegen, Dept Mol Biol, Fac Sci, Nijmegen, Netherlands.
    Lathrop, Mark
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada;McGill Univ, Montreal, PQ, Canada;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.
    Pastinen, Tomi
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada;McGill Univ, Montreal, PQ, Canada;Genome Quebec Innovat Ctr, Montreal, PQ, Canada;Ctr Pediat Genom Med, Kansas City, MO USA.
    Laprise, Catherine
    Univ Quebec Chicoutimi, Dept Sci Fondamentales, Saguenay, PQ, Canada;Ctr Integre Univ Sante & Serv Sociaux Saguenay La, Saguenay, PQ, Canada.
    Exploring rare and low-frequency variants in the Saguenay-Lac-Saint-Jean population identified genes associated with asthma and allergy traits2019Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, nr 1, s. 90-101Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Saguenay-Lac-Saint-Jean (SLSJ) region is located in northeastern Quebec and is known for its unique demographic history and founder effect. As founder populations are enriched with population-specific variants, we characterized the variants distribution in SLSJ and compared it with four European populations (Finnish, Sweden, United Kingdom and France), of which the Finnish population is another founder population. Targeted sequencing of the coding and non-coding immune regulatory regions of the SLSJ asthma familial cohort and the four European populations were performed. Rare and low-frequency coding and non-coding regulatory variants identified in the SLSJ population were then investigated for variant-and gene-level associations with asthma and allergy-related traits (eosinophil percentage, immunoglobulin (Ig) E levels and lung function). Our data showed that (1) rare or deleterious variants were not enriched in the two founder populations as compared with the three non-founder European populations; (2) a larger proportion of founder population-specific variants occurred with higher frequencies; and (3) low-frequency variants appeared to be more deleterious. Furthermore, a rare variant, rs1386931, located in the 3'-UTR of CXCR6 and intron of FYCO1 was found to be associated with eosinophil percentage. Gene-based analyses identified NRP2, MRPL44 and SERPINE2 to be associated with various asthma and allergy-related traits. Our study demonstrated the usefulness of using a founder population to identify new genes associated with asthma and allergy-related traits; thus better understand the genes and pathways implicated in pathophysiology.

  • 162. Morris, Andrew P.
    et al.
    Voight, Benjamin F.
    Teslovich, Tanya M.
    Ferreira, Teresa
    Segre, Ayellet V.
    Steinthorsdottir, Valgerdur
    Strawbridge, Rona J.
    Khan, Hassan
    Grallert, Harald
    Mahajan, Anubha
    Prokopenko, Inga
    Kang, Hyun Min
    Dina, Christian
    Esko, Tonu
    Fraser, Ross M.
    Kanoni, Stavroula
    Kumar, Ashish
    Lagou, Vasiliki
    Langenberg, Claudia
    Luan, Jian'an
    Lindgren, Cecilia M.
    Mueller-Nurasyid, Martina
    Pechlivanis, Sonali
    Rayner, N. William
    Scott, Laura J.
    Wiltshire, Steven
    Yengo, Loic
    Kinnunen, Leena
    Rossin, Elizabeth J.
    Raychaudhuri, Soumya
    Johnson, Andrew D.
    Dimas, Antigone S.
    Loos, Ruth J. F.
    Vedantam, Sailaja
    Chen, Han
    Florez, Jose C.
    Fox, Caroline
    Liu, Ching-Ti
    Rybin, Denis
    Couper, David J.
    Kao, Wen Hong L.
    Li, Man
    Cornelis, Marilyn C.
    Kraft, Peter
    Sun, Qi
    van Dam, Rob M.
    Stringham, Heather M.
    Chines, Peter S.
    Fischer, Krista
    Fontanillas, Pierre
    Holmen, Oddgeir L.
    Hunt, Sarah E.
    Jackson, Anne U.
    Kong, Augustine
    Lawrence, Robert
    Meyer, Julia
    Perry, John R. B.
    Platou, Carl G. P.
    Potter, Simon
    Rehnberg, Emil
    Robertson, Neil
    Sivapalaratnam, Suthesh
    Stancakova, Alena
    Stirrups, Kathleen
    Thorleifsson, Gudmar
    Tikkanen, Emmi
    Wood, Andrew R.
    Almgren, Peter
    Atalay, Mustafa
    Benediktsson, Rafn
    Bonnycastle, Lori L.
    Burtt, Noel
    Carey, Jason
    Charpentier, Guillaume
    Crenshaw, Andrew T.
    Doney, Alex S. F.
    Dorkhan, Mozhgan
    Edkins, Sarah
    Emilsson, Valur
    Eury, Elodie
    Forsen, Tom
    Gertow, Karl
    Gigante, Bruna
    Grant, George B.
    Groves, Christopher J.
    Guiducci, Candace
    Herder, Christian
    Hreidarsson, Astradur B.
    Hui, Jennie
    James, Alan
    Jonsson, Anna
    Rathmann, Wolfgang
    Klopp, Norman
    Kravic, Jasmina
    Krjutskov, Kaarel
    Langford, Cordelia
    Leander, Karin
    Lindholm, Eero
    Lobbens, Stephane
    Mannisto, Satu
    Mirza, Ghazala
    Muehleisen, Thomas W.
    Musk, Bill
    Parkin, Melissa
    Rallidis, Loukianos
    Saramies, Jouko
    Sennblad, Bengt
    Shah, Sonia
    Sigurdsson, Gunnar
    Silveira, Angela
    Steinbach, Gerald
    Thorand, Barbara
    Trakalo, Joseph
    Veglia, Fabrizio
    Wennauer, Roman
    Winckler, Wendy
    Zabaneh, Delilah
    Campbell, Harry
    van Duijn, Cornelia
    Uitterlinden, Andre G.
    Hofman, Albert
    Sijbrands, Eric
    Abecasis, Goncalo R.
    Owen, Katharine R.
    Zeggini, Eleftheria
    Trip, Mieke D.
    Forouhi, Nita G.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Eriksson, Johan G.
    Peltonen, Leena
    Noethen, Markus M.
    Balkau, Beverley
    Palmer, Colin N. A.
    Lyssenko, Valeriya
    Tuomi, Tiinamaija
    Isomaa, Bo
    Hunter, David J.
    Qi, Lu
    Shuldiner, Alan R.
    Roden, Michael
    Barroso, Ines
    Wilsgaard, Tom
    Beilby, John
    Hovingh, Kees
    Price, Jackie F.
    Wilson, James F.
    Rauramaa, Rainer
    Lakka, Timo A.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Dedoussis, George
    Njolstad, Inger
    Pedersen, Nancy L.
    Khaw, Kay-Tee
    Wareham, Nicholas J.
    Keinanen-Kiukaanniemi, Sirkka M.
    Saaristo, Timo E.
    Korpi-Hyovalti, Eeva
    Saltevo, Juha
    Laakso, Markku
    Kuusisto, Johanna
    Metspalu, Andres
    Collins, Francis S.
    Mohlke, Karen L.
    Bergman, Richard N.
    Tuomilehto, Jaakko
    Boehm, Bernhard O.
    Gieger, Christian
    Hveem, Kristian
    Cauchi, Stephane
    Froguel, Philippe
    Baldassarre, Damiano
    Tremoli, Elena
    Humphries, Steve E.
    Saleheen, Danish
    Danesh, John
    Ingelsson, Erik
    Ripatti, Samuli
    Salomaa, Veikko
    Erbel, Raimund
    Joeckel, Karl-Heinz
    Moebus, Susanne
    Peters, Annette
    Illig, Thomas
    de Faire, Ulf
    Hamsten, Anders
    Morris, Andrew D.
    Donnelly, Peter J.
    Frayling, Timothy M.
    Hattersley, Andrew T.
    Boerwinkle, Eric
    Melander, Olle
    Kathiresan, Sekar
    Nilsson, Peter M.
    Deloukas, Panos
    Thorsteinsdottir, Unnur
    Groop, Leif C.
    Stefansson, Kari
    Hu, Frank
    Pankow, James S.
    Dupuis, Josee
    Meigs, James B.
    Altshuler, David
    Boehnke, Michael
    McCarthy, Mark I.
    Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes2012Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, nr 9, s. 981-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genomewide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

  • 163. Mälarstig, Anders
    et al.
    Sigurdsson, Snaevar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Eriksson, Per
    Paulsson-Berne, Gabrielle
    Hedin, Ulf
    Wallentin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Hamsten, Anders
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Variants of the interferon regulatory factor 5 gene regulate expression of IRF5 mRNA in atherosclerotic tissue but are not associated with myocardial infarction2008Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 28, nr 5, s. 975-982Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Signaling events after activation of toll-like receptors (TLRs) are important mechanisms promoting inflammation in the atherosclerotic plaque. INF regulatory factor 5 (IRF5) is one of the mediators of downstream effects of TLRs. Several single nucleotide polymorphisms (SNPs) in the IRF5 gene have been found to be associated with systemic lupus erythematosus.

    METHODS AND RESULTS:

    We examined IRF5 mRNA expression in carotid atherosclerotic tissue (n=99) and the case-control association between SNPs in the IRF5 gene with myocardial infarction (MI) (n=376+387) and unstable coronary artery disease (CAD) (n=3101+445). Among unstable CAD patients, association of IRF5 SNPs with recurrent coronary events (n=401) was also investigated. The IRF5 mRNA expression was increased in atherosclerotic tissue compared with control tissue (P<0.001). Significant associations with IRF5 expression was observed for 6 of 10 SNPs in the study. However, the IRF5 SNPs examined were neither associated with the risk of precocious MI, nor with unstable CAD or risk of recurrent cardiovascular events in unstable CAD patients.

    CONCLUSIONS:

    IRF5 mRNA is expressed in cells in atherosclerotic tissue and its expression is modified by SNPs in the IRF5 gene. Genetic variation at the IRF5 locus was, however, not associated with CAD or related phenotypes.

  • 164.
    Mälarstig, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Tenno, Taavo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Johnston, Nina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lagerqvist, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Wallentin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Genetic variations in the tissue factor gene are associated with clinical outcome in acute coronary syndrome and expression levels in human monocytes2005Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 25, nr 12, s. 2667-2672Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    Tissue factor (TF) has, among other factors, a prominent role in acute coronary syndrome (ACS). Our goal was to investigate whether single nucleotide polymorphisms (SNP) in the TF gene (F3) are associated with plasma TF, risk, and outcome in patients with ACS. Moreover, we wanted to investigate the impact of associated TF SNPs on mRNA production in human monocytes.

    METHODS AND RESULTS:

    In 725 patients with ACS [Fragmin and Fast Revascularization during Instability in Coronary Artery Disease II (FRISC-II) study] and 376 controls, 13 SNPs were genotyped and plasma TF measured. Thereafter, the 5466 A>G and the -1812 C>T were genotyped among all of the FRISC-II participants (n=3143) and assessed concerning clinical outcome. Associated SNPs were genotyped in 92 healthy blood donors for comparison of TF activity and TF mRNA expression. None of the SNPs were associated with patient/control status. The 5466 A>G SNP was associated with cardiovascular death (odds ratio, 1.8; P=0.025). The CG haplotype by -1812 C>T and 5466 A>G was associated with a 3-fold increased risk of death (P<0.001). TF mRNA and basal TF activity was significantly lower among 5466 AG carriers, whereas the increase in monocyte TF activity on lipopolysaccharide stimulation was significantly stronger (P=0.04).

    CONCLUSIONS:

    The 5466 AG genotype is a novel predictor of cardiovascular death in ACS and may act through a high TF response.

  • 165. Nastase Mannila, Maria
    et al.
    Mahdessian, Hovsep
    Franco-Cereceda, Anders
    Eggertsen, Gösta
    de Faire, Ulf
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Eriksson, Per
    Hamsten, Anders
    van't Hooft, Ferdinand M
    Identification of a Functional Apolipoprotein E Promoter Polymorphism Regulating Plasma Apolipoprotein E Concentration2013Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 33, nr 5, s. 1063-1069Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    There is compelling evidence that the plasma apolipoprotein E (APOE) concentration, in addition to the APOE ε2/ε3/ε4 genotype, influences plasma lipoprotein levels, but the functional genetic variants influencing the plasma APOE concentration have not been identified.

    APPROACH AND RESULTS

    Genome-wide association studies in 2 cohorts of healthy, middle-aged subjects identified the APOE locus as the only genetic locus showing robust associations with the plasma APOE concentration. Fine-mapping of the APOE locus confirmed that the rs7412 ε2-allele is the primary genetic variant responsible for the relationship with plasma APOE concentration. Further mapping of the APOE locus uncovered that rs769446 (-427T/C) in the APOE promoter is independently associated with the plasma APOE concentration. Expression studies in 199 human liver samples demonstrated that the rs769446 C-allele is associated with increased APOE mRNA levels (P=0.015). Transient transfection studies and electrophoretic mobility shift assays in human hepatoma HepG2 cells corroborated the role of rs769446 in transcriptional regulation of APOE. However, no relationships were found between rs769446 genotype and plasma lipoprotein levels in 2 cohorts (n=1648 and n=1039) of healthy middle-aged carriers of the APOE ε3/ε3 genotype.

    CONCLUSIONS:

    rs769446 is a functional polymorphism involved in the regulation of the plasma APOE concentration.

  • 166. Newton-Cheh, Christopher
    et al.
    Johnson, Toby
    Gateva, Vesela
    Tobin, D
    Bochud, Murielle
    Coin, Lachlan
    Najjar, S
    Zhao, Hua
    Heath, C
    Eyheramendy, Susana
    Papadakis, Konstantinos
    Voight, F
    Scott, J
    Zhang, Feng
    Farrall, Martin
    Tanaka, Toshiko
    Wallace, Chris
    Chambers, C
    Khaw, Kay-Tee
    Nilsson, Peter
    van der Harst, Pim
    Polidoro, Silvia
    Grobbee, E
    Onland-Moret, Charlotte
    Bots, L
    Wain, V
    Elliott, S
    Teumer, Alexander
    Luan, Jian'an
    Lucas, Gavin
    Kuusisto, Johanna
    Burton, R
    Hadley, David
    McArdle, L
    Brown, Morris
    Dominiczak, Anna
    Newhouse, J
    Samani, J
    Webster, John
    Zeggini, Eleftheria
    Beckmann, S
    Bergmann, Sven
    Lim, Noha
    Song, Kijoung
    Vollenweider, Peter
    Waeber, Gerard
    Waterworth, M
    Yuan, Xin
    Groop, Leif
    Orho-Melander, Marju
    Allione, Alessandra
    Di Gregorio, Alessandra
    Guarrera, Simonetta
    Panico, Salvatore
    Ricceri, Fulvio
    Romanazzi, Valeria
    Sacerdote, Carlotta
    Vineis, Paolo
    Barroso, Ines
    Sandhu, S
    Luben, N
    Crawford, J
    Jousilahti, Pekka
    Perola, Markus
    Boehnke, Michael
    Bonnycastle, L
    Collins, S
    Jackson, U
    Mohlke, L
    Stringham, M
    Valle, T
    Willer, J
    Bergman, N
    Morken, A
    Doering, Angela
    Gieger, Christian
    Illig, Thomas
    Meitinger, Thomas
    Org, Elin
    Pfeufer, Arne
    Wichmann, Erich
    Kathiresan, Sekar
    Marrugat, Jaume
    O'Donnell, J
    Schwartz, M
    Siscovick, S
    Subirana, Isaac
    Freimer, B
    Hartikainen, Anna-Liisa
    McCarthy, I
    O'Reilly, F
    Peltonen, Leena
    Pouta, Anneli
    de Jong, E
    Snieder, Harold
    van Gilst, H
    Clarke, Robert
    Goel, Anuj
    Hamsten, Anders
    Peden, F
    Seedorf, Udo
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Tognoni, Giovanni
    Lakatta, G
    Sanna, Serena
    Scheet, Paul
    Schlessinger, David
    Scuteri, Angelo
    Doerr, Marcus
    Ernst, Florian
    Felix, B
    Homuth, Georg
    Lorbeer, Roberto
    Reffelmann, Thorsten
    Rettig, Rainer
    Voelker, Uwe
    Galan, Pilar
    Gut, G
    Hercberg, Serge
    Lathrop, Mark
    Zelenika, Diana
    Deloukas, Panos
    Soranzo, Nicole
    Williams, M
    Zhai, Guangju
    Salomaa, Veikko
    Laakso, Markku
    Elosua, Roberto
    Forouhi, G
    Volzke, Henry
    Uiterwaal, S
    van der Schouw, T
    Numans, E
    Matullo, Giuseppe
    Navis, Gerjan
    Berglund, Goran
    Bingham, A
    Kooner, S
    Connell, M
    Bandinelli, Stefania
    Ferrucci, Luigi
    Watkins, Hugh
    Spector, D
    Tuomilehto, Jaakko
    Altshuler, David
    Strachan, P
    Laan, Maris
    Meneton, Pierre
    Wareham, J
    Uda, Manuela
    Jarvelin, Marjo-Riitta
    Mooser, Vincent
    Melander, Olle
    Loos, F
    Elliott, Paul
    Abecasis, R
    Caulfield, Mark
    Munroe, Patricia B.
    Genome-wide association study identifies eight loci associated with blood pressure2009Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 41, nr 6, s. 666-676Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10−24), CYP1A2 (P = 1 × 10−23), FGF5 (P = 1 × 10−21), SH2B3 (P = 3 × 10−18), MTHFR (P = 2 × 10−13), c10orf107 (P = 1 × 10−9), ZNF652 (P = 5 × 10−9) and PLCD3 (P = 1 × 10−8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

  • 167. Ng, Esther
    et al.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Mahajan, Anubha
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindgren, Cecilia M
    van Bavel, Bert
    Morris, Andrew P
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Genome-wide association study of plasma levels of polychlorinated biphenyls disclose an association with the CYP2B6 gene in a population-based sample2015Inngår i: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 140, s. 95-101Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Polychlorinated biphenyls (PCBs) are a group of man-made environmental pollutants which accumulate in humans with adverse health effects. To date, very little effort has been devoted to the study of the metabolism of PCBs on a genome-wide level.

    OBJECTIVES: Here, we conducted a genome-wide association study (GWAS) to identify genomic regions involved in the metabolism of PCBs.

    METHODS: Plasma levels of 16 PCBs ascertained in a cohort of elderly individuals from Sweden (n=1016) were measured using gas chromatography-high resolution mass spectrophotometry (GC-HRMS). DNA samples were genotyped on the Infinium Omni Express bead microarray, and imputed up to reference panels from the 1000 Genomes Project. Association testing was performed in a linear regression framework under an additive model.

    RESULTS: Plasma levels of PCB-99 demonstrated genome-wide significant association with single nucleotide polymorphisms (SNPs) mapping to chromosome 19q13.2. The SNP with the strongest association was rs8109848 (p=3.7×10(-13)), mapping to an intronic region of CYP2B6. Moreover, when all PCBs were conditioned on PCB-99, further signals were revealed for PCBs -74, -105 and -118, mapping to the same genomic region. The lead SNPs were rs8109848 (p=3.8×10(-12)) for PCB-118, rs4802104 (p=1.4×10(-9)) for PCB-74 and rs4803413 (p=2.5×10(-9)) for PCB-105, all of which map to CYP2B6.

    CONCLUSIONS: In our study, we found plasma levels of four lower-chlorinated PCBs to be significantly associated with the genetic region mapping to the CYP2B6 locus. These findings show that CYP2B6 is of importance for the metabolism of PCBs in humans, and may help to identify individuals who may be susceptible to PCB toxicity.

  • 168.
    Nolte, Ilja M.
    et al.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Munoz, M. Loretto
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Tragante, Vinicius
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands..
    Amare, Azmeraw T.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands.;Univ Adelaide, Sch Med, Dept Epidemiol, Adelaide, SA 5005, Australia.;Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar 6000, Ethiopia..
    Jansen, Rick
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Vaez, Ahmad
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands.;Isfahan Univ Med Sci, Sch Med, Esfahan 8174673461, Iran..
    von der Heyde, Benedikt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Avery, Christy L.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA..
    Dierckx, Bram
    Dept Child & Adolescent Psychiat, Dept Child & Adolescent Psychiat Psychol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Erasmus MC, Generat Study Grp R, POB 2060, NL-3000 CB0 Rotterdam, Netherlands..
    van Dongen, Jenny
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands..
    Gogarten, Stephanie M.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Goyette, Philippe
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada..
    Hernesniemi, Jussi
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland.;Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere 33521, Finland..
    Huikari, Ville
    Univ Oulu, Ctr Life Course Hlth Res, Oulu 90014, Finland..
    Hwang, Shih-Jen
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Jaju, Deepali
    Sultan Qaboos Univ Hosp, Dept Clin Physiol, Muscat 123, Oman..
    Kerr, Kathleen F.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Kluttig, Alexander
    Martin Luther Univ Halle Wittenberg, Inst Med Epidemiol Biostat & Informat, D-06097 Halle, Germany..
    Krijthe, Bouwe P.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Kumar, Jitender
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    van der Laan, Sander W.
    Univ Med Ctr Utrecht, Dept Heart & Lung, Lab Expt Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Maihofer, Adam X.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    Minassian, Arpi
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    van der Most, Peter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Mueller-Nurasyid, Martina
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Dept Med, Univ Hosp Munich, D-80539 Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany..
    Nivard, Michel
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Salvi, Erika
    Univ Milan, Dept Hlth Sci, I-20122 Milan, Italy..
    Stewart, James D.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA.;Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC 27599 USA..
    Thayer, Julian F.
    Ohio State Univ, Dept Psychol, 1835 Neil Ave, Columbus, OH 43210 USA..
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Wong, Andrew
    UCL, MRC Unit Lifelong Hlth & Ageing, 33 Bedford Pl, London WC1B 5JU, England..
    Zabaneh, Delilah
    Kings Coll London, Inst Psychiat Psychol & Neurosci, De Crespigny Pk, London SE5 8AF, England.;UCL, Genet Inst, London WC1E 6BT, England..
    Zafarmand, Mohammad H.
    Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, NL-1105 AZ Amsterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Dept Obstet & Gynaecol, NL-1105 AZ Amsterdam, Netherlands..
    Abdellaoui, Abdel
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Albarwani, Sulayma
    Sultan Qaboos Univ, Coll Med & Hlth Sci, Dept Physiol, Muscat Al Khoudh 123, Oman..
    Albert, Christine
    Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA..
    Alonso, Alvaro
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA..
    Ashar, Foram
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA..
    Auvinen, Juha
    Univ Oulu, Ctr Life Course Hlth Res, Oulu 90014, Finland.;Oulu Univ Hosp, Unit Primary Hlth Care, Oulu 90220, Finland..
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Baker, Dewleen G.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    de Bakker, Paul I. W.
    Univ Med Ctr Utrecht, Dept Genet, Ctr Mol Med, NL-3584 CX Utrecht, Netherlands.;Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3584 CX Utrecht, Netherlands..
    Barcella, Matteo
    Univ Milan, Dept Hlth Sci, I-20122 Milan, Italy..
    Bayoumi, Riad
    Mohammed Bin Rashid Univ, Coll Med, Dubai Healthcare City, POB 505055, Dubai, U Arab Emirates..
    Bieringa, Rob J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Boomsma, Dorret
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Boucher, Gabrielle
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada..
    Britton, Annie R.
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Christophersen, Ingrid E.
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02114 USA.;MIT, Cambridge, MA 02114 USA.;Baerum Hosp, Vestre Viken Hosp Trust, Dept Med Res, N-1346 Rud, Norway..
    Dietrich, Andrea
    Univ Groningen, Univ Med Ctr Groningen, Dept Child & Adolescent Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Ehret, George B.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA.;Geneva Univ Hosp, Dept Specialties Internal Med, Cardiol, CH-1211 Geneva, Switzerland..
    Ellinor, Patrick T.
    Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02114 USA.;MIT, Cambridge, MA 02114 USA.;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Eskola, Markku
    Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Cardiol, Tampere 33014, Finland..
    Felix, Janine F.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Floras, John S.
    Univ Toronto, Univ Hlth Network, Toronto, ON, Canada.;Univ Toronto, Mt Sinai Hosp, Div Cardiol, Dept Med, Toronto, ON, Canada.;Univ Hlth Network, Toronto Gen Res Inst, Toronto, ON M5G 2C4, Canada..
    Franco, Oscar H.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Friberg, Peter
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Med, Dept Mol & Clin Med, SE-41345 Gothenburg, Sweden..
    Gademan, Maaike G. J.
    Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, NL-1105 AZ Amsterdam, Netherlands..
    Geyer, Mark A.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA..
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Hemerich, Daiane
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands.;Minist Educ Brazil, CAPES Fdn, BR-70040020 Brasilia, DF, Brazil..
    Hofman, Albert
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Huikuri, Heikki
    Oulu Univ Hosp, Med Res Ctr, Res Unit Internal Med, Oulu 90220, Finland.;Univ Oulu, SF-90220 Oulu, Finland..
    Hutri-Kahonen, Nina
    Tampere Univ Hosp, Dept Pediat, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Pediat, Tampere 33014, Finland..
    Jouven, Xavier
    Paris Descartes Univ, INSERM, U970, F-75006 Paris, France..
    Junttila, Juhani
    Oulu Univ Hosp, Med Res Ctr, Res Unit Internal Med, Oulu 90220, Finland.;Univ Oulu, SF-90220 Oulu, Finland..
    Juonala, Markus
    Univ Turku, Dept Med, Turku 20520, Finland.;Turku Univ Hosp, Div Med, Turku 20521, Finland..
    Kiviniemi, Antti M.
    Oulu Univ Hosp, Med Res Ctr, Res Unit Internal Med, Oulu 90220, Finland.;Univ Oulu, SF-90220 Oulu, Finland..
    Kors, Jan A.
    Erasmus MC, Dept Med Informat, NL-3015 CE Rotterdam, Netherlands..
    Kumari, Meena
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.;Essex Univ, ISER, Colchester CO4 3SQ, Essex, England..
    Kuznetsova, Tatiana
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Studies Coordinating Ctr, Res Unit Hypertens & Cardiovasc Epidemiol, B-3000 Leuven, Belgium..
    Laurie, Cathy C.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Lefrandt, Joop D.
    Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Vasc Med, POB 30001, NL-9700 RB Groningen, Netherlands..
    Li, Yong
    Univ Freiburg, Fac Med, Med Center, Div Genet Epidemiol,Inst Med Biometry & Stat, D-79110 Freiburg, Germany..
    Li, Yun
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA..
    Liao, Duanping
    Penn State Univ, Coll Med, Dept Publ Hlth Sci, Div Epidemiol, Hershey, PA 17033 USA..
    Limacher, Marian C.
    Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL 32611 USA..
    Lin, Henry J.
    Harbor UCLA Med Ctr, Dept Pediat, Los Angeles Biomed Res Inst Harbor, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Div Med Genet, Torrance, CA 90502 USA..
    Lindgren, Cecilia M.
    Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford OX3 7BN, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Lubitz, Steven A.
    Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02114 USA.;MIT, Cambridge, MA 02114 USA.;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    McKnight, Barbara
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA.;Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA.;Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA..
    zu Schwabedissen, Henriette Meyer
    Univ Basel, Dept Pharmaceut Sci, Biopharm, CH-4056 Basel, Switzerland..
    Milaneschi, Yuri
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Mononen, Nina
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England..
    Nalls, Mike A.
    NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA..
    Navis, Gerjan
    Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Nephrol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Neijts, Melanie
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Nikus, Kjell
    Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Cardiol, Tampere 33014, Finland..
    North, Kari E.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA.;Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA..
    O'Connor, Daniel T.
    Univ Calif San Diego, Dept Med, San Diego, CA 92093 USA..
    Ormel, Johan
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Perz, Siegfried
    Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany..
    Peters, Annette
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;German Ctr Diabet Res, D-85764 Neuherberg, Germany..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA.;Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA.;Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20520, Finland..
    Risbrough, Victoria B.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    Sinner, Moritz F.
    Ludwig Maximilians Univ Munchen, Dept Med, Univ Hosp Munich, D-80539 Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany..
    Siscovick, David
    New York Acad Med, New York, NY 10029 USA..
    Smit, Johannes H.
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Smith, Nicholas L.
    Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA.;Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA.;Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA 98108 USA..
    Soliman, Elsayed Z.
    Wake Forest Sch Med, Div Publ Hlth Sci, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC 27157 USA..
    Sotoodehnia, Nona
    Univ Washington, Dept Med & Epidemiol, Div Cardiol, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA..
    Staessen, Jan A.
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Studies Coordinating Ctr, Res Unit Hypertens & Cardiovasc Epidemiol, B-3000 Leuven, Belgium..
    Stein, Phyllis K.
    Washington Univ, Heart Rate Variabil Lab, Sch Med, St Louis, MO 63108 USA..
    Stilp, Adrienne M.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Stolarz-Skrzypek, Katarzyna
    Jagiellonian Univ, Med Coll, Dept Cardiol Intervent Electrocardi & Hypertens 1, PL-31008 Krakow, Poland..
    Strauch, Konstantin
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany..
    Sundstrom, Johan
    Uppsala Univ, Dept Med Sci Cardiovasc Epidemiol, S-75185 Uppsala, Sweden..
    Swenne, Cees A.
    Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Tardif, Jean-Claude
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada.;Univ Montreal, Montreal, PQ H3T IJ4, Canada..
    Taylor, Kent D.
    Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat & Med, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany..
    Thornton, Timothy A.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Tinker, Lesley E.
    Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA..
    Uitterlinden, Andre G.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Erasmus Univ, Med Ctr, Dept Internal Med, NL-3015 CE Rotterdam, Netherlands.;Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, NL-2300 RC Leiden, Netherlands..
    van Setten, Jessica
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands..
    Voss, Andreas
    IGHT Jena Ernst Abbe Hsch, Inst Innovat Hlth Technol, D-07745 Jena, Germany..
    Waldenberger, Melanie
    Dept Child & Adolescent Psychiat, Dept Child & Adolescent Psychiat Psychol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany..
    Wilhelmsen, Kirk C.
    Univ N Carolina, Dept Genet & Neurol, Chapel Hill, NC 27599 USA.;Renaissance Comp Inst, Chapel Hill, NC 27599 USA..
    Willemsen, Gonneke
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Wong, Quenna
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Zhang, Zhu-Ming
    Wake Forest Sch Med, Div Publ Hlth Sci, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC 27157 USA.;Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA..
    Zonderman, Alan B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Cusi, Daniele
    Italian Natl Res Council, CNR, Inst Biomed Technol, I-20090 Milan, Italy.;KOS Genet SRL, I-20091 Milan, Italy..
    Evans, Michele K.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Greiser, Halina K.
    German Canc Res Ctr, Div Canc Epidemiol, D-69210 Heidelberg, Germany..
    van der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Hassan, Mohammad
    Sultan Qaboos Univ, Coll Med & Hlth Sci, Dept Physiol, Muscat Al Khoudh 123, Oman..
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 USA..
    Jarvelin, Marjo-Riitta
    Univ Oulu, Ctr Life Course Hlth Res, Oulu 90014, Finland.;Oulu Univ Hosp, Unit Primary Hlth Care, Oulu 90220, Finland.;Imperial Coll London, Fac Med, Sch Publ Hlth, Dept Epidemiol & Biostat, St Marys Campus, London, England.;Univ Oulu, Bioctr Oulu, Oulu 90014, Finland..
    Kaab, Stefan
    Ludwig Maximilians Univ Munchen, Dept Med, Univ Hosp Munich, D-80539 Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Clin Physiol, Tampere 33014, Finland..
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Kooperberg, Charles
    Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA..
    Kuh, Diana
    UCL, MRC Unit Lifelong Hlth & Ageing, 33 Bedford Pl, London WC1B 5JU, England..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Lind, Lars
    Uppsala Univ, Dept Med Sci Cardiovasc Epidemiol, S-75185 Uppsala, Sweden..
    Nievergelt, Caroline M.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    O'Donnell, Chris J.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA.;Boston Vet Adm Healthcare Boston, Cardiol Sect, Boston, MD 02132 USA..
    Oldehinkel, Albertine J.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Penninx, Brenda
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Reiner, Alexander P.
    Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA.;Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA..
    Riese, Harriette
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    van Roon, Arie M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Vasc Med, POB 30001, NL-9700 RB Groningen, Netherlands..
    Rioux, John D.
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada.;Univ Montreal, Montreal, PQ H3T IJ4, Canada..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat & Med, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Sofer, Tamar
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Stricker, Bruno H.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Inspectorate Hlth Care, NL-2511 VX The Hague, Netherlands..
    Tiemeier, Henning
    Dept Child & Adolescent Psychiat, Dept Child & Adolescent Psychiat Psychol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Vrijkotte, Tanja G. M.
    Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, NL-1105 AZ Amsterdam, Netherlands..
    Asselbergs, Folkert W.
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands.;UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England.;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands..
    Brundel, Bianca J. J. M.
    Vrije Univ Amsterdam, Inst Cardiovasc Res, Dept Physiol, Med Ctr, De Boelelaan 1118, NL-1081 HV Amsterdam, Netherlands..
    Heckbert, Susan R.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA.;Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA..
    Whitsel, Eric A.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA..
    den Hoed, Marcel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    de Geus, Eco J. C.
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Genetic loci associated with heart rate variability and their effects on cardiac disease risk2017Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikkel-id 15805Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

  • 169. Nordgard, Silje H
    et al.
    Johansen, Fredrik E
    Alnæs, Grethe I G
    Bucher, Elmar
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Naume, Bjørn
    Børresen-Dale, Anne-Lise
    Kristensen, Vessela N
    Genome-wide analysis identifies 16q deletion associated with survival, molecular subtypes, mRNA expression, and germline haplotypes in breast cancer patients2008Inngår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 47, nr 8, s. 680-696Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Breast carcinomas are characterized by DNA copy number alterations (CNAs) with biological and clinical significance. This explorative study integrated CNA, expression, and germline genotype data of 112 early-stage breast cancer patients. Recurrent CNAs differed substantially between tumor subtypes classified according to expression pattern. Deletion of 16q was overrepresented in Luminal A, and a predictor of good prognosis, both overall and for the nonluminal A subgroups. The deleted region most significantly associated with survival mapped to 16q22.2, harboring the genes TXNL4B and DXH38, whose expression was strongly correlated with the deletion. The area most frequently deleted resided on 16q23.1, 3.5 MB downstream of the area most significantly associated with survival, and included the tumor suppressor gene ADAMTS18 and the cell recognition gene CNTNAP4. Whole-genome association analysis identified germline single nucleotide polymorphisms (SNPs) and their corresponding haplotypes, residing on several different chromosomes, to be associated with deletion of 16q. The genes where these SNPs reside encode proteins involved in the extracellular matrix (CHST3 and SPOCK2), in regulation of the cell cycle (JMY, PTPRN2, and Cwf19L2) and chromosome stability (KPNB1).

  • 170.
    Nordlund, Jessica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Backlin, Carin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Wahlberg, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Forestier, E.
    Heyman, M.
    Soderhall, S.
    Schmiegelow, K.
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Gustafsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Syvanen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    The DNA Methylation Landscape of Paediatric Acute Lymphoblastic Leukemia2012Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, nr S5, s. S141-S141Artikkel i tidsskrift (Fagfellevurdert)
  • 171.
    Nordlund, Jessica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bäcklin, Christofer L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Wahlberg, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Busche, Stephan
    Berglund, Eva C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Flaegstad, Trond
    Forestier, Erik
    Frost, Britt-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Harila-Saari, Arja
    Heyman, Mats
    Jónsson, Olafur G
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Palle, Josefine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Schmiegelow, Kjeld
    Sinnett, Daniel
    Söderhäll, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Pastinen, Tomi
    Gustafsson, Mats G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia2013Inngår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, nr 9, s. r105-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood.

    RESULTS:

    We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status.

    CONCLUSIONS:

    Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.

  • 172.
    Nordlund, Jessica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Bäcklin, Christofer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Zachariadis, Vasilios
    Karolinska Intstitutet.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Dahlberg, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Öfverholm, Ingegerd
    Karolinska Institutet.
    Barbany, Gisela
    Karolinska Institutet.
    Nordgren, Ann
    Karolinska Institutet.
    Övernäs, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Abrahamsson, Jonas
    Flaegstad, Trond
    Tromsø University.
    Heyman, Mats
    Karolinska Institutet.
    Jónsson, Ólafur
    Kanerva, Jukka
    Helsinki University.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Palle, Josefine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Schmiegelow, Kjeld
    University of Copenhagen.
    Gustafsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Forestier, Erik
    University of Umeå.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia2015Inngår i: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 7, artikkel-id 11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL.

    Results

    We used the methylation status of ~450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations (‘other’ subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5.

    Conclusions

    Our findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients.

  • 173.
    Nordlund, Jessica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Kiialainen, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Karlberg, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Berglund, Eva C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Göransson-Kultima, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Sønderkær, M
    Nielsen, K L
    Gustafsson, Mats G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Behrendtz, M
    Forestier, E
    Perkkiö, M
    Söderhäll, S
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Digital gene expression profiling of primary acute lymphoblastic leukemia cells2012Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, nr 6, s. 1218-1227Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We determined the genome-wide digital gene expression (DGE) profiles of primary acute lymphoblastic leukemia (ALL) cells from 21 patients taking advantage of 'second-generation' sequencing technology. Patients included in this study represent four cytogenetically distinct subtypes of B-cell precursor (BCP) ALL and T-cell lineage ALL (T-ALL). The robustness of DGE combined with supervised classification by nearest shrunken centroids (NSC) was validated experimentally and by comparison with published expression data for large sets of ALL samples. Genes that were differentially expressed between BCP ALL subtypes were enriched to distinct signaling pathways with dic(9;20) enriched to TP53 signaling, t(9;22) to interferon signaling, as well as high hyperdiploidy and t(12;21) to apoptosis signaling. We also observed antisense tags expressed from the non-coding strand of ∼50% of annotated genes, many of which were expressed in a subtype-specific pattern. Antisense tags from 17 gene regions unambiguously discriminated between the BCP ALL and T-ALL subtypes, and antisense tags from 76 gene regions discriminated between the 4 BCP subtypes. We observed a significant overlap of gene regions with alternative polyadenylation and antisense transcription (P<1 × 10(-15)). Our study using DGE profiling provided new insights into the RNA expression patterns in ALL cells.

  • 174.
    Nordlund, Jessica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Marincevic-Zuniga, Yanara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cavelier, Lucia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Raine, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Martin, Tom
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Abrahamsson, Jonas
    Norén-Nyström, Ulrika
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Refined detection and phasing of structural aberrations in pediatric acute lymphoblastic leukemia with linked-read whole genome sequencingManuskript (preprint) (Annet vitenskapelig)
  • 175.
    Nordlund, Jessica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Milani, Lili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Lundmark, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    DNA Methylation Analysis of Bone Marrow Cells at Diagnosis of Acute Lymphoblastic Leukemia and at Remission2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 4, s. e34513-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To detect genes with CpG sites that display methylation patterns that are characteristic of acute lymphoblastic leukemia (ALL) cells, we compared the methylation patterns of cells taken at diagnosis from 20 patients with pediatric ALL to the methylation patterns in mononuclear cells from bone marrow of the same patients during remission and in non-leukemic control cells from bone marrow or blood. Using a custom-designed assay, we measured the methylation levels of 1,320 CpG sites in regulatory regions of 413 genes that were analyzed because they display allele-specific gene expression (ASE) in ALL cells. The rationale for our selection of CpG sites was that ASE could be the result of allele-specific methylation in the promoter regions of the genes. We found that the ALL cells had methylation profiles that allowed distinction between ALL cells and control cells. Using stringent criteria for calling differential methylation, we identified 28 CpG sites in 24 genes with recurrent differences in their methylation levels between ALL cells and control cells. Twenty of the differentially methylated genes were hypermethylated in the ALL cells, and as many as nine of them (AMICA1, CPNE7, CR1, DBC1, EYA4, LGALS8, RYR3, UQCRFS1, WDR35) have functions in cell signaling and/or apoptosis. The methylation levels of a subset of the genes were consistent with an inverse relationship with the mRNA expression levels in a large number of ALL cells from published data sets, supporting a potential biological effect of the methylation signatures and their application for diagnostic purposes.

  • 176.
    Nordlund, Jessica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Epigenetics in pediatric acute lymphoblastic leukemia2018Inngår i: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 51, s. 129-138Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. ALL arises from the malignant transformation of progenitor B- and T-cells in the bone marrow into leukemic cells, but the mechanisms underlying this transformation are not well understood. Recent technical advances and decreasing costs of methods for high-throughput DNA sequencing and SNP genotyping have stimulated systematic studies of the epigenetic changes in leukemic cells from pediatric ALL patients. The results emerging from these studies are increasing our understanding of the epigenetic component of leukemogenesis and have demonstrated the potential of DNA methylation as a biomarker for lineage and subtype classification, prognostication, and disease progression in ALL. In this review, we provide a concise examination of the epigenetic studies in ALL, with a focus on DNA methylation and mutations perturbing genes involved in chromatin modification, and discuss the future role of epigenetic analyses in research and clinical management of ALL.

  • 177.
    Nordmark, Gunnel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kristjansdottir, Gudlaug
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Theander, E.
    Appel, S.
    Eriksson, P.
    Vasaitis, Lilian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Kvarnström, M.
    Delaleu, N.
    Lundmark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Lundmark, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Sjöwall, C.
    Brun, J. G.
    Jonsson, M. V.
    Harboe, E.
    Gøransson, L. G.
    Johnsen, S. J.
    Söderkvist, P.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Alm, G.
    Baecklund, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Wahren-Herlenius, M.
    Omdal, R.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Jonsson, R.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome2011Inngår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 12, nr 2, s. 100-109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We performed a candidate gene association study in 540 patients with primary Sjögren's Syndrome (SS) from Sweden (n=344) and Norway (n=196) and 532 controls (n=319 Swedish, n=213 Norwegian). A total of 1139 single-nucleotide polymorphisms (SNPs) in 84 genes were analyzed. In the meta-analysis of the Swedish and Norwegian cohorts, we found high signals for association between primary SS and SNPs in three gene loci, not previously associated with primary SS. These are the early B-cell factor 1 (EBF1) gene, P=9.9 × 10−5, OR 1.68, the family with sequence similarity 167 member A–B-lymphoid tyrosine kinase (FAM167A–BLK) locus, P=4.7 × 10−4, OR 1.37 and the tumor necrosis factor superfamily (TNFSF4=Ox40L) gene, P=7.4 × 10−4, OR 1.34. We also confirmed the association between primary SS and the IRF5/TNPO3 locus and the STAT4 gene. We found no association between the SNPs in these five genes and the presence of anti-SSA/anti-SSB antibodies. EBF1, BLK and TNFSF4 are all involved in B-cell differentiation and activation, and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS.

  • 178.
    Nordmark, Gunnel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kristjansdottir, Gudlaug
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Theander, E.
    Eriksson, P.
    Brun, J. G.
    Wang, Chuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Padyukov, L.
    Truedsson, L.
    Alm, Gunnar
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Jonsson, R.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome2009Inngår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 10, nr 1, s. 68-76Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Primary Sjögren's syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) >1.4 and P-values <0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P=2.5 × 10−9. The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.

  • 179.
    Nordmark, Gunnel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Wang, Chuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Vasaitis, Lilian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Eriksson, Per
    Theander, Elke
    Kvarnström, Marika
    Forsblad-d'Elia, Helena
    Jazebi, Helmi
    Sjöwall, Christopher
    Reksten, Tove Ragna
    Brun, Johan G
    Jonsson, Malin V
    Johnsen, Svein J
    Wahren-Herlenius, Marie
    Omdal, Roald
    Jonsson, Roland
    Bowman, Simon
    Ng, Wan-Fai
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Association of genes in the NF-κB pathway with antibody positive primary Sjögren's syndrome2013Inngår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 78, nr 5, s. 447-454Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Primary Sjögren's syndrome (SS) is a systemic autoimmune inflammatory disease characterized by focal lymphocytic infiltrates in the lachrymal and salivary glands and autoantibodies against the SSA/Ro and SSB/La antigens. Experimental studies have shown an activation of NF–κB in primary SS. NF-κB activation results in inflammation and autoimmunity and is regulated by inhibitory and activating proteins. Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF-κB, and of IKBKE (IKKε) which is an NF-κB activator. The aim of this study was to analyze single nucleotide polymorphisms (SNPs) in the IKBKE, NFKB1, TNIP1 and TNFAIP3 genes for association with primary SS. A total of 12 SNPs were genotyped in 1105 patients from Scandinavia (Sweden and Norway, n=684) and the UK (n=421) and 4460 controls (Scandinavia, n=1662, UK, n=2798). When patients were stratified for the presence of anti-SSA and/or -SSB antibodies (n=868), case-control meta-analysis found an association between antibody positive primary SS and two SNPs in TNIP1 (= 3.4x10-5, OR = 1.33, 95%CI: 1.16-1.52 for rs3792783 and = 1.3x10-3, OR = 1.21, 95%CI: 1.08-1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody positive primary SS (= 5.7x10-3, OR = 1.47, 95%CI: 1.12-1.92). There were no significant associations with IKBKE, NFKB1 or TNFAIP3 in the meta-analysis of the Scandinavian and UK cohorts. We conclude that polymorphisms in TNIP1 are associated with antibody positive primary SS.

  • 180.
    Norheim, Katrine B.
    et al.
    Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Imgenberg-Kreuz, Juliana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jonsdottir, Kristin
    Stavanger Univ Hosp, Dept Pathol, Stavanger, Norway..
    Janssen, Emiel
    Stavanger Univ Hosp, Dept Pathol, Stavanger, Norway..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Omdal, Roald
    Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Epigenome-Wide DNA Methylation Patterns Associated with Fatigue in Primary Sjogren's Syndrome2015Inngår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, nr Suppl. 10, artikkel-id 1262Artikkel i tidsskrift (Annet vitenskapelig)
  • 181.
    Norheim, Katrine Braekke
    et al.
    Stavanger Univ Hosp, Clin Immunol Unit, Dept Internal Med, Pb 8100 Forus, N-4068 Stavanger, Norway..
    Imgenberg-Kreuz, Juliana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Jonsdottir, Kristin
    Stavanger Univ Hosp, Dept Pathol, N-4068 Stavanger, Norway..
    Janssen, Emiel A. M.
    Stavanger Univ Hosp, Dept Pathol, N-4068 Stavanger, Norway..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Omdal, Roald
    Stavanger Univ Hosp, Clin Immunol Unit, Dept Internal Med, Pb 8100 Forus, N-4068 Stavanger, Norway..
    Epigenome-wide DNA methylation patterns associated with fatigue in primary Sjogren's syndrome2016Inngår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 55, nr 6, s. 1074-1082Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. Chronic fatigue is a common, disabling and poorly understood phenomenon. Recent studies indicate that epigenetic mechanisms may be involved in the expression of fatigue, a prominent feature of primary SS (pSS). The aim of this study was to investigate whether DNA methylation profiles of whole blood are associated with fatigue in patients with pSS. Methods. Forty-eight pSS patients with high (n = 24) or low (n = 24) fatigue as measured by a visual analogue scale were included. Genome-wide DNA methylation was investigated using the Illumina HumanMethylation450 BeadChip array. After quality control, a total of 383 358 Cytosine-phosphate-Guanine (CpG) sites remained for further analysis. Age, sex and differential cell count estimates were included as covariates in the association model. A false discovery rate-corrected P < 0.05 was considered significant, and a cut-off of 3% average difference in methylation levels between high- and low-fatigue patients was applied. Results. A total of 251 differentially methylated CpG sites were associated with fatigue. The CpG site with the most pronounced hypomethylation in pSS high fatigue annotated to the SBF2-antisense RNA1 gene. The most distinct hypermethylation was observed at a CpG site annotated to the lymphotoxin alpha gene. Functional pathway analysis of genes with differently methylated CpG sites in subjects with high vs low fatigue revealed enrichment in several pathways associated with innate and adaptive immunity. Conclusion. Some genes involved in regulation of the immune system and in inflammation are differently methylated in pSS patients with high vs low fatigue. These findings point to functional networks that may underlie fatigue. Epigenetic changes could constitute a fatigue-regulating mechanism in pSS.

  • 182.
    Odqvist, Lina
    et al.
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Jevnikar, Zala
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Riise, Rebecca
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Oberg, Lisa
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Rhedin, Magdalena
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Yrlid, Linda
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Jackson, Sonya
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Mattsson, Johan
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Nanda, Sambit
    Univ Dundee, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee, Scotland.
    Cohen, Philip
    Univ Dundee, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee, Scotland.
    Knebel, Axel
    Univ Dundee, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee, Scotland.
    Arthur, Simon
    Univ Dundee, Sch Life Sci, Div Immunol & Cell Signaling, Dundee, Scotland.
    Thorn, Kristofer
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Svenungsson, Elisabet
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Jonsen, Andreas
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Rheumatol, Lund, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kastbom, Alf
    Linkoping Univ, Dept Rheumatol, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Med Fak, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bengtsson, Anders
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Rheumatol, Lund, Sweden.
    Johansson, Patrik
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Discovery Sci, Molndal, Sweden.
    Sandling, Johanna K.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sjowall, Christopher
    Linkoping Univ, Dept Rheumatol, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Collins, Barry
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Vaarala, Outi
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden;MedImmune LLC, Resp Inflammat & Autoimmun Dept, Gaithersburg, MD 20878 USA.
    Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus2019Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, nr 10, s. 1363-1370Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives

    Genetic variations in TNFAIP3 (A20) deubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-kappa B but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis.

    Methods

    CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926.

    Results

    Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-kappa B signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes.

    Conclusions

    We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.

  • 183.
    Olsson, Charlotta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Waldenström, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Westermark, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Determination of the frequencies of ten allelic variants of the Wilson disease gene (ATP7B), in pooled DNA samples2000Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 8, nr 12, s. 933-938Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Wilson disease is an autosomal recessive disorder characterised by toxic accumulation of copper in liver, brain and other organs. The disorder is caused by mutations in the ATP7B gene, encoding a copper transporting P-type ATPase. Based on the number of known patients with this diagnosis in Sweden, the prevalence can be estimated to 1 in 250 000 to 300 000, whereas the prevalence of Wilson disease has been estimated to be 1 in 30 000 in other populations. We estimated the prevalence of Wilson disease by determining the Swedish population frequencies of two mutant alleles, making up approximately half the mutations in Swedish Wilson patients, in a large number of DNA samples. In addition we determined the allele frequencies of eight common single-nucleotide polymorphisms (SNPs) in the ATP7B gene. For the analyses we devised two strategies for analysing pooled DNA samples using the quantitative minisequencing method. The two procedures allowed sensitive identification of rare mutant alleles present as a mixture with an excess of the normal allele, as well as accurate estimation of the frequencies of the common SNPs in a large pooled DNA sample.

  • 184. Pacek, P
    et al.
    Sajantila, A
    Syvänen, Ann-Christine
    Determination of allele frequencies at loci with length polymorphism by quantitative analysis of DNA amplified from pooled samples1993Inngår i: PCR methods and applications, ISSN 1054-9803, Vol. 2, nr 4, s. 313-317Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We present a new method that allows rapid determination of allele frequencies at loci exhibiting length polymorphism. In this method a fluorescence-labeled PCR primer is used to amplify the polymorphic region from pooled DNA samples originating from a large number of individuals. The fluorescent PCR products are separated by gel electrophoresis on an automatic DNA sequencer and the relative amount of the PCR products are determined. The distribution of the PCR products obtained from the alleles present in the pooled samples directly corresponds to the allele frequency in the population in question. The allele frequencies at a short tandem repeat locus in the von Willebrand factor gene and at the D1S80 locus were determined in the Finnish population. We found that the allele frequencies determined by quantitative analysis of PCR products from pooled DNA samples and by analyzing individual samples were in good agreement.

  • 185. Palmer, Nicholette D
    et al.
    McDonough, Caitrin W
    Hicks, Pamela J
    Roh, Bong H
    Wing, Maria R
    An, S Sandy
    Hester, Jessica M
    Cooke, Jessica N
    Bostrom, Meredith A
    Rudock, Megan E
    Talbert, Matthew E
    Lewis, Joshua P
    Ferrara, Assiamira
    Lu, Lingyi
    Ziegler, Julie T
    Sale, Michele M
    Divers, Jasmin
    Shriner, Daniel
    Adeyemo, Adebowale
    Rotimi, Charles N
    Ng, Maggie C Y
    Langefeld, Carl D
    Freedman, Barry I
    Bowden, Donald W
    Voight, Benjamin F
    Scott, Laura J
    Steinthorsdottir, Valgerdur
    Morris, Andrew P
    Dina, Christian
    Welch, Ryan P
    Zeggini, Eleftheria
    Huth, Cornelia
    Aulchenko, Yurii S
    Thorleifsson, Gudmar
    McCulloch, Laura J
    Ferreira, Teresa
    Grallert, Harald
    Amin, Najaf
    Wu, Guanming
    Willer, Cristen J
    Raychaudhuri, Soumya
    McCarroll, Steve A
    Langenberg, Claudia
    Hofmann, Oliver M
    Dupuis, Josée
    Qi, Lu
    Segrè, Ayellet V
    van Hoek, Mandy
    Navarro, Pau
    Ardlie, Kristin
    Balkau, Beverley
    Benediktsson, Rafn
    Bennett, Amanda J
    Blagieva, Roza
    Boerwinkle, Eric
    Bonnycastle, Lori L
    Boström, Kristina Bengtsson
    Bravenboer, Bert
    Bumpstead, Suzannah
    Burtt, Noël P
    Charpentier, Guillaume
    Chines, Peter S
    Cornelis, Marilyn
    Couper, David J
    Crawford, Gabe
    Doney, Alex S F
    Elliott, Katherine S
    Elliott, Amanda L
    Erdos, Michael R
    Fox, Caroline S
    Franklin, Christopher S
    Ganser, Martha
    Gieger, Christian
    Grarup, Niels
    Green, Todd
    Griffin, Simon
    Groves, Christopher J
    Guiducci, Candace
    Hadjadj, Samy
    Hassanali, Neelam
    Herder, Christian
    Isomaa, Bo
    Jackson, Anne U
    Johnson, Paul R V
    Jørgensen, Torben
    Kao, Wen H L
    Klopp, Norman
    Kong, Augustine
    Kraft, Peter
    Kuusisto, Johanna
    Lauritzen, Torsten
    Li, Man
    Lieverse, Aloysius
    Lindgren, Cecilia M
    Lyssenko, Valeriya
    Marre, Michel
    Meitinger, Thomas
    Midthjell, Kristian
    Morken, Mario A
    Narisu, Narisu
    Nilsson, Peter
    Owen, Katharine R
    Payne, Felicity
    Perry, John R B
    Petersen, Ann-Kristin
    Platou, Carl
    Proença, Christine
    Prokopenko, Inga
    Rathmann, Wolfgang
    Rayner, N William
    Robertson, Neil R
    Rocheleau, Ghislain
    Roden, Michael
    Sampson, Michael J
    Saxena, Richa
    Shields, Beverley M
    Shrader, Peter
    Sigurdsson, Gunnar
    Sparsø, Thomas
    Strassburger, Klaus
    Stringham, Heather M
    Sun, Qi
    Swift, Amy J
    Thorand, Barbara
    Tichet, Jean
    Tuomi, Tiinamaija
    van Dam, Rob M
    van Haeften, Timon W
    van Herpt, Thijs
    van Vliet-Ostaptchouk, Jana V
    Walters, G Bragi
    Weedon, Michael N
    Wijmenga, Cisca
    Witteman, Jacqueline
    Bergman, Richard N
    Cauchi, Stephane
    Collins, Francis S
    Gloyn, Anna L
    Gyllensten, Ulf
    Hansen, Torben
    Hide, Winston A
    Hitman, Graham A
    Hofman, Albert
    Hunter, David J
    Hveem, Kristian
    Laakso, Markku
    Mohlke, Karen L
    Morris, Andrew D
    Palmer, Colin N A
    Pramstaller, Peter P
    Rudan, Igor
    Sijbrands, Eric
    Stein, Lincoln D
    Tuomilehto, Jaakko
    Uitterlinden, Andre
    Walker, Mark
    Wareham, Nicholas J
    Watanabe, Richard M
    Abecasis, Goncalo R
    Boehm, Bernhard O
    Campbell, Harry
    Daly, Mark J
    Hattersley, Andrew T
    Hu, Frank B
    Meigs, James B
    Pankow, James S
    Pedersen, Oluf
    Wichmann, H-Erich
    Barroso, Inês
    Florez, Jose C
    Frayling, Timothy M
    Groop, Leif
    Sladek, Rob
    Thorsteinsdottir, Unnur
    Wilson, James F
    Illig, Thomas
    Froguel, Philippe
    van Duijn, Cornelia M
    Stefansson, Kari
    Altshuler, David
    Boehnke, Michael
    McCarthy, Mark I
    Soranzo, Nicole
    Wheeler, Eleanor
    Glazer, Nicole L
    Bouatia-Naji, Nabila
    Mägi, Reedik
    Randall, Joshua
    Johnson, Toby
    Elliott, Paul
    Rybin, Denis
    Henneman, Peter
    Dehghan, Abbas
    Hottenga, Jouke Jan
    Song, Kijoung
    Goel, Anuj
    Egan, Josephine M
    Lajunen, Taina
    Doney, Alex
    Kanoni, Stavroula
    Cavalcanti-Proença, Christine
    Kumari, Meena
    Timpson, Nicholas J
    Zabena, Carina
    Ingelsson, Erik
    An, Ping
    O'Connell, Jeffrey
    Luan, Jian'an
    Elliott, Amanda
    McCarroll, Steven A
    Roccasecca, Rosa Maria
    Pattou, François
    Sethupathy, Praveen
    Ariyurek, Yavuz
    Barter, Philip
    Beilby, John P
    Ben-Shlomo, Yoav
    Bergmann, Sven
    Bochud, Murielle
    Bonnefond, Amélie
    Borch-Johnsen, Knut
    Böttcher, Yvonne
    Brunner, Eric
    Bumpstead, Suzannah J
    Chen, Yii-Der Ida
    Chines, Peter
    Clarke, Robert
    Coin, Lachlan J M
    Cooper, Matthew N
    Crisponi, Laura
    Day, Ian N M
    de Geus, Eco J C
    Delplanque, Jerome
    Fedson, Annette C
    Fischer-Rosinsky, Antje
    Forouhi, Nita G
    Frants, Rune
    Franzosi, Maria Grazia
    Galan, Pilar
    Goodarzi, Mark O
    Graessler, Jürgen
    Grundy, Scott
    Gwilliam, Rhian
    Hallmans, Göran
    Hammond, Naomi
    Han, Xijing
    Hartikainen, Anna-Liisa
    Hayward, Caroline
    Heath, Simon C
    Hercberg, Serge
    Hicks, Andrew A
    Hillman, David R
    Hingorani, Aroon D
    Hui, Jennie
    Hung, Joe
    Jula, Antti
    Kaakinen, Marika
    Kaprio, Jaakko
    Kesaniemi, Y Antero
    Kivimaki, Mika
    Knight, Beatrice
    Koskinen, Seppo
    Kovacs, Peter
    Kyvik, Kirsten Ohm
    Lathrop, G Mark
    Lawlor, Debbie A
    Le Bacquer, Olivier
    Lecoeur, Cécile
    Li, Yun
    Mahley, Robert
    Mangino, Massimo
    Manning, Alisa K
    Martínez-Larrad, María Teresa
    McAteer, Jarred B
    McPherson, Ruth
    Meisinger, Christa
    Melzer, David
    Meyre, David
    Mitchell, Braxton D
    Mukherjee, Sutapa
    Naitza, Silvia
    Neville, Matthew J
    Oostra, Ben A
    Orrù, Marco
    Pakyz, Ruth
    Paolisso, Giuseppe
    Pattaro, Cristian
    Pearson, Daniel
    Peden, John F
    Pedersen, Nancy L
    Perola, Markus
    Pfeiffer, Andreas F H
    Pichler, Irene
    Polasek, Ozren
    Posthuma, Danielle
    Potter, Simon C
    Pouta, Anneli
    Province, Michael A
    Psaty, Bruce M
    Rayner, Nigel W
    Rice, Kenneth
    Ripatti, Samuli
    Rivadeneira, Fernando
    Rolandsson, Olov
    Sandbaek, Annelli
    Sandhu, Manjinder
    Sanna, Serena
    Sayer, Avan Aihie
    Scheet, Paul
    Seedorf, Udo
    Sharp, Stephen J
    Shields, Beverley
    Sijbrands, Eric J G
    Silveira, Angela
    Simpson, Laila
    Singleton, Andrew
    Smith, Nicholas L
    Sovio, Ulla
    Swift, Amy
    Syddall, Holly
    Syvänen, Ann-Christine
    Tanaka, Toshiko
    Tönjes, Anke
    Uitterlinden, André G
    van Dijk, Ko Willems
    Varma, Dhiraj
    Visvikis-Siest, Sophie
    Vitart, Veronique
    Vogelzangs, Nicole
    Waeber, Gérard
    Wagner, Peter J
    Walley, Andrew
    Ward, Kim L
    Watkins, Hugh
    Wild, Sarah H
    Willemsen, Gonneke
    Witteman, Jaqueline C M
    Yarnell, John W G
    Zelenika, Diana
    Zethelius, Björn
    Zhai, Guangju
    Zhao, Jing Hua
    Zillikens, M Carola
    Borecki, Ingrid B
    Loos, Ruth J F
    Meneton, Pierre
    Magnusson, Patrik K E
    Nathan, David M
    Williams, Gordon H
    Silander, Kaisa
    Salomaa, Veikko
    Smith, George Davey
    Bornstein, Stefan R
    Schwarz, Peter
    Spranger, Joachim
    Karpe, Fredrik
    Shuldiner, Alan R
    Cooper, Cyrus
    Dedoussis, George V
    Serrano-Ríos, Manuel
    Lind, Lars
    Palmer, Lyle J
    Franks, Paul W
    Ebrahim, Shah
    Marmot, Michael
    Kao, W H Linda
    Pramstaller, Peter Paul
    Wright, Alan F
    Stumvoll, Michael
    Hamsten, Anders
    Buchanan, Thomas A
    Valle, Timo T
    Rotter, Jerome I
    Siscovick, David S
    Penninx, Brenda W J H
    Boomsma, Dorret I
    Deloukas, Panos
    Spector, Timothy D
    Ferrucci, Luigi
    Cao, Antonio
    Scuteri, Angelo
    Schlessinger, David
    Uda, Manuela
    Ruokonen, Aimo
    Jarvelin, Marjo-Riitta
    Waterworth, Dawn M
    Vollenweider, Peter
    Peltonen, Leena
    Mooser, Vincent
    Sladek, Robert
    A genome-wide association search for type 2 diabetes genes in African Americans.2012Inngår i: PloS one, ISSN 1932-6203, Vol. 7, nr 1, s. e29202-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

  • 186. Palotie, A
    et al.
    Syvänen, Ann-Christine
    Development of molecular genetic methods for monitoring myeloid malignancies1993Inngår i: Scandinavian journal of clinical & laboratory investigation. Supplementum, ISSN 0085-591X, Vol. 213, s. 29-38Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The malignant diagnosis of a haematological disorder can in most cases be made by clinical signs and routine microscopic examination. However, it has become necessary to characterize the malignant clone with various markers, which give either knowledge of the prognosis of the disease or give tools for the laboratory follow up of the patient. In lymphatic diseases there are excellent markers of clonality. On the contrary in myeloid malignancies the few well characterized markers are mostly helpful in the clinical management of rare myeloid subgroups. The aim of our project has been to develop methods for laboratory monitoring of myeloid diseases by two major approaches 1) detection of methylation alterations in the short arm of chromosome 11 and 2) novel approaches for sensitive point mutation detection. The short arm of chromosome 11 has areas where the DNA becomes hypermethylated in acute leukemias and lymphomas. In this chromosomal area the calcitonin gene serves as a good marker for methylation alterations due to several CpG sites in the 5'area of the gene. Even if the gene is normally methylated in most cases of chronic myeloid leukemia (CML), we have found that the hypermethylation of the calcitonin gene marks progression of CML and precedes any other signs of acceleration with several months. The point mutations of certain proto-oncogenes, such as the N-ras gene, are attractive markers for detecting residual diseases after chemotherapy of high malignant haematological disorders. However, conventional methods for detecting point mutations have been both insensitive and cumbersome, and thus unsuitable for clinical routine laboratories. With the solid-phase minisequencing we can technically easily and accurately detect small quantities of mutated cells.

  • 187. Palotie, L
    et al.
    Ikonen, E
    Syvänen, Ann-Christine
    Halila, R
    Enomaa, N
    Heiskanen, T
    Grön, K
    Aula, P
    [Molecular genetics of aspartylglucosaminuria]1991Inngår i: Duodecim; lääketieteellinen aikakauskirja, ISSN 0012-7183, Vol. 107, nr 23-24, s. 1916-1925Artikkel i tidsskrift (Fagfellevurdert)
  • 188. Parkkinen, S
    et al.
    Mäntyjärvi, R
    Syrjänen, K
    Syvänen, Ann-Christine
    Ranki, M
    Sandwich hybridization in solution: a rapid method to screen HPV 16 DNA in cervical scrapes1989Inngår i: Molecular and Cellular Probes, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 3, nr 1, s. 1-11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A solution hybridization method is introduced as a rapid diagnostic method for demonstration of papillomavirus DNA in cervical scrapes. 32P-Labelled detector probe and the biotinylated capture probes were hybridized with DNA of the specimen after pretreatment by boiling in alkaline SDS. After 4 h of hybridization the hybrids were collected onto avidin coated beads and measured. The sensitivity of the method was 1–5 × 105 HPV 16 DNA molecules. Cervical carcinoma cell lines CaSki and SiHa were informative as to the sensitivity of the solution hybridization and the in situ hybridization methods. CaSki cells containing about 700 HPV 16 DNA copies per cell were positive by both methods. SiHa cells with one HPV 16 DNA copy per cell were positive by the sandwich assay but remained negative in the in situ test. A series of 126 cervical scrapes collected from consecutive patients participating in a follow-up study for cervical HPV infection were tested for HPV 16 DNA by both methods. The detection rate of the sandwich test was 19/126 (15%) and that of the in situ method 21/126 (17%) yielding 26 diagnoses altogether. Twelve of these were obtained by one method only. The results obtained by studying the cervical cell lines and repeated specimens taken from constantly HPV 16 positive patients suggested that the two methods can measure different types of infections and thus complement each other in the diagnosis of cervical HPV infections.

  • 189. Paré, Guillaume
    et al.
    Eriksson, Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Lehr, Thorsten
    Connolly, Stuart
    Eikelboom, John
    Ezekowitz, Michael D
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Haertter, Sebastian
    Oldgren, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Reilly, Paul
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Wadelius, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Zimdahl-Gelling, Heike
    Yusuf, Salim
    Wallentin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding2013Inngår i: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 127, nr 13, s. 1404-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in prevention of stroke in atrial fibrillation patients compared to warfarin. We hypothesized that genetic variants could contribute to inter-individual variability in blood concentrations of the active metabolite of dabigatran etexilate, and influence the safety and efficacy of dabigatran.

    Methods and Results

    We successfully conducted a genome-wide association study in 2,944 RE-LY participants. The CES1 SNP rs2244613 was associated with trough concentrations, and the ABCB1 SNP rs4148738 and CES1 SNP rs8192935 were associated with peak concentrations at genome-wide significance (P<9 x 10-8) with a gene-dose effect. Each minor allele of the CES1 SNP rs2244613 was associated with lower trough concentrations (15% decrease per allele, 95%CI 10-19%; P=1.2 x 10-8) and a lower risk of any bleeding (OR=0.67, 95%CI 0.55-0.82; P=7 x 10-5) in dabigatran-treated participants, with a consistent but non-significant lower risk of major bleeding (OR=0.66, 95%CI 0.43-1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (P=0.002) with carriers having less bleeding with dabigatran than warfarin (HR=0.59, 95%CI 0.46-0.76; P=5.2 x 10-5) in contrast to no difference in noncarriers (HR=0.96, 95%CI 0.81-1.14; P=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events.

    Conclusions

    Genome-wide association analysis identified that carriage of CES1 rs2244613 minor allele occurred in 32.8% of patients in RELY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding.

  • 190. Pastinen, T
    et al.
    Kurg, A
    Metspalu, A
    Peltonen, L
    Syvänen, Ann-Christine
    Minisequencing: a specific tool for DNA analysis and diagnostics on oligonucleotide arrays1997Inngår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 7, nr 6, s. 606-614Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We describe a method for multiplex detection of mutations in which the solid-phase minisequencing principle is applied to an oligonucleotide array format. The mutations are detected by extending immobilized primers that anneal to their template sequences immediately adjacent to the mutant nucleotide positions with single labeled dideoxynucleoside triphosphates using a DNA polymerase. The arrays were prepared by coupling one primer per mutation to be detected on a small glass area. Genomic fragments spanning nine disease mutations, which were selected as targets for the assay, were amplified in multiplex PCR reactions and used as templates for the minisequencing reactions on the primer array. The genotypes of homozygous and heterozygous genomic DNA samples were unequivocally defined at each analyzed nucleotide position by the highly specific primer extension reaction. In a comparison to hybridization with immobilized allele-specific probes in the same assay format, the power of discrimination between homozygous and heterozygous genotypes was one order of magnitude higher using the minisequencing method. Therefore, single-nucleotide primer extension is a promising principle for future high-throughput mutation detection and genotyping using high density DNA-chip technology.

  • 191. Pastinen, T
    et al.
    Partanen, J
    Syvänen, Ann-Christine
    Multiplex, fluorescent, solid-phase minisequencing for efficient screening of DNA sequence variation1996Inngår i: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 42, nr 9, s. 1391-1397Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We developed a multiplex, solid-phase minisequencing method to detect multiple single-nucleotide polymorphisms in an undivided sample. The amplified DNA templates are first captured on a manifold. Then, with multiple minisequencing primers of various sizes, single-nucleotide extension reactions are carried out simultaneously with fluorescently labeled dideoxynucleotides. The size of the extended product, determined by using a DNA sequencing instrument, defines the site of the polymorphisms, and the incorporated nucleotide gives the identity of the nucleotide at each site. HLA-DQA1 typing was used as a model system to evaluate the method. The DR2 subgroup of the HLA-DRB1 gene was typed along with the DQA1 gene to demonstrate the feasibility of the method in analyzing multiple genes at multiple sites simultaneously. The method is generally applicable for screening any single-nucleotide polymorphisms or point mutations, and its manifold format allows practical handling of large numbers of samples.

  • 192. Pastinen, Tomi
    et al.
    Raitio, Mirja
    Lindroos, Katarina
    Tainola, Päivi
    Peltonen, Leena
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    A system for specific, high-throughput genotyping by allele-specific primer extension on microarrays2000Inngår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 10, nr 7, s. 1031-1042Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study describes a practical system that allows high-throughput genotyping of single nucleotide polymorphisms (SNPs) and detection of mutations by allele-specific extension on primer arrays. The method relies on the sequence-specific extension of two immobilized allele-specific primers that differ at their 3′-nucleotide defining the alleles, by a reverse transcriptase (RT) enzyme at optimized reaction conditions. We show the potential of this simple one-step procedure performed on spotted primer arrays of low redundancy by generating over 8000 genotypes for 40 mutations or SNPs. The genotypes formed three easily identifiable clusters and all known genotypes were assigned correctly. Higher degrees of multiplexing will be possible with this system as the power of discrimination between genotypes remained unaltered in the presence of over 100 amplicons in a single reaction. The enzyme-assisted reaction provides highly specific allele distinction, evidenced by its ability to detect minority sequence variants present in 5% of a sample at multiple sites. The assay format based on miniaturized reaction chambers at standard 384-well spacing on microscope slides carrying arrays with two primers per SNP for 80 samples results in low consumption of reagents and makes parallel analysis of a large number of samples convenient. In the assay one or two fluorescent nucleotide analogs are used as labels, and thus the genotyping results can be interpreted with presently available array scanners and software. The general accessibility, simple set-up, and the robust procedure of the array-based genotyping system described here will offer an easy way to increase the throughput of SNP typing in any molecular biology laboratory.

  • 193. Paunio, T
    et al.
    Kangas, H
    Kiuru, S
    Palo, J
    Peltonen, L
    Syvänen, Ann-Christine
    Tissue distribution and levels of gelsolin mRNA in normal individuals and patients with gelsolin-related amyloidosis.1997Inngår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 406, nr 1-2, s. 49-55Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We measured quantitatively the mRNA levels of intracellular and secretory forms of gelsolin, an actin-modulating protein, in human tissues from subjects of different ages. The intracellular gelsolin mRNA constituted the major type of gelsolin steady-state mRNA in all tissues analyzed. Both forms of gelsolin were expressed in most adult tissues, with particularly high mRNA levels in all types of muscle and interestingly in skin. Between the adult and infantile tissues the most striking difference in expression levels was found in liver, as the adult liver contained only a subtle amount of gelsolin mRNA. Skin and muscle samples from patients with gelsolin-related amyloidosis (FAF), with significantly increased concentrations of serum gelsolin, did not reveal an increased expression of the gene, and both mutant and wild-type alleles were expressed in equal amounts. The high level of expression of the gelsolin gene in the skin in general could locally contribute to the characteristic skin amyloidosis in FAF patients.

  • 194. Paunio, T
    et al.
    Kiuru, S
    Hongell, V
    Mustonen, E
    Syvänen, Ann-Christine
    Bengström, M
    Palo, J
    Peltonen, L
    Solid-phase minisequencing test reveals Asp187 → Asn (G654 → A) mutation of gelsolin in all affected individuals with finnish type of familial amyloidosis1992Inngår i: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 13, nr 1, s. 237-239Artikkel i tidsskrift (Fagfellevurdert)
  • 195. Paunio, T
    et al.
    Reima, I
    Syvänen, Ann-Christine
    Preimplantation diagnosis by whole-genome amplification, PCR amplification, and solid-phase minisequencing of blastomere DNA1996Inngår i: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 42, nr 9, s. 1382-1390Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have developed a new method for preimplantation diagnosis of inherited diseases. Our procedure for the identification of point mutations in single cells combines whole-genome amplification using 15-mer random primers (primer extension preamplification, PEP) with a single locus-specific PCR amplification, followed by detection of the mutation by solid-phase minisequencing. The procedure was evaluated by detecting three disease-causing mutations and seven polymorphic nucleotides located on different human chromosomes from single granuloma and blastomere cells. The correct genotype of the cell was identified at 96% of the nucleotide positions analyzed, showing that a representative part of the genome is amplified during PEP. We estimate that PEP yielded at least 1000 copies of the genome. The quantitative nature of the solid-phase minisequencing method allowed us to notice that preferential amplification of one allele occurs at heterozygous loci during PEP, which is a potential problem in preimplantation diagnosis.

  • 196.
    Penell, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lundmark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Morris, Andrew P
    Lindgren, Cecilia
    Mahajan, Anubha
    Salihovic, Samira
    van Bavel, Bert
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, P Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Genetic variation in the CYP2B6 Gene is related to circulating 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) concentrations: an observational population-based study2014Inngår i: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 13, s. 34-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Since human CYP2B6 has been identified as the major CYP enzyme involved in the metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and that human 2B6 is a highly polymorphic CYP, with known functional variants, we evaluated if circulating concentrations of a major brominated flame retardant, BDE-47, were related to genetic variation in the CYP2B6 gene in a population sample.

    METHODS:

    In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (men and women all aged 70), 25 single nucleotide polymorphisms (SNPs) in the CYP2B6 gene were genotyped. Circulating concentrations of BDE-47 were analyzed by high-resolution gas chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS).

    RESULTS:

    Several SNPs in the CYP2B6 gene were associated with circulating concentrations of BDE-47 (P = 10-4 to 10-9). The investigated SNPs came primarily from two haplotypes, although the correlation between the haplotypes was rather high. Conditional analyses adjusting for the SNP with the strongest association with the exposure (rs2014141) did not provide evidence for independent signals.

    CONCLUSION:

    Circulating concentrations of BDE-47 were related to genetic variation in the CYP2B6 gene in an elderly population.

  • 197. Pielberg, Gerli
    et al.
    Olsson, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Andersson, L
    Unexpectedly High Allelic Diversity at the KIT Locus Causing DominantWhite Color in the Domestic Pig2002Inngår i: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 160, nr 1, s. 305-311Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in KIT encoding the mast/stem cell growth factor receptor (MGF) are responsible for coat color variation in domestic pigs. The dominant white phenotype is caused by two mutations, a gene duplication and a splice mutation in one of the copies leading to skipping of exon 17. Here we applied minisequencing and pyrosequencing for quantitative analysis of the number of copies with the splice form. An unexpectedly high genetic diversity was revealed in white pigs. We found four different KIT alleles in a small sample of eight Large White females used as founder animals in a wild boar intercross. A similar number of KIT alleles was found in commercial populations of white Landrace and Large White pigs. We provide evidence for at least two new KIT alleles in pigs, both with a triplication of the gene. The results imply that KIT alleles with the duplication are genetically unstable and new alleles are most likely generated by unequal crossing over. This study provides an improved method for genotyping the complicated Dominant white/KIT locus in pigs. The results also suggest that some alleles may be associated with negative pleiotropic effects on other traits.

  • 198. Popov, Sergej
    et al.
    Silveira, Angela
    Wågsäter, Dick
    Takemori, Hiroshi
    Oguro, Ryousuke
    Matsumoto, Sachiko
    Sugimoto, Ken
    Kamide, Kei
    Hirose, Takuo
    Satoh, Michihiro
    Metoki, Hirohito
    Kikuya, Masahiro
    Ohkubo, Takayoshi
    Katsuya, Tomohiro
    Rakugi, Hiromi
    Imai, Yutaka
    Sanchez, Fabio
    Leosdottir, Margret
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hamsten, Anders
    Melander, Olle
    Bertorello, Alejandro M
    Salt-inducible kinase 1 influences Na+,K+-ATPase activity in vascular smooth muscle cells and associates with variations in blood pressure2011Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 29, nr 12, s. 2395-2403Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Essential hypertension is a complex condition whose cause involves the interaction of multiple genetic and environmental factors such as salt intake. Salt-inducible kinase 1 (SIK1) is a sucrose-nonfermenting-like kinase isoform that belongs to the AMPK (5' adenosine monophosphate-activated protein kinase) family. SIK1 activity is increased by high salt intake and plays an essential role in regulating the plasma membrane Na,K-ATPase. The objective of this study was to examine whether SIK1 is present in vascular smooth muscle cells (VSMCs) and endothelial cells, whether it affects VSMC Na,K-ATPase activity and whether human SIK1 (hSIK1) represents a potential candidate for blood pressure regulation. METHODS: Localization of SIK1 was performed using immunohistochemistry, mRNA and western blot. Functional assays (Na,K-ATPase activity) were performed in VSMCs derived from rat aorta. Genotype-phenotype association studies were performed in three Swedish and one Japanese population-based cohorts. RESULTS: SIK1 was localized in human VSMCs and endothelial cells, as well as a cell line derived from rat aorta. A nonsynonymous single nucleotide polymorphism in the hSIK1 gene exon 3 (C→T, rs3746951) results in the amino acid change Gly→Ser in the SIK1 protein. SIK1-Ser was found to increase plasma membrane Na,K-ATPase activity in cultured VSMC line from rat aorta. Genotype-phenotype association studies in three Swedish and one Japanese population-based cohorts suggested that T allele (coding for Ser) was associated with lower blood pressure (P = 0.005 for SBP and P = 0.002 for DBP) and with a decrease in left ventricular mass (P = 0.048). CONCLUSION: The hSIK1 appears to be of potential relevance within VSMC function and blood pressure regulation.

  • 199. Prokopenko, Inga
    et al.
    Poon, Wenny
    Mägi, Reedik
    Prasad B, Rashmi
    Salehi, S Albert
    Almgren, Peter
    Osmark, Peter
    Bouatia-Naji, Nabila
    Wierup, Nils
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Stančáková, Alena
    Barker, Adam
    Lagou, Vasiliki
    Osmond, Clive
    Xie, Weijia
    Lahti, Jari
    Jackson, Anne U
    Cheng, Yu-Ching
    Liu, Jie
    O'Connell, Jeffrey R
    Blomstedt, Paul A
    Fadista, Joao
    Alkayyali, Sami
    Dayeh, Tasnim
    Ahlqvist, Emma
    Taneera, Jalal
    Lecoeur, Cecile
    Kumar, Ashish
    Hansson, Ola
    Hansson, Karin
    Voight, Benjamin F
    Kang, Hyun Min
    Levy-Marchal, Claire
    Vatin, Vincent
    Palotie, Aarno
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mari, Andrea
    Weedon, Michael N
    Loos, Ruth J F
    Ong, Ken K
    Nilsson, Peter
    Isomaa, Bo
    Tuomi, Tiinamaija
    Wareham, Nicholas J
    Stumvoll, Michael
    Widen, Elisabeth
    Lakka, Timo A
    Langenberg, Claudia
    Tönjes, Anke
    Rauramaa, Rainer
    Kuusisto, Johanna
    Frayling, Timothy M
    Froguel, Philippe
    Walker, Mark
    Eriksson, Johan G
    Ling, Charlotte
    Kovacs, Peter
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    McCarthy, Mark I
    Shuldiner, Alan R
    Silver, Kristi D
    Laakso, Markku
    Groop, Leif
    Lyssenko, Valeriya
    A Central Role for GRB10 in Regulation of Islet Function in Man2014Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, nr 4, artikkel-id e1004235Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

  • 200.
    Pullabhatla, Venu
    et al.
    Guys & St Thomas NHS Fdn Trust, Comprehens Biomed Res Ctr, GSTFT, NIHR,KCL, London SE1 9RT, England..
    Roberts, Amy L.
    Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England..
    Lewis, Myles J.
    Queen Mary Univ London, William Harvey Res Inst, Ctr Expt Med & Rheumatol, London EC1M 6BQ, England..
    Mauro, Daniele
    Queen Mary Univ London, William Harvey Res Inst, Ctr Expt Med & Rheumatol, London EC1M 6BQ, England..
    Morris, David L.
    Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England..
    Odhams, Christopher A.
    Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England..
    Tombleson, Philip
    Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England..
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Vyse, Simon
    Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England.;Inst Canc Res, Dept Canc Biol, London SW3 6JB, England..
    Simpson, Michael A.
    Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England..
    Sauer, Sascha
    Max Planck Inst Mol Genet, Nutrigen & Gene Regulat Res Grp, Otto Warburg Labs, D-14195 Berlin, Germany.;Max Delbruck Ctr Mol Med, BIMSB, Lab Funct Gen Nutrigen & Syst Biol, Sci Genom Platforms,BIH, D-13092 Berlin, Germany..
    de Rinaldis, Emanuele
    Guys & St Thomas NHS Fdn Trust, Comprehens Biomed Res Ctr, GSTFT, NIHR,KCL, London SE1 9RT, England..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Vyse, Timothy J.
    Kings Coll London, Fac Life Sci & Med, Dept Med & Mol Genet, London SE1 9RT, England..
    De novo mutations implicate novel genes in systemic lupus erythematosus2018Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, nr 3, s. 421-429Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The omnigenic model of complex disease stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing, high-density imputation, and in vitro cellular assays, we identify candidate core genes in the pathogenesis of systemic lupus erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies. In a follow-up cohort of 10, 995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. Gene-level analyses indicate three functional candidates: DNMT3A, PRKCD, and C1QTNF4. We identify a burden of rare variants across PRKCD associated with SLE risk (P = 0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P = 0.0005 and P = 0.0033). We further characterise the TNF-dependent functions of the third candidate gene C1QTNF4 on NF-kappa B activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results identify three novel genes in SLE susceptibility and support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.

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