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  • 101. Koettgen, Anna
    et al.
    Albrecht, Eva
    Teumer, Alexander
    Vitart, Veronique
    Krumsiek, Jan
    Hundertmark, Claudia
    Pistis, Giorgio
    Ruggiero, Daniela
    O'Seaghdha, Conall M.
    Haller, Toomas
    Yang, Qiong
    Tanaka, Toshiko
    Johnson, Andrew D.
    Kutalik, Zoltan
    Smith, Albert V.
    Shi, Julia
    Struchalin, Maksim
    Middelberg, Rita P. S.
    Brown, Morris J.
    Gaffo, Angelo L.
    Pirastu, Nicola
    Li, Guo
    Hayward, Caroline
    Zemunik, Tatijana
    Huffman, Jennifer
    Yengo, Loic
    Zhao, Jing Hua
    Demirkan, Ayse
    Feitosa, Mary F.
    Liu, Xuan
    Malerba, Giovanni
    Lopez, Lorna M.
    van der Harst, Pim
    Li, Xinzhong
    Kleber, Marcus E.
    Hicks, Andrew A.
    Nolte, Ilja M.
    Johansson, Åsa
    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 immunologi, genetik och patologi.
    Murgia, Federico
    Wild, Sarah H.
    Bakker, Stephan J. L.
    Peden, John F.
    Dehghan, Abbas
    Steri, Maristella
    Tenesa, Albert
    Lagou, Vasiliki
    Salo, Perttu
    Mangino, Massimo
    Rose, Lynda M.
    Lehtimaki, Terho
    Woodward, Owen M.
    Okada, Yukinori
    Tin, Adrienne
    Mueller, Christian
    Oldmeadow, Christopher
    Putku, Margus
    Czamara, Darina
    Kraft, Peter
    Frogheri, Laura
    Thun, Gian Andri
    Grotevendt, Anne
    Gislason, Gauti Kjartan
    Harris, Tamara B.
    Launer, Lenore J.
    McArdle, Patrick
    Shuldiner, Alan R.
    Boerwinkle, Eric
    Coresh, Josef
    Schmidt, Helena
    Schallert, Michael
    Martin, Nicholas G.
    Montgomery, Grant W.
    Kubo, Michiaki
    Nakamura, Yusuke
    Tanaka, Toshihiro
    Munroe, Patricia B.
    Samani, Nilesh J.
    Jacobs, David R., Jr.
    Liu, Kiang
    D'Adamo, Pio
    Ulivi, Sheila
    Rotter, Jerome I.
    Psaty, Bruce M.
    Vollenweider, Peter
    Waeber, Gerard
    Campbell, Susan
    Devuyst, Olivier
    Navarro, Pau
    Kolcic, Ivana
    Hastie, Nicholas
    Balkau, Beverley
    Froguel, Philippe
    Esko, Tonu
    Salumets, Andres
    Khaw, Kay Tee
    Langenberg, Claudia
    Wareham, Nicholas J.
    Isaacs, Aaron
    Kraja, Aldi
    Zhang, Qunyuan
    Wild, Philipp S.
    Scott, Rodney J.
    Holliday, Elizabeth G.
    Org, Elin
    Viigimaa, Margus
    Bandinelli, Stefania
    Metter, Jeffrey E.
    Lupo, Antonio
    Trabetti, Elisabetta
    Sorice, Rossella
    Doering, Angela
    Lattka, Eva
    Strauch, Konstantin
    Theis, Fabian
    Waldenberger, Melanie
    Wichmann, H-Erich
    Davies, Gail
    Gow, Alan J.
    Bruinenberg, Marcel
    Stolk, Ronald P.
    Kooner, Jaspal S.
    Zhang, Weihua
    Winkelmann, Bernhard R.
    Boehm, Bernhard O.
    Lucae, Susanne
    Penninx, Brenda W.
    Smit, Johannes H.
    Curhan, Gary
    Mudgal, Poorva
    Plenge, Robert M.
    Portas, Laura
    Persico, Ivana
    Kirin, Mirna
    Wilson, James F.
    Leach, Irene Mateo
    van Gilst, Wiek H.
    Goel, Anuj
    Ongen, Halit
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, Andre G.
    Imboden, Medea
    von Eckardstein, Arnold
    Cucca, Francesco
    Nagaraja, Ramaiah
    Piras, Maria Grazia
    Nauck, Matthias
    Schurmann, Claudia
    Budde, Kathrin
    Ernst, Florian
    Farrington, Susan M.
    Theodoratou, Evropi
    Prokopenko, Inga
    Stumvoll, Michael
    Jula, Antti
    Perola, Markus
    Salomaa, Veikko
    Shin, So-Youn
    Spector, Tim D.
    Sala, Cinzia
    Ridker, Paul M.
    Kaehoenen, Mika
    Viikari, Jorma
    Hengstenberg, Christian
    Nelson, Christopher P.
    Meschia, James F.
    Nalls, Michael A.
    Sharma, Pankaj
    Singleton, Andrew B.
    Kamatani, Naoyuki
    Zeller, Tanja
    Burnier, Michel
    Attia, John
    Laan, Maris
    Klopp, Norman
    Hillege, Hans L.
    Kloiber, Stefan
    Choi, Hyon
    Pirastu, Mario
    Tore, Silvia
    Probst-Hensch, Nicole M.
    Voelzke, Henry
    Gudnason, Vilmundur
    Parsa, Afshin
    Schmidt, Reinhold
    Whitfield, John B.
    Fornage, Myriam
    Gasparini, Paolo
    Siscovick, David S.
    Polasek, Ozren
    Campbell, Harry
    Rudan, Igor
    Bouatia-Naji, Nabila
    Metspalu, Andres
    Loos, Ruth J. F.
    van Duijn, Cornelia M.
    Borecki, Ingrid B.
    Ferrucci, Luigi
    Gambaro, Giovanni
    Deary, Ian J.
    Wolffenbuttel, Bruce H. R.
    Chambers, John C.
    Maerz, Winfried
    Pramstaller, Peter P.
    Snieder, Harold
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Wright, Alan F.
    Navis, Gerjan
    Watkins, Hugh
    Witteman, Jacqueline C. M.
    Sanna, Serena
    Schipf, Sabine
    Dunlop, Malcolm G.
    Toenjes, Anke
    Ripatti, Samuli
    Soranzo, Nicole
    Toniolo, Daniela
    Chasman, Daniel I.
    Raitakari, Olli
    Kao, W. H. Linda
    Ciullo, Marina
    Fox, Caroline S.
    Caulfield, Mark
    Bochud, Murielle
    Gieger, Christian
    Genome-wide association analyses identify 18 new loci associated with serum urate concentrations2013Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, nr 2, s. 145-154Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

  • 102. Kostareli, E
    et al.
    Gounari, M
    Janus, A
    Murray, Fiona
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Brochet, X
    Giudicelli, V
    Pospisilova, S
    Oscier, D
    Foroni, L
    di Celle, P F
    Tichy, B
    Pedersen, L B
    Jurlander, J
    Ponzoni, M
    Kouvatsi, A
    Anagnostopoulos, A
    Thompson, K
    Darzentas, N
    Lefranc, M-P
    Belessi, C
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Davi, F
    Ghia, P
    Stamatopoulos, K
    Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity2012Ingår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, nr 5, s. 1127-1131Artikel i tidskrift (Refereegranskat)
  • 103.
    Kruczyk, Marcin
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Umer, Husen Muhammad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Komorowski, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi.
    Peak Finder Metaserver - a novel application for finding peaks in ChIP-seq data2013Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 14, s. 280-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Finding peaks in ChIP-seq is an important process in biological inference. In some cases, such as positioning nucleosomes with specific histone modifications or finding transcription factor binding specificities, the precision of the detected peak plays a significant role. There are several applications for finding peaks (called peak finders) based on different algorithms (e.g. MACS, Erange and HPeak). Benchmark studies have shown that the existing peak finders identify different peaks for the same dataset and it is not known which one is the most accurate. We present the first meta-server called Peak Finder MetaServer (PFMS) that collects results from several peak finders and produces consensus peaks. Our application accepts three standard ChIP-seq data formats: BED, BAM, and SAM. Results: Sensitivity and specificity of seven widely used peak finders were examined. For the experiments we used three previously studied Transcription Factors (TF) ChIP-seq datasets and identified three of the selected peak finders that returned results with high specificity and very good sensitivity compared to the remaining four. We also ran PFMS using the three selected peak finders on the same TF datasets and achieved higher specificity and sensitivity than the peak finders individually. Conclusions: We show that combining outputs from up to seven peak finders yields better results than individual peak finders. In addition, three of the seven peak finders outperform the remaining four, and running PFMS with these three returns even more accurate results. Another added value of PFMS is a separate report of the peaks returned by each of the included peak finders.

  • 104.
    Larsson, Chatarina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ali, Muhammad Akhtar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    He, Liqun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Tatjana Djureinovic, Tatjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    DIP2C regulates expression of the tumor suppressor gene CDKN2AManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized candidate

    breast and lung cancer gene. The gene contains a DMAP1 binding domain, pointing to

    potential involvement in DNMT1-dependent methylation. To study the role of DIP2C in

    tumor development, we engineered human DIP2C knockout cell systems by rAAV-mediated

    gene targeting. Homo- and heterozygous RKO DIP2C knockout cells displayed enlarged cells

    and growth retardation. This phenotype was most pronounced in DIP2C-/- knockouts, and

    these cells also displayed a significant decrease in DIP2C mRNA levels. RNA sequencing

    revealed 780 genes affected by the loss of DIP2C, including the cellular senescence marker

    P16INK4a. Functional annotation of the regulated genes shows enrichment of genes involved

    with cell death processes, cell structure and motility. Furthermore, KEGG pathway analysis

    shows association of 19 genes with pathways in cancer. In conclusion, the phenotypic data

    and expression changes induced by loss of DIP2C indicate that the gene function may be

    important for several biological processes implicated in cancer, and that loss of gene function

    may be a trigger of cellular senescence.

  • 105. Lauc, Gordan
    et al.
    Huffman, Jennifer E.
    Pucic, Maja
    Zgaga, Lina
    Adamczyk, Barbara
    Muzinic, Ana
    Novokmet, Mislav
    Polasek, Ozren
    Gornik, Olga
    Kristic, Jasminka
    Keser, Toma
    Vitart, Veronique
    Scheijen, Blanca
    Uh, Hae-Won
    Molokhia, Mariam
    Patrick, Alan Leslie
    McKeigue, Paul
    Kolcic, Ivana
    Lukic, Ivan Kresimir
    Swann, Olivia
    van Leeuwen, Frank N.
    Ruhaak, L. Renee
    Houwing-Duistermaat, Jeanine J.
    Slagboom, P. Eline
    Beekman, Marian
    de Craen, Anton J. M.
    Deelder, Andre M.
    Zeng, Qiang
    Wang, Wei
    Hastie, Nicholas D.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wilson, James F.
    Wuhrer, Manfred
    Wright, Alan F.
    Rudd, Pauline M.
    Hayward, Caroline
    Aulchenko, Yurii
    Campbell, Harry
    Rudan, Igor
    Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers2013Ingår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, nr 1, s. e1003225-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2,247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1,848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci (P<2.27x10(-9)) in the discovery analysis and two of the same loci (B4GALT1 and MGAT3) in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e. g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, diabetes type 1, multiple sclerosis, Graves' disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG N-glycan traits, we explored biomarker potential of affected N-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (area under the curve=0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer.

  • 106.
    Lembring, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Köpenhamns universitet, University of Copenhagen.
    Application of Mitochondrial DNA Analysis in Contemporary and Historical Samples2013Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The mitochondrion is a tiny organelle that is the power supplier of the cell and vital to the functioning of the body organs. Additionally it contains a small circular genome of about 16 kb, present in many copies which makes the mitochondrial DNA more viable than nuclear DNA. Mitochondrial DNA is also maternally inherited and thus provides a direct link to maternal relatives. These two properties are of particular use for forensic samples, which only contain limited or degraded amounts of DNA, and for historical samples (ancient DNA). This thesis presents work on the mitochondrial DNA in the hypervariable regions (HV) I and II, in both contemporary and historical samples. Forensic genetics makes use of mitochondrial DNA analysis in court as circumstantial evidence, and population databases are used for the calculation of evidence value. Population samples (299) across Sweden have been analysed in order to enrich the EDNAP mtDNA database (EMPOP) (paper I). The application of mitochondrial DNA analysis allowed for analysis of historical skeletal remains: Copernicus, 1473-1543 (paper II), Karin Göring, 1888-1931 (paper III) and Medieval bones, 880-1000 AD, from a mass grave found in Sigtuna, Sweden (paper IV). The thesis also includes analyses of bones and teeth from the shipwrecked crew of the Vasa warship, 1628, samples from the Vasa museum, Stockholm, Sweden (paper V). Overall, the varying age of the samples and the different conservation environments (soil and water) accounted for variations in quality, but still allowed for successful DNA analysis.

    Delarbeten
    1. Mitochondrial DNA analysis of Swedish population samples
    Öppna denna publikation i ny flik eller fönster >>Mitochondrial DNA analysis of Swedish population samples
    2013 (Engelska)Ingår i: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 127, nr 6, s. 1097-1099Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    As a contribution to the geographic coverage of EMPOP, currently the best available forensic mitochondrial DNA (mtDNA) database, a total of 299 Swedish individuals were analysed by sequencing of the first and second hypervariable regions of the mtDNA genome. In this sample set, a total of 179 different haplotypes were detected. The genetic diversity was estimated to be 0.9895 (±0.0023), and the random match probability was 1.39 %. The most abundant haplogroups were HV (including its subhaplogroups H and V) with a frequency of 46.5 %, followed by haplogroup U (including its subhaplogroup K) at 27.8 %, haplogroup T at 10.0 % and haplogroup J at 7.0 %, a distribution that is consistent with previous observations in other European populations.

    Nyckelord
    Forensic DNA database, Haplogroup, Haplotype, mtDNA, Northern Europe, Sweden
    Nationell ämneskategori
    Biologiska vetenskaper Genetik
    Identifikatorer
    urn:nbn:se:uu:diva-209955 (URN)10.1007/s00414-013-0908-6 (DOI)000326190200006 ()24077990 (PubMedID)
    Tillgänglig från: 2013-10-28 Skapad: 2013-10-28 Senast uppdaterad: 2017-12-06
    2. Genetic identification of putative remains of the famous astronomer Nicolaus Copernicus
    Öppna denna publikation i ny flik eller fönster >>Genetic identification of putative remains of the famous astronomer Nicolaus Copernicus
    Visa övriga...
    2009 (Engelska)Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 30, s. 12279-12282Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We report the results of mitochondrial and nuclear DNA analyses of skeletal remains exhumed in 2005 at Frombork Cathedral in Poland, that are thought to be those of Nicolaus Copernicus (1473-1543). The analyzed bone remains were found close to the altar Nicolaus Copernicus was responsible for during his tenure as priest. The mitochondrial DNA (mtDNA) profiles from 3 upper molars and the femurs were identical, suggesting that the remains originate from the same individual. Identical mtDNA profiles were also determined in 2 hairs discovered in a calendar now exhibited at Museum Gustavianum in Uppsala, Sweden. This calendar was the property of Nicolaus Copernicus for much of his life. These findings, together with anthropological data, support the identification of the human remains found in Frombork Cathedral as those of Nicolaus Copernicus. Up-to-now the particular mtDNA haplotype has been observed only 3 times in Germany and once in Denmark. Moreover, Y-chromosomal and autosomal short tandem repeat markers were analyzed in one of the tooth samples, that was much better preserved than other parts of the skeleton. Molecular sex determination revealed that the skeleton is from a male individual, and this result is consistent with morphological investigations. The minimal Y-chromosomal haplotype determined in the putative remains of Nicolaus Copernicus has been observed previously in many countries, including Austria, Germany, Poland, and the Czech Republic. Finally, an analysis of the SNP located in the HERC2 gene revealed the C/C genotype that is predominant in blue-eyed humans, suggesting that Copernicus may have had a light iris color.

    Nyckelord
    eye-color marker, hairs, human remains, identification, mitochondrial and nuclear DNA
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-107559 (URN)10.1073/pnas.0901848106 (DOI)000268440200016 ()19584252 (PubMedID)
    Tillgänglig från: 2009-08-17 Skapad: 2009-08-17 Senast uppdaterad: 2017-12-13
    3. An Analysis of the Alleged Skeletal Remains of Carin Göring
    Öppna denna publikation i ny flik eller fönster >>An Analysis of the Alleged Skeletal Remains of Carin Göring
    Visa övriga...
    2012 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 12, s. e44366-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In 1991, treasure hunters found skeletal remains in an area close to the destroyed country residence of former Nazi leader Hermann Göring in northeastern Berlin. The remains, which were believed to belong to Carin Göring, who was buried at the site, were examined to determine whether it was possible to make a positive identification. The anthropological analysis showed that the remains come from an adult woman. The DNA analysis of several bone elements showed female sex, and a reference sample from Carin's son revealed mtDNA sequences identical to the remains. The profile has one nucleotide difference from the Cambridge reference sequence (rCRS), the common variant 263G. A database search resulted in a frequency of this mtDNA sequence of about 10% out of more than 7,000 European haplotypes. The mtDNA sequence found in the ulna, the cranium and the reference sample is, thus, very common among Europeans. Therefore, nuclear DNA analysis was attempted. The remains as well as a sample from Carin's son were successfully analysed for the three nuclear markers TH01, D7S820 and D8S1179. The nuclear DNA analysis of the two samples revealed one shared allele for each of the three markers, supporting a mother and son relationship. This genetic information together with anthropological and historical files provides an additional piece of circumstantial evidence in our efforts to identify the remains of Carin Göring.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-192064 (URN)10.1371/journal.pone.0044366 (DOI)000312694300001 ()
    Tillgänglig från: 2013-01-17 Skapad: 2013-01-15 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    4. Mitochondrial DNA analysis of a Swedish Medieval mass grave
    Öppna denna publikation i ny flik eller fönster >>Mitochondrial DNA analysis of a Swedish Medieval mass grave
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Naturvetenskap
    Forskningsämne
    Genetik
    Identifikatorer
    urn:nbn:se:uu:diva-209964 (URN)
    Tillgänglig från: 2013-10-29 Skapad: 2013-10-29 Senast uppdaterad: 2014-01-23Bibliografiskt granskad
    5. Mitochondrial DNA analysis of the human remains found on the Vasa warship
    Öppna denna publikation i ny flik eller fönster >>Mitochondrial DNA analysis of the human remains found on the Vasa warship
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Naturvetenskap
    Forskningsämne
    Genetik
    Identifikatorer
    urn:nbn:se:uu:diva-209966 (URN)
    Tillgänglig från: 2013-10-29 Skapad: 2013-10-29 Senast uppdaterad: 2014-01-23Bibliografiskt granskad
  • 107.
    Lembring, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    van Oven, Mannis
    Montelius, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Mitochondrial DNA analysis of Swedish population samples2013Ingår i: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 127, nr 6, s. 1097-1099Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    As a contribution to the geographic coverage of EMPOP, currently the best available forensic mitochondrial DNA (mtDNA) database, a total of 299 Swedish individuals were analysed by sequencing of the first and second hypervariable regions of the mtDNA genome. In this sample set, a total of 179 different haplotypes were detected. The genetic diversity was estimated to be 0.9895 (±0.0023), and the random match probability was 1.39 %. The most abundant haplogroups were HV (including its subhaplogroups H and V) with a frequency of 46.5 %, followed by haplogroup U (including its subhaplogroup K) at 27.8 %, haplogroup T at 10.0 % and haplogroup J at 7.0 %, a distribution that is consistent with previous observations in other European populations.

  • 108. Lessard, Christopher J.
    et al.
    Adrianto, Indra
    Kelly, Jennifer A.
    Kaufman, Kenneth M.
    Grundahl, Kiely M.
    Adler, Adam
    Williams, Adrienne H.
    Gallant, Caroline J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Alarcon-Riquelme, Marta E.
    Anaya, Juan-Manuel
    Bae, Sang-Cheol
    Boackle, Susan A.
    Brown, Elizabeth E.
    Chang, Deh-Ming
    Criswell, Lindsey A.
    Edberg, Jeffrey C.
    Freedman, Barry I.
    Gregersen, Peter K.
    Gilkeson, Gary S.
    Jacob, Chaim O.
    James, Judith A.
    Kamen, Diane L.
    Kimberly, Robert P.
    Martin, Javier
    Merrill, Joan T.
    Niewold, Timothy B.
    Park, So-Yeon
    Petri, Michelle A.
    Pons-Estel, Bernardo A.
    Ramsey-Goldman, Rosalind
    Reveille, John D.
    Song, Yeong Wook
    Stevens, Anne M.
    Tsao, Betty P.
    Vila, Luis M.
    Vyse, Timothy J.
    Yu, Chack-Yung
    Guthridge, Joel M.
    Bruner, Gail R.
    Langefeld, Carl D.
    Montgomery, Courtney
    Harley, John B.
    Scofield, R. Hal
    Gaffney, Patrick M.
    Moser, Kathy L.
    Identification of a Systemic Lupus Erythematosus Susceptibility Locus at 11p13 between PDHX and CD44 in a Multiethnic Study2011Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, nr 1, s. 83-91Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 x 10(-8)) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 x 10(-8), OR = 0.83) and rs387619 (p = 7.7 x 10(-7), OR = 0.83) in the European samples with p(meta) = 1.82 x 10(-9) for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 x 10(-3), OR = 0.81 and p = 4.3 x 10(-4), OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced p(meta) = 2.36 x 10(-13). This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex.

  • 109.
    Lind, Sara Bergström
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Artemenko, Konstantin A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Elfineh, Lioudmila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Zhao, Yanhong
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Post translational modifications in adenovirus type 22013Ingår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 447, nr 1-2, s. 104-111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have combined 2-D SOS-PAGE with liquid chromatography-high resolving mass spectrometry (LC-MS) to explore the proteome of the adenovirus type 2 (Ad2) at the level of post translational modifications (PTMs). The experimental design included in-solution digestion, followed by titanium dioxide enrichment, as well as in-gel digestion of polypeptides after separation of Ad2 capsid proteins by 1-D and 2-D SOS-PAGE. All samples were analyzed using LC-MS with subsequent manual verification of PTM positions. The results revealed new phosphorylation sites that can explain the observed trains of protein spots observed for the pIII, pIIIa and ply proteins. The pin protein was found to be the most highly modified protein with now 18 verified sites of phosphorylation, three sites of nitrated tyrosine and one sulfated tyrosine. Nitrated tyrosines were also identified in pII. Lysine acetylations were detected in pII and pVI. The findings make the Ad2 virion much more complex than hitherto believed. 

  • 110.
    Lindén, Mårten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Lind, Sara Bergström
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Mayrhofer, Corina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Segersten, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Wester, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Lyutvinskiy, Yaroslav
    Zubarev, Roman
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Malmström, Per-Uno
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Proteomic analysis of urinary biomarker candidates for nonmuscle invasive bladder cancer2012Ingår i: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 12, nr 1, s. 135-144Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nonmuscle invasive tumors of the bladder often recur and thereby bladder cancer patients need regular re-examinations which are invasive, unpleasant, and expensive. A noninvasive and less expensive method, e.g. a urine dipstick test, for monitoring recurrence would thus be advantageous. In this study, the complementary techniques mass spectrometry (MS) and Western blotting (WB)/dot blot (DB) were used to screen the urine samples from bladder cancer patients. High resolving MS was used to analyze and quantify the urinary proteome and 29 proteins had a significantly higher abundance (p<0.05) in bladder cancer samples compared with control urine samples. The increased abundance found in urine from bladder cancer patients compared with controls was confirmed with Western blot for four selected proteins; fibrinogen β chain precursor, apolipoprotein E, α-1-antitrypsin, and leucine-rich α-2-glycoprotein 1. Dot blot analysis of an independent urine sample set pointed out fibrinogen β chain and α-1-antitrypsin as most interesting biomarkers having sensitivity and specificity values in the range of 66-85%. Exploring the Human Protein Atlas (HPA) also revealed that bladder cancer tumors are the likely source of these proteins. They have the potential of being useful in diagnosis, monitoring of recurrence and thus may improve the treatment of bladder tumors, especially nonmuscle invasive tumors.

  • 111.
    Lindén, Mårten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Segersten, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Runeson, Marcus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Wester, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Busch, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Bergström Lind, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Malmström, Per-Uno
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Tumour expression of bladder cancer-associated urinary proteins2013Ingår i: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 112, nr 3, s. 407-415Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?:

    • The current basis for diagnosis and prognosis in urinary bladder cancer is based on the pathologists' assessment of a biopsy of the tumour. Urinary biomarkers are preferable as they can be non-invasively sampled. Urinary cytology is the only test with widespread use but is hampered by poor reproducibility and low sensitivity.
    • By studying the protein expression in bladder tumour tissue samples of proteins previously found in elevated levels in the urine of patients with bladder cancer, we have been able to show that these proteins originate from the tumour. The immunoreactivity of three of the investigated proteins increased with higher stage. Also a serine peptidase inhibitor was found to be predictive of progression from non-muscle-invasive to muscle-invasive tumours.

    OBJECTIVES:

    • To analyse the expression of five bladder cancer-associated urinary proteins and investigate if expression is related to the malignant phenotype of the tumour.
    • To explore the possible prognostic value of these proteins.

    PATIENTS AND METHODS:

    • Urine samples, 16 from patients with bladder cancer and 26 from controls, were used in Western Blotting experiments.
    • Tissue microarrays with bladder tissue from 344 patients diagnosed with bladder cancer between 1984 and 2005 was used in immunohistochemistry experiments.
    • The proteins apolipoprotein E (APOE), fibrinogen β chain precursor (FGB), leucine-rich α2-glycoprotein (LRG1), polymerase (RNA) I polypeptide E (POLR1E), α1-antitrypsin (SERPINA1) and topoisomerase 2A (TOP2A) were probed with antibodies validated by the Human Protein Atlas.

    RESULTS:

    • Increased expressions of APOE, FGB and POLR1E were correlated with increased tumour stage (P < 0.001).
    • Expression of SERPINA1 in Ta and T1 tumours was found to increase the risk of tumour progression (hazard ratio 2.57, 95% confidence interval 1.13-5.87; P = 0.025)

    CONCLUSIONS:

    • All proteins previously detected in urine from patients with bladder cancer were also expressed in bladder cancer tissue.
    • The expression of APOE, FGB and POLR1E increased with stage and they are potential diagnostic markers.
    • SERPINA1 was identified as a prognostic marker candidate.
  • 112. MacDonald, Jeffrey R.
    et al.
    Ziman, Robert
    Yuen, Ryan K. C.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Scherer, Stephen W.
    The Database of Genomic Variants: a curated collection of structural variation in the human genome2014Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, nr D1, s. D986-D992Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Over the past decade, the Database of Genomic Variants (DGV; http://dgv.tcag.ca/) has provided a publicly accessible, comprehensive curated catalogue of structural variation (SV) found in the genomes of control individuals from worldwide populations. Here, we describe updates and new features, which have expanded the utility of DGV for both the basic research and clinical diagnostic communities. The current version of DGV consists of 55 published studies, comprising >2.5 million entries identified in >22 300 genomes. Studies included in DGV are selected from the accessioned data sets in the archival SV databases dbVar (NCBI) and DGVa (EBI), and then further curated for accuracy and validity. The core visualization tool (gbrowse) has been upgraded with additional functions to facilitate data analysis and comparison, and a new query tool has been developed to provide flexible and interactive access to the data. The content from DGV is regularly incorporated into other large-scale genome reference databases and represents a standard data resource for new product and database development, in particular for copy number variation testing in clinical labs. The accurate cataloguing of variants in DGV will continue to enable medical genetics and genome sequencing research.

  • 113.
    Mansouri, Larry
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Gunnarsson, Rebeqa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hooper, Sean D.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mayrhofer, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Juliusson, Gunnar
    Isaksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Next generation RNA-sequencing in prognostic subsets of chronic lymphocytic leukemia2012Ingår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 87, nr 7, s. 737-740Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Advances in next-generation RNA-sequencing have revealed the complexity of transcriptomes by allowing both coding and noncoding (nc) RNAs to be analyzed. However, limited data exist regarding the whole transcriptional landscape of chronic lymphocytic leukemia (CLL). In this pilot-study, we evaluated RNA-sequencing in CLL by comparing two subsets which carry almost identical or `` stereotyped'' B-cell receptors with distinct clinical outcome, that is the poor-prognostic subset # 1 (n = 4) and the more favorable-prognostic subset # 4 (n = 4). Our analysis revealed that 156 genes (e.g. LPL, WNT9A) and 76 ncRNAs, (e. g. SNORD48, SNORD115) were differentially expressed between the subsets. This technology also enabled us to identify numerous subset-specific splice variants (n = 406), which were predominantly expressed in subset # 1, including a splice-isoform of MSI2 with a novel start exon. A further important application of RNA-sequencing was for mutation detection and revealed 16-30 missense mutations per sample; notably many of these changes were found in genes with a strong potential for involvement in CLL pathogenesis, e. g., ATM and NOTCH2. This study not only demonstrates the effectiveness of RNA-sequencing for identifying mutations, quantifying gene expression and detecting splicing events, but also highlights the potential such global approaches have to significantly advance our understanding of the molecular mechanisms behind CLL development. 

  • 114. Marincevic-Zuniga, Yanara
    et al.
    Gustavsson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Multiply-primed rolling circle amplification of human papillomavirus using sequence-specific primers2012Ingår i: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 432, nr 1, s. 57-62Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Multiply-primed rolling circle amplification (RCA) is a suitable technique for amplification of circular templates and has been used to identify novel human papillomaviruses (HPV). In this study we develop an efficient RCA for whole genome amplification of HPV using HPV-specific primers in clinical samples and establish a protocol for whole genome sequencing using the Sanger method. Amplification of cloned HPV-genomes by RCA was compared using specific primers against random hexamers. Using HPV-specific primers increased the effectiveness on average 15.2 times and the enrichment of HPV relative to human gDNA on average 62.2 times, as compared to using random hexamer. RCA products were sequenced without need for cloning, even when using low-input amounts. The technique was successfully used on 4 patient samples from FTA cards, to generate whole HPV-genome sequences. Degenerated HPV-specific primers for RCA produce DNA of sufficient quality and quantity suitable for sequencing and other potential downstream analyses.

  • 115.
    Mathot, Lucy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Falk Sörqvist, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Moens, Lotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nilsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Automated Genotyping of Biobank Samples by Multiplex Amplification of Insertion/Deletion Polymorphisms2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 12, s. e52750-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The genomic revolution in oncology will entail mutational analyses of vast numbers of patient-matched tumor and normal tissue samples. This has meant an increased risk of patient sample mix up due to manual handling. Therefore, scalable genotyping and sample identification procedures are essential to pathology biobanks. We have developed an efficient alternative to traditional genotyping methods suited for automated analysis. By targeting 53 prevalent deletions and insertions found in human populations with fluorescent multiplex ligation dependent genome amplification, followed by separation in a capillary sequencer, a peak spectrum is obtained that can be automatically analyzed. 24 tumor-normal patient samples were successfully matched using this method. The potential use of the developed assay for forensic applications is discussed.

  • 116.
    Mathot, Lucy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wallin, Monica
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Automated serial extraction of DNA and RNA from biobanked tissue specimens2013Ingår i: BMC Biotechnology, ISSN 1472-6750, E-ISSN 1472-6750, Vol. 13, s. 66-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: With increasing biobanking of biological samples, methods for large scale extraction of nucleic acids are in demand. The lack of such techniques designed for extraction from tissues results in a bottleneck in downstream genetic analyses, particularly in the field of cancer research. We have developed an automated procedure for tissue homogenization and extraction of DNA and RNA into separate fractions from the same frozen tissue specimen. A purpose developed magnetic bead based technology to serially extract both DNA and RNA from tissues was automated on a Tecan Freedom Evo robotic workstation. Results: 864 fresh-frozen human normal and tumor tissue samples from breast and colon were serially extracted in batches of 96 samples. Yields and quality of DNA and RNA were determined. The DNA was evaluated in several downstream analyses, and the stability of RNA was determined after 9 months of storage. The extracted DNA performed consistently well in processes including PCR-based STR analysis, HaloPlex selection and deep sequencing on an Illumina platform, and gene copy number analysis using microarrays. The RNA has performed well in RT-PCR analyses and maintains integrity upon storage. Conclusions: The technology described here enables the processing of many tissue samples simultaneously with a high quality product and a time and cost reduction for the user. This reduces the sample preparation bottleneck in cancer research. The open automation format also enables integration with upstream and downstream devices for automated sample quantitation or storage.

  • 117.
    Mayrhofer, Markus
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Kultima, Hanna Göransson
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Birgisson, Helgi
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Sundström, Magnus
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Mathot, Lucy
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Edlund, Karolina
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Viklund, Björn
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Sjöblom, Tobias
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Botling, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Micke, Patrick
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Påhlman, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Isaksson, Anders
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II-III colon cancer2014Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, s. 872-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The clinical behaviour of colon cancer is heterogeneous. Five-year overall survival is 50-65% with all stages included. Recurring somatic chromosomal alterations have been identified and some have shown potential as markers for dissemination of the tumour, which is responsible for most colon cancer deaths. We investigated 115 selected stage II-IV primary colon cancers for associations between chromosomal alterations and tumour dissemination. Methods: Follow-up was at least 5 years for stage II-III patients without distant recurrence. Affymetrix SNP 6.0 microarrays and allele-specific copy number analysis were used to identify chromosomal alterations. Fisher's exact test was used to associate alterations with tumour dissemination, detected at diagnosis (stage IV) or later as recurrent disease (stage II-III). Results: Loss of 1p36.11-21 was associated with tumour dissemination in microsatellite stable tumours of stage II-IV (odds ratio = 5.5). It was enriched to a similar extent in tumours with distant recurrence within stage II and stage III subgroups, and may therefore be used as a prognostic marker at diagnosis. Loss of 1p36.11-21 relative to average copy number of the genome showed similar prognostic value compared to absolute loss of copies. Therefore, the use of relative loss as a prognostic marker would benefit more patients by applying also to hyperploid cancer genomes. The association with tumour dissemination was supported by independent data from the The Cancer Genome Atlas. Conclusion: Deletions on 1p36 may be used to guide adjuvant treatment decisions in microsatellite stable colon cancer of stages II and III.

  • 118. Mbulawa, Zizipho Z. A.
    et al.
    Johnson, Leigh F.
    Marais, Dianne J.
    Gustavsson, Inger
    Moodley, Jennifer R.
    Coetzee, David
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Williamson, Anna-Lise
    Increased alpha-9 human papillomavirus species viral load in human immunodeficiency virus positive women2014Ingår i: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 14, s. 51-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Persistent high-risk (HR) human papillomavirus (HPV) infection and increased HR-HPV viral load are associated with the development of cancer. This study investigated the effect of human immunodeficiency virus (HIV) co-infection, HIV viral load and CD4 count on the HR-HPV viral load; and also investigated the predictors of cervical abnormalities. Methods: Participants were 292 HIV-negative and 258 HIV-positive women. HR-HPV viral loads in cervical cells were determined by the real-time polymerase chain reaction. Results: HIV-positive women had a significantly higher viral load for combined alpha-9 HPV species compared to HIV-negative women (median 3.9 copies per cell compared to 0.63 copies per cell, P = 0.022). This was not observed for individual HPV types. HIV-positive women with CD4 counts > 350/mu l had significantly lower viral loads for alpha-7 HPV species (median 0.12 copies per cell) than HIV-positive women with CD4 = 350/mu l (median 1.52 copies per cell, P = 0.008), but low CD4 count was not significantly associated with increased viral load for other HPV species. High viral loads for alpha-6, alpha-7 and alpha-9 HPV species were significant predictors of abnormal cytology in women. Conclusion: HIV co-infection significantly increased the combined alpha-9 HPV viral load in women but not viral loads for individual HPV types. High HR-HPV viral load was associated with cervical abnormal cytology.

  • 119. McQuillan, Ruth
    et al.
    Eklund, Niina
    Pirastu, Nicola
    Kuningas, Maris
    McEvoy, Brian P
    Esko, Tõnu
    Corre, Tanguy
    Davies, Gail
    Kaakinen, Marika
    Lyytikäinen, Leo-Pekka
    Kristiansson, Kati
    Havulinna, Aki S
    Gögele, Martin
    Vitart, Veronique
    Tenesa, Albert
    Aulchenko, Yurii
    Hayward, Caroline
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Boban, Mladen
    Ulivi, Sheila
    Robino, Antonietta
    Boraska, Vesna
    Igl, Wilmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wild, Sarah H
    Zgaga, Lina
    Amin, Najaf
    Theodoratou, Evropi
    Polašek, Ozren
    Girotto, Giorgia
    Lopez, Lorna M
    Sala, Cinzia
    Lahti, Jari
    Laatikainen, Tiina
    Prokopenko, Inga
    Kals, Mart
    Viikari, Jorma
    Yang, Jian
    Pouta, Anneli
    Estrada, Karol
    Hofman, Albert
    Freimer, Nelson
    Martin, Nicholas G
    Kähönen, Mika
    Milani, Lili
    Heliövaara, Markku
    Vartiainen, Erkki
    Räikkönen, Katri
    Masciullo, Corrado
    Starr, John M
    Hicks, Andrew A
    Esposito, Laura
    Kolčić, Ivana
    Farrington, Susan M
    Oostra, Ben
    Zemunik, Tatijana
    Campbell, Harry
    Kirin, Mirna
    Pehlic, Marina
    Faletra, Flavio
    Porteous, David
    Pistis, Giorgio
    Widén, Elisabeth
    Salomaa, Veikko
    Koskinen, Seppo
    Fischer, Krista
    Lehtimäki, Terho
    Heath, Andrew
    McCarthy, Mark I
    Rivadeneira, Fernando
    Montgomery, Grant W
    Tiemeier, Henning
    Hartikainen, Anna-Liisa
    Madden, Pamela A F
    d'Adamo, Pio
    Hastie, Nicholas D
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wright, Alan F
    van Duijn, Cornelia M
    Dunlop, Malcolm
    Rudan, Igor
    Gasparini, Paolo
    Pramstaller, Peter P
    Deary, Ian J
    Toniolo, Daniela
    Eriksson, Johan G
    Jula, Antti
    Raitakari, Olli T
    Metspalu, Andres
    Perola, Markus
    Järvelin, Marjo-Riitta
    Uitterlinden, André
    Visscher, Peter M
    Wilson, James F
    Evidence of Inbreeding Depression on Human Height2012Ingår i: PLOS Genetics, ISSN 1553-7404, Vol. 8, nr 7, s. e1002655-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

  • 120.
    Mohammad, Faizaan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pandey, Gaurav Kumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mondal, Tanmoy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Redrup, Lisa
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kanduri, Chandrasekhar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing2012Ingår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, nr 15, s. 2792-2803Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Establishment of silencing by noncoding RNAs (ncRNAs) via targeting of chromatin remodelers is relatively well investigated; however, their role in the maintenance of silencing is poorly understood. Here, we explored the functional role of the long ncRNA Kcnq1ot1 in the maintenance of transcriptional gene silencing in the one mega-base Kcnq1 imprinted domain in a transgenic mouse model. By conditionally deleting the Kcnq1ot1 ncRNA at different stages of mouse development, we suggest that Kcnq1ot1 ncRNA is required for the maintenance of the silencing of ubiquitously imprinted genes (UIGs) at all developmental stages. In addition, Kcnq1ot1 ncRNA is also involved in guiding and maintaining the CpG methylation at somatic differentially methylated regions flanking the UIGs, which is a hitherto unknown role for a long ncRNA. On the other hand, silencing of some of the placental-specific imprinted genes (PIGs) is maintained independently of Kcnq1ot1 ncRNA. Interestingly, the non-imprinted genes (NIGs) that escape RNA-mediated silencing are enriched with enhancer-specific modifications. Taken together, this study illustrates the gene-specific maintenance mechanisms operational at the Kcnq1 locus for tissue-specific transcriptional gene silencing and activation.

  • 121.
    Mondal, Tanmoy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Epigenetic Regulation by Noncoding RNA2011Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    High throughput transcriptomic analyses have realized us with the fact that eukaryotic genome encodes thousands of noncoding RNAs (ncRNAs) with unknown function. In my thesis, I sought to address epigenetic regulation of transcription by ncRNA using the Kcnq1 imprinted cluster as a model system. Genomic imprinting is an epigenetic phenomenon whereby one of the parental alleles is silenced by epigenetic mechanism in a parent of origin-specific manner. A long ncRNA Kcnq1ot1 regulates imprinting of nearly 8 protein coding genes in the Kcnq1 imprinted cluster. Expression of Kcnq1ot1 is restricted to the paternal chromosome while that of protein-coding genes to the maternal chromosome.

    Kcnq1ot1 is a 91kb long, moderately stable, nuclear localized and RNAPII encoded transcript. We demonstrated that Kcnq1ot1 RNA itself mediates lineage specific silencing on the paternal chromosome by interacting with chromatin and recruiting the repressive chromatin modifiers to the imprinted gene promoters. Previously we identified an 890bp silencing domain (SD) at the 5´end of the Kcnq1ot1 RNA which is responsible for gene silencing. Targeted deletion of the 890SD in mouse resulted in specific loss of silencing of ubiquitously imprinted genes. We have further shown that Kcnq1ot1 interacts with Dnmt1 and recruit Dnmt1 at the somatic DMRs flanking some of the ubiquitously imprinted genes. We next addressed the stability of the Kcnq1ot1 mediated epigenetic silencing using transgenic mouse where we have conditionally deleted the Kcnq1ot1 RNA at different developmental stages and we found that Kcnq1ot1 RNA is required to maintain the silencing of the ubiquitously imprinted genes. In addition, DNA methylation, which controls imprinting of the ubiquitous genes require Kcnq1ot1 for its maintenance.

    To characterize the ncRNAs that mediate gene regulation through chromatin interaction we have isolated chromatin associated RNAs (CARs) from sucrose gradient fractioned chromatin. High-throughput sequencing of the CARs resulted in the identification of the 141 intronic and 74 intergenic regions harboring CARs. We characterized one of the intergenic CARs which regulate the transcription of the two neighboring genes by modulating the chromatin marks.

    In summary current thesis has uncovered unprecedented role of ncRNAs in gene expression via chromatin level regulation.

    Delarbeten
    1. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation
    Öppna denna publikation i ny flik eller fönster >>Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation
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    2008 (Engelska)Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 32, nr 2, s. 232-46Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Recent investigations have implicated long antisense noncoding RNAs in the epigenetic regulation of chromosomal domains. Here we show that Kcnq1ot1 is an RNA polymerase II-encoded, 91 kb-long, moderately stable nuclear transcript and that its stability is important for bidirectional silencing of genes in the Kcnq1 domain. Kcnq1ot1 interacts with chromatin and with the H3K9- and H3K27-specific histone methyltransferases G9a and the PRC2 complex in a lineage-specific manner. This interaction correlates with the presence of extended regions of chromatin enriched with H3K9me3 and H3K27me3 in the Kcnq1 domain in placenta, whereas fetal liver lacks both chromatin interactions and heterochromatin structures. In addition, the Kcnq1 domain is more often found in contact with the nucleolar compartment in placenta than in liver. Taken together, our data describe a mechanism whereby Kcnq1ot1 establishes lineage-specific transcriptional silencing patterns through recruitment of chromatin remodeling complexes and maintenance of these patterns through subsequent cell divisions occurs via targeting the associated regions to the perinucleolar compartment.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-86979 (URN)10.1016/j.molcel.2008.08.022 (DOI)000260546800012 ()18951091 (PubMedID)
    Tillgänglig från: 2008-12-11 Skapad: 2008-12-11 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1
    Öppna denna publikation i ny flik eller fönster >>Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1
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    2010 (Engelska)Ingår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 137, nr 15, s. 2493-2499Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A long noncoding RNA, Kcnq1ot1, regulates the expression of both ubiquitously and tissue-specific imprinted genes within the Kcnq1 domain. However, the functional sequences of the Kcnq1ot1 RNA that mediate lineage-specific imprinting are unknown. Here, we have generated a knockout mouse with a deletion encompassing an 890-bp silencing domain (Delta890) downstream of the Kcnq1ot1 promoter. Maternal transmission of the Delta890 allele has no effect on imprinting, whereas paternal inheritance of the deletion leads to selective relaxation of the imprinting of ubiquitously imprinted genes to a variable extent in a tissue-specific manner. Interestingly, the deletion affects DNA methylation at somatically acquired differentially methylated regions (DMRs), but does not affect the histone modifications of the ubiquitously imprinted genes. Importantly, we found that Kcnq1ot1 recruits Dnmt1 to somatic DMRs by interacting with Dnmt1, and that this interaction was significantly reduced in the Delta890 mice. Thus, the ubiquitous and placental-specific imprinting of genes within the Kcnq1 domain might be mediated by distinct mechanisms, and Kcnq1ot1 RNA might mediate the silencing of ubiquitously imprinted genes by maintaining allele-specific methylation through its interactions with Dnmt1.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-128879 (URN)10.1242/dev.048181 (DOI)000279828300006 ()20573698 (PubMedID)
    Tillgänglig från: 2010-07-29 Skapad: 2010-07-29 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    3. Maintenance of tissue-specific transcriptional silencing by a long noncoding RNA
    Öppna denna publikation i ny flik eller fönster >>Maintenance of tissue-specific transcriptional silencing by a long noncoding RNA
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-160064 (URN)
    Tillgänglig från: 2011-10-13 Skapad: 2011-10-13 Senast uppdaterad: 2011-11-23
    4. Characterization of the RNA content of chromatin
    Öppna denna publikation i ny flik eller fönster >>Characterization of the RNA content of chromatin
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    2010 (Engelska)Ingår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 20, nr 7, s. 899-907Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Noncoding RNA (ncRNA) constitutes a significant portion of the mammalian transcriptome. Emerging evidence suggests that it regulates gene expression in cis or trans by modulating the chromatin structure. To uncover the functional role of ncRNA in chromatin organization, we deep sequenced chromatin-associated RNAs (CARs) from human fibroblast (HF) cells. This resulted in the identification of 141 intronic regions and 74 intergenic regions harboring CARs. The intronic and intergenic CARs show significant conservation across 44 species of placental mammals. Functional characterization of one of the intergenic CARs, Intergenic10, revealed that it regulates gene expression of neighboring genes through modulating the chromatin structure in cis. Our data suggest that ncRNA is an integral component of chromatin and that it may regulate various biological functions through fine-tuning of the chromatin architecture.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-136028 (URN)10.1101/gr.103473.109 (DOI)000279404700004 ()
    Tillgänglig från: 2010-12-10 Skapad: 2010-12-09 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
  • 122.
    Nordquist, Niklas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Luthman, Holger
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Eriksson, Ulf J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Linkage study of embryopathy-Polygenic inheritance of diabetes-induced skeletal malformations in the rat2012Ingår i: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 33, nr 3, s. 297-307Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We developed an inbred rat model of diabetic embryopathy, in which the offspring displays skeletal malformations (agnathia or micrognathia) when the mother is diabetic, and no malformations when she is not diabetic. Our aim was to find genes controlling the embryonic maldevelopment in a diabetic environment.

    We contrasted the fetal outcome in inbred Sprague-Dawley L rats (20% skeletal malformations in diabetic pregnancy) with that of inbred Wistar Furth rats (denoted W, no skeletal malformations in diabetic pregnancy). We used offspring from the backcross F-1 x L to probe for the genetic basis for malformation of the mandible in diabetic pregnancy. A set of 186 fetuses (93 affected, 93 unaffected) was subjected to a whole genome scan with 160 micro satellites. Analysis of genotype distribution indicated 7 loci on chromosome 4, 10 (3 loci), 14, 18, and 19 in the teratogenic process (and 14 other loci on 12 chromosomes with less strong association to the malformations), several of which contained genes implicated in other experimental studies of diabetic embryopathy. These candidate genes will be scrutinized in further experimentation.

    We conclude that the genetic involvement in rodent diabetic embryopathy is polygenic and predisposing for congenital malformations.

  • 123.
    Nyström, Niklas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Berg, Tove
    Lundin, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Skog, Oskar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Hansson, Inga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Frisk, Gun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Juko-Pecirep, Ivana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Nilsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Finkel, Yigael
    Fuxe, Jonas
    Wanders, Alkwin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Human enterovirus species B in ileocecal Crohn's disease2013Ingår i: Clinical and Translational Gastroenterology, ISSN 2155-384X, E-ISSN 2155-384X, Vol. 4, artikel-id e38Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES:

    Advanced ileocecal Crohn's disease (ICD) is characterized by strictures, inflammation in the enteric nervous system (myenteric plexitis), and a high frequency of NOD2 mutations. Recent findings implicate a role of NOD2 and another CD susceptibility gene, ATG16L1, in the host response against single-stranded RNA (ssRNA) viruses. However, the role of viruses in CD is unknown. We hypothesized that human enterovirus species B (HEV-B), which are ssRNA viruses with dual tropism both for the intestinal epithelium and the nervous system, could play a role in ICD.

    METHODS:

    We used immunohistochemistry and in situ hybridization to study the general presence of HEV-B and the presence of the two HEV-B subspecies, Coxsackie B virus (CBV) and Echovirus, in ileocecal resections from 9 children with advanced, stricturing ICD and 6 patients with volvulus, and in intestinal biopsies from 15 CD patients at the time of diagnosis.

    RESULTS:

    All patients with ICD had disease-associated polymorphisms in NOD2 or ATG16L1. Positive staining for HEV-B was detected both in the mucosa and in myenteric nerve ganglia in all ICD patients, but in none of the volvulus patients. Expression of the cellular receptor for CBV, CAR, was detected in nerve cell ganglia.

    CONCLUSIONS:

    The common presence of HEV-B in the mucosa and enteric nervous system of ICD patients in this small cohort is a novel finding that warrants further investigation to analyze whether HEV-B has a role in disease onset or progress. The presence of CAR in myenteric nerve cell ganglia provides a possible route of entry for CBV into the enteric nervous system.

  • 124. Ostensson, Ellinor
    et al.
    Hellstrom, Ann-Cathrin
    Hellman, Kristina
    Gustavsson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Wilander, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Zethraeus, Niklas
    Andersson, Sonia
    Projected cost-effectiveness of repeat high-risk human papillomavirus testing using self-collected vaginal samples in the Swedish cervical cancer screening program2013Ingår i: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 92, nr 7, s. 830-840Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Human papillomavirus (HPV) testing is not currently used in primary cervical cancer screening in Sweden, and corresponding cost-effectiveness is unclear. Objective From a societal perspective, to evaluate the cost-effectiveness of high-risk (HR)-HPV testing using self-collected vaginal samples. Design A cost-effectiveness analysis. Setting The Swedish organized cervical cancer screening program. Methods We constructed a model to simulate the natural history of cervical cancer using Swedish data on cervical cancer risk. For the base-case analysis we evaluated two screening strategies with different screening intervals: (i) cytology screening throughout the woman's lifetime (i.e. conventional cytology strategy) and (ii) conventional cytology screening until age 35years, followed by HR-HPV testing using self-collected vaginal samples in women aged 35years (i.e. combination strategy). Sensitivity analyses were performed, varying model parameters over a significant range of values to identify cost-effective screening strategies. Main outcome measures Average lifetime cost, discounted and undiscounted life-years gained, reduction in cervical cancer risk, incremental cost-effectiveness ratios with and without the cost of added life-years. Results Depending on screening interval, the incremental cost-effectiveness ratios for the combination strategy ranged from Euro43000 to Euro180000 per life-years gained without the cost of added life-years, and from Euro74000 to Euro206000 with costs of added life-years included. Conclusion The combination strategy with a 5-year screening interval is potentially cost-effective compared with no screening, and with current screening practice when using a threshold value of Euro80000 per life-years gained.

  • 125.
    Ostrowska Dahlgren, Bozena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Lindström, Anne-Cristine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Bjerke, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Blomström-Lundqvist, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    A novel variant in plakophilin-2 gene detected in a family with arrhythmogenic right ventricular cardiomyopathy2012Ingår i: Journal of interventional cardiac electrophysiology (Print), ISSN 1383-875X, E-ISSN 1572-8595, Vol. 34, nr 1, s. 11-18Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty replacement of muscular fibers predominantly in the right ventricle and with ventricular arrhythmias as the main clinical manifestation. Mutations in several components of the desmosome genes have been identified and mutations of the plakophilin-2 (PKP-2) gene are a common cause of ARVC. The aim of this study is to investigate the correlation between genotype and phenotype in a family with a novel PKP-2 variant.

    METHODS AND RESULTS: This study describes the clinical findings and genetic analysis in a family with ARVC. A part of the family has been followed clinically long term for up to 27 years. Two not previously reported PKP-2 variants (L506P and T526A) have been identified in this family. Even though all members of this family share the novel variant L506P, the clinical features, i.e., their phenotypes are different. The L506P variant is located in exon 7 and affects a highly conserved residue. The same amino acid, leucine, is present in all species evaluated, indicating a functional importance and the variant is predicted to be damaging. The novel L506P variant in the PKP-2 gene is thus a possible pathogenic alteration in the described family with ARVC. In contrast, the T526A variant is weakly conserved and predicted to be tolerated.

    CONCLUSION: While many of the reported ARVC mutations are truncating mutations, the possibly damaging variant found in this family, is a missense alteration affecting a highly conserved residue 506 located in exon 7.

  • 126. Pang, Andy Wing Chun
    et al.
    Migita, Ohsuke
    MacDonald, Jeffrey R.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Scherer, Stephen W.
    Mechanisms of Formation of Structural Variation in a Fully Sequenced Human Genome2013Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, nr 2, s. 345-354Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Even with significant advances in technology, few studies of structural variation have yet resolved to the level of the precise nucleotide junction. We examined the sequence of 408,532 gains, 383,804 losses, and 166 inversions from the first sequenced personal genome, to quantify the relative proportion of mutational mechanisms. Among small variants (<1kb), we observed that 72.6% of them were associated with nonhomologous processes and 24.9% with microsatellites events. Medium-size variants (<10kb) were commonly related to minisatellites (25.8%) and retrotransposons (24%), whereas 46.2% of large variants (>10kb) were associated with nonallelic homologous recombination. We genotyped eight new breakpoint-resolved inversions at (3q26.1, Xp11.22, 7q11.22, 16q23.1, 4q22.1, 1q31.3, 6q27, and 16q24.1) in human populations to elucidate the structure of these presumed benign variants. Three of these inversions (3q26.1, 7q11.22, and 16q23.1) were accompanied by unexpected complex rearrangements. In particular, the 16q23.1 inversion and an accompanying deletion would create conjoined chymotrypsinogen genes (CTRB1 and CTRB2), disrupt their gene structure, and exhibit differentiated allelic frequencies among populations. Also, two loci (Xp11.3 and 6q27) of potential reference assembly orientation errors were found. This study provides a thorough account of formation mechanisms for structural variants, and reveals a glimpse of the dynamic structure of inversions.

  • 127. Parsa, Afshin
    et al.
    Fuchsberger, Christian
    Koettgen, Anna
    O'Seaghdha, Conall M.
    Pattaro, Cristian
    de Andrade, Mariza
    Chasman, Daniel I.
    Teumer, Alexander
    Endlich, Karlhans
    Olden, Matthias
    Chen, Ming-Huei
    Tin, Adrienne
    Kim, Young J.
    Taliun, Daniel
    Li, Man
    Feitosa, Mary
    Gorski, Mathias
    Yang, Qiong
    Hundertmark, Claudia
    Foster, Meredith C.
    Glazer, Nicole
    Isaacs, Aaron
    Rao, Madhumathi
    Smith, Albert V.
    O'Connell, Jeffrey R.
    Struchalin, Maksim
    Tanaka, Toshiko
    Li, Guo
    Hwang, Shih-Jen
    Atkinson, Elizabeth J.
    Lohman, Kurt
    Cornelis, Marilyn C.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Toenjes, Anke
    Dehghan, Abbas
    Couraki, Vincent
    Holliday, Elizabeth G.
    Sorice, Rossella
    Kutalik, Zoltan
    Lehtimaeki, Terho
    Esko, Tonu
    Deshmukh, Harshal
    Ulivi, Sheila
    Chu, Audrey Y.
    Murgia, Federico
    Trompet, Stella
    Imboden, Medea
    Kollerits, Barbara
    Pistis, Giorgio
    Harris, Tamara B.
    Launer, Lenore J.
    Aspelund, Thor
    Eiriksdottir, Gudny
    Mitchell, Braxton D.
    Boerwinkle, Eric
    Schmidt, Helena
    Hofer, Edith
    Hu, Frank
    Demirkan, Ayse
    Oostra, Ben A.
    Turner, Stephen T.
    Ding, Jingzhong
    Andrews, Jeanette S.
    Freedman, Barry I.
    Giulianini, Franco
    Koenig, Wolfgang
    Illig, Thomas
    Doering, Angela
    Wichmann, H. -Erich
    Zgaga, Lina
    Zemunik, Tatijana
    Boban, Mladen
    Minelli, Cosetta
    Wheeler, Heather E.
    Igl, Wilmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Zaboli, Ghazal
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Wild, Sarah H.
    Wright, Alan F.
    Campbell, Harry
    Ellinghaus, David
    Noethlings, Ute
    Jacobs, Gunnar
    Biffar, Reiner
    Ernst, Florian
    Homuth, Georg
    Kroemer, Heyo K.
    Nauck, Matthias
    Stracke, Sylvia
    Voelker, Uwe
    Voelzke, Henry
    Kovacs, Peter
    Stumvoll, Michael
    Maegi, Reedik
    Hofman, Albert
    Uitterlinden, Andre G.
    Rivadeneira, Fernando
    Aulchenko, Yurii S.
    Polasek, Ozren
    Hastie, Nick
    Vitart, Veronique
    Helmer, Catherine
    Wang, Jie Jin
    Stengel, Benedicte
    Ruggiero, Daniela
    Bergmann, Sven
    Kaehoenen, Mika
    Viikari, Jorma
    Nikopensius, Tiit
    Province, Michael
    Colhoun, Helen
    Doney, Alex
    Robino, Antonietta
    Kraemer, Bernhard K.
    Portas, Laura
    Ford, Ian
    Buckley, Brendan M.
    Adam, Martin
    Thun, Gian-Andri
    Paulweber, Bernhard
    Haun, Margot
    Sala, Cinzia
    Mitchell, Paul
    Ciullo, Marina
    Vollenweider, Peter
    Raitakari, Olli
    Metspalu, Andres
    Palmer, Colin
    Gasparini, Paolo
    Pirastu, Mario
    Jukema, J. Wouter
    Probst-Hensch, Nicole M.
    Kronenberg, Florian
    Toniolo, Daniela
    Gudnason, Vilmundur
    Shuldiner, Alan R.
    Coresh, Josef
    Schmidt, Reinhold
    Ferrucci, Luigi
    Van Duijn, Cornelia M.
    Borecki, Ingrid
    Kardia, Sharon L. R.
    Liu, Yongmei
    Curhan, Gary C.
    Rudan, Igor
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Wilson, James F.
    Franke, Andre
    Pramstaller, Peter P.
    Rettig, Rainer
    Prokopenko, Inga
    Witteman, Jacqueline
    Hayward, Caroline
    Ridker, Paul M.
    Bochud, Murielle
    Heid, Iris M.
    Siscovick, David S.
    Fox, Caroline S.
    Kao, W. Linda
    Boeger, Carsten A.
    Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function2013Ingår i: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 24, nr 12, s. 2105-2117Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

  • 128. Pattaro, Cristian
    et al.
    Koettgen, Anna
    Teumer, Alexander
    Garnaas, Maija
    Boeger, Carsten A.
    Fuchsberger, Christian
    Olden, Matthias
    Chen, Ming-Huei
    Tin, Adrienne
    Taliun, Daniel
    Li, Man
    Gao, Xiaoyi
    Gorski, Mathias
    Yang, Qiong
    Hundertmark, Claudia
    Foster, Meredith C.
    O'Seaghdha, Conall M.
    Glazer, Nicole
    Isaacs, Aaron
    Liu, Ching-Ti
    Smith, Albert V.
    O'Connell, Jeffrey R.
    Struchalin, Maksim
    Tanaka, Toshiko
    Li, Guo
    Johnson, Andrew D.
    Gierman, Hinco J.
    Feitosa, Mary
    Hwang, Shih-Jen
    Atkinson, Elizabeth J.
    Lohman, Kurt
    Cornelis, Marilyn C.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Toenjes, Anke
    Dehghan, Abbas
    Chouraki, Vincent
    Holliday, Elizabeth G.
    Sorice, Rossella
    Kutalik, Zoltan
    Lehtimaeki, Terho
    Esko, Tonu
    Deshmukh, Harshal
    Ulivi, Sheila
    Chu, Audrey Y.
    Murgia, Federico
    Trompet, Stella
    Imboden, Medea
    Kollerits, Barbara
    Pistis, Giorgio
    Harris, Tamara B.
    Launer, Lenore J.
    Aspelund, Thor
    Eiriksdottir, Gudny
    Mitchell, Braxton D.
    Boerwinkle, Eric
    Schmidt, Helena
    Cavalieri, Margherita
    Rao, Madhumathi
    Hu, Frank B.
    Demirkan, Ayse
    Oostra, Ben A.
    de Andrade, Mariza
    Turner, Stephen T.
    Ding, Jingzhong
    Andrews, Jeanette S.
    Freedman, Barry I.
    Koenig, Wolfgang
    Illig, Thomas
    Doering, Angela
    Wichmann, H. -Erich
    Kolcic, Ivana
    Zemunik, Tatijana
    Boban, Mladen
    Minelli, Cosetta
    Wheeler, Heather E.
    Igl, Wilmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Zaboli, Ghazal
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Wild, Sarah H.
    Wright, Alan F.
    Campbell, Harry
    Ellinghaus, David
    Nothlings, Ute
    Jacobs, Gunnar
    Biffar, Reiner
    Endlich, Karlhans
    Ernst, Florian
    Homuth, Georg
    Kroemer, Heyo K.
    Nauck, Matthias
    Stracke, Sylvia
    Voelker, Uwe
    Voelzke, Henry
    Kovacs, Peter
    Stumvoll, Michael
    Magi, Reedik
    Hofman, Albert
    Uitterlinden, Andre G.
    Rivadeneira, Fernando
    Aulchenko, Yurii S.
    Polasek, Ozren
    Hastie, Nick
    Vitart, Veronique
    Helmer, Catherine
    Wang, Jie Jin
    Ruggiero, Daniela
    Bergmann, Sven
    Kaehoenen, Mika
    Viikari, Jorma
    Nikopensius, Tiit
    Province, Michael
    Ketkar, Shamika
    Colhoun, Helen
    Doney, Alex
    Robino, Antonietta
    Giulianini, Franco
    Kraemer, Bernhard K.
    Portas, Laura
    Ford, Ian
    Buckley, Brendan M.
    Adam, Martin
    Thun, Gian-Andri
    Paulweber, Bernhard
    Haun, Margot
    Sala, Cinzia
    Metzger, Marie
    Mitchell, Paul
    Ciullo, Marina
    Kim, Stuart K.
    Vollenweider, Peter
    Raitakari, Olli
    Metspalu, Andres
    Palmer, Colin
    Gasparini, Paolo
    Pirastu, Mario
    Jukema, J. Wouter
    Probst-Hensch, Nicole M.
    Kronenberg, Florian
    Toniolo, Daniela
    Gudnason, Vilmundur
    Shuldiner, Alan R.
    Coresh, Josef
    Schmidt, Reinhold
    Ferrucci, Luigi
    Siscovick, David S.
    van Duijn, Cornelia M.
    Borecki, Ingrid
    Kardia, Sharon L. R.
    Liu, Yongmei
    Curhan, Gary C.
    Rudan, Igor
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Wilson, James F.
    Franke, Andre
    Pramstaller, Peter P.
    Rettig, Rainer
    Prokopenko, Inga
    Witteman, Jacqueline C. M.
    Hayward, Caroline
    Ridker, Paul
    Parsa, Afshin
    Bochud, Murielle
    Heid, Iris M.
    Goessling, Wolfram
    Chasman, Daniel I.
    Kao, W. H. Linda
    Fox, Caroline S.
    Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function2012Ingår i: PLoS Genetics, ISSN 1553-7390, Vol. 8, nr 3, s. e1002584-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genomewide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

  • 129. Pena, Cristina
    et al.
    Virtudes Cespedes, Maria
    Lindh, Maja Bradic
    Kiflemariam, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Mezheyeuski, Artur
    Edqvist, Per-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Hagglof, Christina
    Birgisson, Helgi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Bojmar, Linda
    Jirstrom, Karin
    Sandstrom, Per
    Olsson, Eleonor
    Veerla, Srinivas
    Gallardo, Alberto
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Chang, Andy C. -M.
    Reddel, Roger R.
    Mangues, Ramon
    Augsten, Martin
    Ostman, Arne
    STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer2013Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, nr 4, s. 1287-1297Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis.

  • 130. Phongsavan, Keokedthong
    et al.
    Gustavsson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Marions, Lena
    Phengsavanh, Alongkone
    Wahlstrom, Rolf
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Detection of Human Papillomavirus Among Women in Laos Feasibility of Using Filter Paper Card and Prevalence of High-Risk Types2012Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 22, nr 8, s. 1398-1406Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Persistent infection with high-risk (HR) human papillomavirus (HPV) is a well-recognized cause of cervical cancer, but little is known about the situation in Laos. The aims of the study were to determine the prevalence of HR-HPV among Lao women and to evaluate the use of a filter paper card (FTA Elute Micro Card) for collection of cervical cells in the humid tropical climate. Methods: This is a cross-sectional study including 1922 women from 3 provinces in Laos. During a gynecological examination, cervical cells were collected and applied to the FTA card followed by HPV typing using a real-time polymerase chain reaction (PCR)-based assay. Results: Overall, 213 of the 1922 women were positive for HR-HPV (11%). The most common type was the group HPV33/52/58 (3%), followed by the single type 16 (2%) and the group 18/45 (1%), respectively. Only 11 cards (0.6%) did not contain a sufficient amount of genomic DNA for polymerase chain reaction-based analysis. Conclusions: The prevalence of HR-HPV infections in Laos is similar to other Asian countries, and 40% of the women with an HR-HPV infection will be target of the present HPV vaccines. The FTA card is suitable for collection of cervical cells for HR-HPV typing in tropical conditions. This information is important for planning and establishing primary and secondary prevention of cervical cancer in Laos.

  • 131. Pichler, Irene
    et al.
    Schwienbacher, Christine
    Zanon, Alessandra
    Fuchsberger, Christian
    Serafin, Alice
    Facheris, Maurizio F.
    Marroni, Fabio
    Pattaro, Cristian
    Shen, Yiping
    Tellgren-Roth, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gusella, James F.
    Hicks, Andrew A.
    Pramstaller, Peter P.
    Fine-Mapping of Restless Legs Locus 4 (RLS4) Identifies a Haplotype over the SPATS2L and KCTD18 Genes2013Ingår i: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 49, nr 3, s. 600-605Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Restless legs syndrome (RLS) is a sleep-related movement disorder that affects up to 15 % of the population. Linkage studies have identified several genomic loci in single families (12q, 14q, 9p, 2q, 20p and 16p, respectively). However, confirmation of these loci has not always been achieved, and causative mutations have not yet been identified. The locus on chromosome 2q33 (RLS4) was identified in two South Tyrolean families who shared a haplotype of microsatellite marker alleles across an 8.2-cM region. To pinpoint the gene localisation within RLS4, additional families from the same geographic region were evaluated, and linkage was replicated in one family. Within the candidate region, we initially found a haplotype of 23 single nucleotide polymorphism markers spanning 131.6 Kb shared by all affected members of the three linked families. Using a next generation sequencing approach, we further restricted the shared candidate region to 46.9 Kb over the potassium channel-related gene KCTD18 and exons 10-13 of SPATS2L.

  • 132. Pugliese, Alberto
    et al.
    Kawasaki, Eiji
    Zeller, Markus
    Yu, Liping
    Babu, Sunanda
    Solimena, Michele
    Moraes, Carlos T.
    Pietropaolo, Massimo
    Friday, Robert P.
    Trucco, Massimo
    Ricordi, Camillo
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Noble, Janelle A.
    Erlich, Henry A.
    Eisenbarth, George S.
    Sequence analysis of the diabetes-protective human leukocyte antigen-DQB1*0602 allele in unaffected, islet cell antibody-positive first degree relatives and in rare patients with type 1 diabetes1999Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 84, nr 5, s. 1722-1728Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The human leukocyte antigen (HLA)-DQA1*0102/DQB1*0602/DRB1*1501 (DR2) haplotype confers strong protection from type 1 diabetes. Growing evidence suggests that such protection may be mostly encoded by the DQB1*0602 allele, and we reported that even first degree relatives with islet cell antibodies (ICA) have an extremely low diabetes risk if they carry DQB1*0602. Recently, novel variants of the DQB1*0602 and *0603 alleles were reported in four patients with type 1 diabetes originally typed as DQB1*0602 with conventional techniques. One inference from this observation is that DQB1*0602 may confer absolute protection and may never occur in type 1 diabetes. By this hypothesis, all patients typed as DQB1*0602 positive with conventional techniques should carry one of the above diabetes-permissive variants instead of the protective DQB1*0602. Such variants could also occur in ICA/DQB1*0602-positive relatives, with the implication that their diabetes risk could be significantly higher than previously estimated. We therefore sequenced the DQB1*0602 and DQA1*0102 alleles in all ICA/DQB1*0602-positive relatives (n = 8) previously described and in six rare patients with type 1 diabetes and DQB1*0602. We found that all relatives and patients carry the known DQB1*0602 and DQA1*0102 sequences, and none of them has the mtDNA A3243G mutation associated with late-onset diabetes in ICA-positive individuals. These findings suggest that diabetes-permissive DQB1*0602/3 variants may be very rare. Thus, although the protective effect associated with DQB1*0602 is extremely powerful, it is not absolute. Nonetheless, the development of diabetes in individuals with DQB1*0602 remains extremely unlikely, even in the presence of ICA, as confirmed by our further evaluation of ICA/DQB1*0602-positive relatives, none of whom has yet developed diabetes.

  • 133.
    Radomska, Katarzyna J.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Halvardson, Jonatan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Reinius, Björn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Carlström, Eva Lindholm
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Emilsson, Lina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jazin, Elena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    RNA-binding protein QKI regulates Glial fibrillary acidic protein expression in human astrocytes2013Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 22, nr 7, s. 1373-1382Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Linkage, association and expression studies previously pointed to the human QKI, KH domain containing, RNA-binding (QKI) as a candidate gene for schizophrenia. Functional studies of the mouse orthologue Qk focused mainly on its role in oligodendrocyte development and myelination, while its function in astroglia remained unexplored. Here, we show that QKI is highly expressed in human primary astrocytes and that its splice forms encode proteins targeting different subcellular localizations. Uncovering the role of QKI in astrocytes is of interest in light of growing evidence implicating astrocyte dysfunction in the pathogenesis of several disorders of the central nervous system. We selectively silenced QKI splice variants in human primary astrocytes and used RNA sequencing to identify differential expression and splice variant composition at the genome-wide level. We found that an mRNA expression of Glial fibrillary acidic protein (GFAP), encoding a major component of astrocyte intermediate filaments, was down-regulated after QKI7 splice variant silencing. Moreover, we identified a potential QKI-binding site within the 3 untranslated region of human GFAP. This sequence was not conserved between mice and humans, raising the possibility that GFAP is a target for QKI in humans but not rodents. Haloperidol treatment of primary astrocytes resulted in coordinated increases in QKI7 and GFAP expression. Taken together, our results provide the first link between QKI and GFAP, two genes with alterations previously observed independently in schizophrenic patients. Our findings for QKI, together with its well-known role in myelination, suggest that QKI is a hub regulator of glia function in humans.

  • 134. Randall, Joshua C.
    et al.
    Winkler, Thomas W.
    Kutalik, Zoltan
    Berndt, Sonja I.
    Jackson, Anne U.
    Monda, Keri L.
    Kilpelaeinen, Tuomas O.
    Esko, Tonu
    Maegi, Reedik
    Li, Shengxu
    Workalemahu, Tsegaselassie
    Feitosa, Mary F.
    Croteau-Chonka, Damien C.
    Day, Felix R.
    Fall, Tove
    Ferreira, Teresa
    Gustafsson, Stefan
    Locke, Adam E.
    Mathieson, Iain
    Scherag, Andre
    Vedantam, Sailaja
    Wood, Andrew R.
    Liang, Liming
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Dermitzakis, Emmanouil T.
    Dimas, Antigone S.
    Karpe, Fredrik
    Min, Josine L.
    Nicholson, George
    Clegg, Deborah J.
    Person, Thomas
    Krohn, Jon P.
    Bauer, Sabrina
    Buechler, Christa
    Eisinger, Kristina
    Bonnefond, Amelie
    Froguel, Philippe
    Hottenga, Jouke-Jan
    Prokopenko, Inga
    Waite, Lindsay L.
    Harris, Tamara B.
    Smith, Albert Vernon
    Shuldiner, Alan R.
    McArdle, Wendy L.
    Caulfield, Mark J.
    Munroe, Patricia B.
    Gronberg, Henrik
    Chen, Yii-Der Ida
    Li, Guo
    Beckmann, Jacques S.
    Johnson, Toby
    Thorsteinsdottir, Unnur
    Teder-Laving, Maris
    Khaw, Kay-Tee
    Wareham, Nicholas J.
    Zhao, Jing Hua
    Amin, Najaf
    Oostra, Ben A.
    Kraja, Aldi T.
    Province, Michael A.
    Cupples, L. Adrienne
    Heard-Costa, Nancy L.
    Kaprio, Jaakko
    Ripatti, Samuli
    Surakka, Ida
    Collins, Francis S.
    Saramies, Jouko
    Tuomilehto, Jaakko
    Jula, Antti
    Salomaa, Veikko
    Erdmann, Jeanette
    Hengstenberg, Christian
    Loley, Christina
    Schunkert, Heribert
    Lamina, Claudia
    Wichmann, H. Erich
    Albrecht, Eva
    Gieger, Christian
    Hicks, Andrew A.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Pramstaller, Peter P.
    Kathiresan, Sekar
    Speliotes, Elizabeth K.
    Penninx, Brenda
    Hartikainen, Anna-Liisa
    Jarvelin, Marjo-Riitta
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Boomsma, Dorret I.
    Campbell, Harry
    Wilson, James F.
    Chanock, Stephen J.
    Farrall, Martin
    Goel, Anuj
    Medina-Gomez, Carolina
    Rivadeneira, Fernando
    Estrada, Karol
    Uitterlinden, Andre G.
    Hofman, Albert
    Zillikens, M. Carola
    den Heijer, Martin
    Kiemeney, Lambertus A.
    Maschio, Andrea
    Hall, Per
    Tyrer, Jonathan
    Teumer, Alexander
    Voelzke, Henry
    Kovacs, Peter
    Toenjes, Anke
    Mangino, Massimo
    Spector, Tim D.
    Hayward, Caroline
    Rudan, Igor
    Hall, Alistair S.
    Samani, Nilesh J.
    Attwood, Antony Paul
    Sambrook, Jennifer G.
    Hung, Joseph
    Palmer, Lyle J.
    Lokki, Marja-Liisa
    Sinisalo, Juha
    Boucher, Gabrielle
    Huikuri, Heikki
    Lorentzon, Mattias
    Ohlsson, Claes
    Eklund, Niina
    Eriksson, Johan G.
    Barlassina, Cristina
    Rivolta, Carlo
    Nolte, Ilja M.
    Snieder, Harold
    Van der Klauw, Melanie M.
    Van Vliet-Ostaptchouk, Jana V.
    Gejman, Pablo V.
    Shi, Jianxin
    Jacobs, Kevin B.
    Wang, Zhaoming
    Bakker, Stephan J. L.
    Leach, Irene Mateo
    Navis, Gerjan
    van der Harst, Pim
    Martin, Nicholas G.
    Medland, Sarah E.
    Montgomery, Grant W.
    Yang, Jian
    Chasman, Daniel I.
    Ridker, Paul M.
    Rose, Lynda M.
    Lehtimaki, Terho
    Raitakari, Olli
    Absher, Devin
    Iribarren, Carlos
    Basart, Hanneke
    Hovingh, Kees G.
    Hyppoenen, Elina
    Power, Chris
    Anderson, Denise
    Beilby, John P.
    Hui, Jennie
    Jolley, Jennifer
    Sager, Hendrik
    Bornstein, Stefan R.
    Schwarz, Peter E. H.
    Kristiansson, Kati
    Perola, Markus
    Lindstrom, Jaana
    Swift, Amy J.
    Uusitupa, Matti
    Atalay, Mustafa
    Lakka, Timo A.
    Rauramaa, Rainer
    Bolton, Jennifer L.
    Fowkes, Gerry
    Fraser, Ross M.
    Price, Jackie F.
    Fischer, Krista
    KrjutAikov, Kaarel
    Metspalu, Andres
    Mihailov, Evelin
    Langenberg, Claudia
    Luan, Jian'an
    Ong, Ken K.
    Chines, Peter S.
    Keinanen-Kiukaanniemi, Sirkka M.
    Saaristo, Timo E.
    Edkins, Sarah
    Franks, Paul W.
    Hallmans, Goran
    Shungin, Dmitry
    Morris, Andrew David
    Palmer, Colin N. A.
    Erbel, Raimund
    Moebus, Susanne
    Noethen, Markus M.
    Pechlivanis, Sonali
    Hveem, Kristian
    Narisu, Narisu
    Hamsten, Anders
    Humphries, Steve E.
    Strawbridge, Rona J.
    Tremoli, Elena
    Grallert, Harald
    Thorand, Barbara
    Illig, Thomas
    Koenig, Wolfgang
    Mueller-Nurasyid, Martina
    Peters, Annette
    Boehm, Bernhard O.
    Kleber, Marcus E.
    Maerz, Winfried
    Winkelmann, Bernhard R.
    Kuusisto, Johanna
    Laakso, Markku
    Arveiler, Dominique
    Cesana, Giancarlo
    Kuulasmaa, Kari
    Virtamo, Jarmo
    Yarnell, John W. G.
    Kuh, Diana
    Wong, Andrew
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    de Faire, Ulf
    Gigante, Bruna
    Magnusson, Patrik K. E.
    Pedersen, Nancy L.
    Dedoussis, George
    Dimitriou, Maria
    Kolovou, Genovefa
    Kanoni, Stavroula
    Stirrups, Kathleen
    Bonnycastle, Lori L.
    Njolstad, Inger
    Wilsgaard, Tom
    Ganna, Andrea
    Rehnberg, Emil
    Hingorani, Aroon
    Kivimaki, Mika
    Kumari, Meena
    Assimes, Themistocles L.
    Barroso, Ine S.
    Boehnke, Michael
    Borecki, Ingrid B.
    Deloukas, Panos
    Fox, Caroline S.
    Frayling, Timothy
    Groop, Leif C.
    Haritunians, Talin
    Hunter, David
    Ingelsson, Erik
    Kaplan, Robert
    Mohlke, Karen L.
    O'Connell, Jeffrey R.
    Schlessinger, David
    Strachan, David P.
    Stefansson, Kari
    van Duijn, Cornelia M.
    Abecasis, Goncalo R.
    McCarthy, Mark I.
    Hirschhorn, Joel N.
    Qi, Lu
    Loos, Ruth J. F.
    Lindgren, Cecilia M.
    North, Kari E.
    Heid, Iris M.
    Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits2013Ingår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, nr 6, s. e1003500-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5x10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

  • 135.
    Rask-Andersen, Mathias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Sällman Almén, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Jacobsson, Josefin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Moschonis, George
    Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece.
    Manios, Yannis
    Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece.
    Marcus, Claude
    Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Division of Pediatrics, National Childhood Obesity Centre, Stockholm, Sweden.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Ultra-deep targeted re-sequencing of TMEM18 in two cohorts of European children detects new genetic variants associated with obesity2013Ingår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Artikel i tidskrift (Refereegranskat)
  • 136.
    Reinius, Björn
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Johansson, Martin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Radomska, Katarzyna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Morrow, Edward H
    Pandey, Gaurav Kumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Chandrasekhar, Kanduri
    Sandberg, Rickard
    Williams, Robert W
    Jazin, Elena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Abundance of female-biased and paucity of male-biased somatically expressed genes on the mouse X-chromosome2012Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, s. 607-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:

    Empirical evaluations of sexually dimorphic expression of genes on the mammalian X-chromosome are needed to understand the evolutionary forces and the gene-regulatory mechanisms controlling this chromosome. We performed a large-scale sex-bias expression analysis of genes on the X-chromosome in six different somatic tissues from mouse.

    RESULTS:

    Our results show that the mouse X-chromosome is enriched with female-biased genes and depleted of male-biased genes. This suggests that feminisation as well as de-masculinisation of the X-chromosome has occurred in terms of gene expression in non-reproductive tissues. Several mechanisms may be responsible for the control of female-biased expression on chromosome X, and escape from X-inactivation is a main candidate. We confirmed escape in case of Tmem29 using RNA-FISH analysis. In addition, we identified novel female-biased non-coding transcripts located in the same female-biased cluster as the well-known coding X-inactivation escapee Kdm5c, likely transcribed from the transition-region between active and silenced domains. We also found that previously known escapees only partially explained the overrepresentation of female-biased X-genes, particularly for tissue-specific female-biased genes. Therefore, the gene set we have identified contains tissue-specific escapees and/or genes controlled by other sexually skewed regulatory mechanisms. Analysis of gene age showed that evolutionarily old X-genes (>100 myr, preceding the radiation of placental mammals) are more frequently female-biased than younger genes.

    CONCLUSION:

    Altogether, our results have implications for understanding both gene regulation and gene evolution of mammalian X-chromosomes, and suggest that the final result in terms of the X-gene composition (masculinisation versus feminisation) is a compromise between different evolutionary forces acting on reproductive and somatic tissues.

  • 137. Reynolds, R.
    et al.
    Walker, K.
    Varlaro, J.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Clark, E.
    Alavaren, M.
    Erlich, H.
    Detection of sequence variation in the HVII region of the humanmitochondrial genome in 689 individuals using immobilizedsequence-specific oligonucleotide probes2000Ingår i: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 45, nr 6, s. 1210-1231Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have developed a rapid, immobilized probe-based assay for the detection of sequence variation in the hypervariable segment II (HVII) of the mitochondrial DNA (mtDNA) control region. Using a panel of 17 sequence-specific oligonucleotide (SSO) probes immobilized on nylon membrane strips, we typed 689 individuals from four population groups. The genetic diversity value for each population was calculated from the frequency data, and the frequencies of distinct "mitotypes" in each group were determined. We performed DNA sequence analysis of 129 samples to characterize the sequences associated with "blanks" (absence of probe signals) and weak probe signals. Out of 689 samples, we observed five heteroplasmic samples (excluding the variable C-stretch beginning at position 303) using the immobilized SSO probe panel. The SSO probe strips were used for the analysis of shed hairs and bloodstains from several criminal cases in Sweden, one of which is described here. We conclude that this mtDNA typing system is useful for human identification and significantly decreases casework turnaround time.

  • 138.
    Siegbahn, Agneta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap.
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Eriksson, Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Hagström, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Varenhorst, Christoph
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Åkerblom, Axel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Bertilsson, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Barratt, Bryan J.
    Becker, Richard C.
    Himmelmann, Anders
    James, Stefan K.
    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.
    Katus, Hugo A.
    Steg, Philippe G.
    Storey, Robert F.
    Syvanen, Ann-Christine
    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.
    Evaluation of the Effect of Interleukin 18 Associated Genetic Polymorphisms on Risk of Cardiovascular Events in Patients With Acute Coronary Syndrome2013Ingår i: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 128, nr 22Artikel i tidskrift (Övrigt vetenskapligt)
  • 139. Spiegel, Konen
    et al.
    Pines, Ophry
    Ta-Shma, Asaf
    Burak, Efrat
    Shaag, Avraham
    Halvardson, Jonatan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Edvardson, Shimon
    Mahajna, Muhammad
    Zenvirt, Shamir
    Saada, Ann
    Shalev, Stavit
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Elpeleg, Orly
    Infantile Cerebellar-Retinal Degeneration Associated with a Mutation in Mitochondrial Aconitase, ACO22012Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, nr 3, s. 518-523Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Degeneration of the cerebrum, cerebellum, and retina in infancy is part of the clinical spectrum of lysosomal storage disorders, mitochondrial respiratory chain defects, carbohydrate glycosylation defects, and infantile neuroaxonal dystrophy. We studied eight individuals from two unrelated families who presented at 2-6 months of age with truncal hypotonia and athetosis, seizure disorder, and ophthalmologic abnormalities. Their course was characterized by failure to acquire developmental milestones and culminated in profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Despite their debilitating state, the disease was compatible with survival of up to 18 years. Laboratory investigations were normal, but the oxidation of glutamate by muscle mitochondria was slightly reduced. Serial brain MRI displayed progressive, prominent cerebellar atrophy accompanied by thinning of the corpus callosum, dysmyelination, and frontal and temporal cortical atrophy. Homozygosity mapping followed by whole-exome sequencing disclosed a Ser112Arg mutation in ACO2, encoding mitochondrial aconitase, a component of the Krebs cycle. Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded, indicating that this mutation is pathogenic. Thus, a defect in mitochondrial aconitase is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. In the absence of noninvasive biomarkers, determination of the ACO2 sequence or of aconitase activity in lymphoblasts are warranted in similarly affected individuals, based on clinical and neuroradiologic grounds.

  • 140. Spiegel, Ronen
    et al.
    Saada, Ann
    Halvardson, Jonatan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Soiferman, Devorah
    Shaag, Avraham
    Edvardson, Simon
    Horovitz, Yoseph
    Khayat, Morad
    Shalev, Stavit A.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Elpeleg, Orly
    Deleterious mutation in FDX1L gene is associated with a novel mitochondrial muscle myopathy2014Ingår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 22, nr 7, s. 902-906Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Isolated metabolic myopathies encompass a heterogeneous group of disorders, with mitochondrial myopathies being a subgroup, with depleted skeletal muscle energy production manifesting either by recurrent episodes of myoglobinuria or progressive muscle weakness. In this study, we investigated the genetic cause of a patient from a consanguineous family who presented with adolescent onset autosomal recessive mitochondrial myopathy. Analysis of enzyme activities of the five respiratory chain complexes in our patients' skeletal muscle showed severely impaired activities of iron sulfur (Fe-S)-dependent complexes I, II and III and mitochondrial aconitase. We employed exome sequencing combined with homozygosity mapping to identify a homozygous mutation, c.1A > T, in the FDX1L gene, which encodes the mitochondrial ferredoxin 2 (Fdx2) protein. The mutation disrupts the ATG initiation translation site resulting in severe reduction of Fdx2 content in the patient muscle and fibroblasts mitochondria. Fdx2 is the second component of the Fe-S cluster biogenesis machinery, the first being IscU that is associated with isolated mitochondrial myopathy. We suggest adding genetic analysis of FDX1L in cases of mitochondrial myopathy especially when associated with reduced activity of the respiratory chain complexes I, II and III.

  • 141.
    Sreedharan, Smitha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Carlini, Valeria P
    Departamento de Farmacología, Universidad Nacional de Córdoba, Argentina.
    Jacobsson, Josefin A
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Olszewski, Pawel K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Haitina, Tatjana
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Hammer, Joanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Stephansson, Olga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Crona, Filip
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Sommer, Wolfgang H
    Department of Psychopharmacology, Central institute of Mental Health, Mannheim, Germany.
    Riserus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Levine, Allen S
    Department of Food Science and Nutrition, Minnesota Obesity Center.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Marcus, Claude
    Department for Clinical Science, Intervention and Technology, Karolinska Institute.
    Heilig, Marcus
    Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
    de Barioglio, Susan R
    Departamento de Farmacología, Universidad Nacional de Córdoba, Argentina.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    GPR162 is expressed in the hypothalamus and is involved in food intake related behaviour2011Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    The Rhodopsin family of G protein-coupled receptors (GPCRs) includes about 270 non-olfactory receptors and is the largest family of GPCRs. About sixty non-olfactory Rhodopsin GPCRs are still orphans without known ligands, and fairly little is known about their functions. In this study, we present molecular, neuroanatomical, genetic and behavioral data implicating a Rhodopsin family protein, GPR162, in the regulation of food intake-related behaviour and glucose homeostasis. The real-time PCR data show that GPR162 is predominantly expressed in the CNS. The in situ hybridization results confirmed significant expression of GPR162 in several hypothalamic sites, amygdala, substantia nigra and ventral tegmental area, among others regions. In line with the distribution of the GPR162 mRNA in the feeding circuitry, antisense oligo knockdown of GPR162 caused a significant reduction in food intake but no effect was observed towards reduction in body weight in rats. Our human genetics studies suggest that genetic variants of GPR162 affect glucose homeostasis. In conclusion, this study provides evidence linking the orphan GPR162 gene with the regulation of food intake-related behaviour.

  • 142.
    Staaf, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Åkerström, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Ljungström, Viktor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Larsson, Sune
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Karlsson, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hög tid att söka till nya MD/PhD-programmet vid Uppsala universitet: Tidig bro mellan preklinisk forskning och klinik2012Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, nr 17-18, s. 898-898Artikel i tidskrift (Refereegranskat)
  • 143.
    Stoimenov, Ivaylo
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Ali, Muhammad Akhtar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Djureinovic, Tatjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Computational and molecular tools for scalable rAAV mediated genome editingManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The rapid discovery of potential driver mutations through large scale mutational analyses of human cancers generates a need to characterize their cellular phenotypes. Among the techniques for genome editing, recombinant adeno-associated virus (rAAV) mediated gene targeting is particularly suited to knock-in of single nucleotide substitutions. However, the generation of gene targeting constructs and the targeting process is time consuming and labor-intense. To facilitate rAAV mediated gene targeting, we developed the first software and complementary automation friendly vector tools to generate optimized targeting constructs for editing human protein encoding genes. By computational approaches, rAAV constructs for editing ~72% of bases in protein-coding exons were designed. Similarly, ~81% of genes were predicted to be targetable by rAAV mediated knock-out. A Gateway based cloning system for facile generation of rAAV constructs suitable for robotic automation was developed and used in successful generation of targeting constructs. Together, these tools enable automated rAAV targeting construct design, generation as well as enrichment and expansion of targeted cells with desired integrations.

  • 144. Surakka, Ida
    et al.
    Isaacs, Aaron
    Karssen, Lennart C.
    Laurila, Pirkka-Pekka P.
    Middelberg, Rita P. S.
    Tikkanen, Emmi
    Ried, Janina S.
    Lamina, Claudia
    Mangino, Massimo
    Igl, Wilmar
    Hottenga, Jouke-Jan
    Lagou, Vasiliki
    van der Harst, Pim
    Leach, Irene Mateo
    Esko, Tonu
    Kutalik, Zoltan
    Wainwright, Nicholas W.
    Struchalin, Maksim V.
    Sarin, Antti-Pekka
    Kangas, Antti J.
    Viikari, Jorma S.
    Perola, Markus
    Rantanen, Taina
    Petersen, Ann-Kristin
    Soininen, Pasi
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Soranzo, Nicole
    Heath, Andrew C.
    Papamarkou, Theodore
    Prokopenko, Inga
    Toenjes, Anke
    Kronenberg, Florian
    Doering, Angela
    Rivadeneira, Fernando
    Montgomery, Grant W.
    Whitfield, John B.
    Kahonen, Mika
    Lehtimaki, Terho
    Freimer, Nelson B.
    Willemsen, Gonneke
    de Geus, Eco J. C.
    Palotie, Aarno
    Sandhu, Manj S.
    Waterworth, Dawn M.
    Metspalu, Andres
    Stumvoll, Michael
    Uitterlinden, Andre G.
    Jula, Antti
    Navis, Gerjan
    Wijmenga, Cisca
    Wolffenbuttel, Bruce H. R.
    Taskinen, Marja-Riitta
    Ala-Korpela, Mika
    Kaprio, Jaakko
    Kyvik, Kirsten O.
    Boomsma, Dorret I.
    Pedersen, Nancy L.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Wilson, James F.
    Rudan, Igor
    Campbell, Harry
    Pramstaller, Peter P.
    Spector, Tim D.
    Witteman, Jacqueline C. M.
    Eriksson, Johan G.
    Salomaa, Veikko
    Oostra, Ben A.
    Raitakari, Olli T.
    Wichmann, H. -Erich
    Gieger, Christian
    Jaervelin, Marjo-Riitta
    Martin, Nicholas G.
    Hofman, Albert
    McCarthy, Mark I.
    Peltonen, Leena
    van Duijn, Cornelia M.
    Aulchenko, Yurii S.
    Ripatti, Samuli
    A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol2011Ingår i: PLoS Genetics, ISSN 1553-7390, Vol. 7, nr 10, s. e1002333-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain similar to 25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79 x 10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.

  • 145.
    Sutton, L. A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Young, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cortese, Diego
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Navrkalova, V.
    Malcikova, J.
    Muggen, A. F.
    Trbusek, M.
    Davi, F.
    Belessi, C.
    Langerak, A. W.
    Ghia, P.
    Pospisilova, S.
    Stamatopoulos, K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rosenquist, R.
    Targeted Next-Generation Sequencing for Mutational Screening in Chronic Lymphocytic Leukemia: A High-Throughput Yet Tailored Approach Will Facilitate Implementation Within a Clinical Setting2014Ingår i: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, nr S1, s. 313-314Artikel i tidskrift (Övrigt vetenskapligt)
  • 146. Thanabalasingham, Gaya
    et al.
    Huffman, Jennifer E.
    Kattla, Jayesh J.
    Novokmet, Mislav
    Rudan, Igor
    Gloyn, Anna L.
    Hayward, Caroline
    Adamczyk, Barbara
    Reynolds, Rebecca M.
    Muzinic, Ana
    Hassanali, Neelam
    Pucic, Maja
    Bennett, Amanda J.
    Essafi, Abdelkader
    Polasek, Ozren
    Mughal, Saima A.
    Redzic, Irma
    Primorac, Dragan
    Zgaga, Lina
    Kokic, Ivana
    Hansen, Torben
    Gasperikova, Daniela
    Tjora, Erling
    Strachan, Mark W. J.
    Nielsen, Trine
    Stanik, Juraj
    Klimes, Iwar
    Pedersen, Oluf B.
    Njolstad, Pal R.
    Wild, Sarah H.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Gornik, Olga
    Wilson, James F.
    Hastie, Nicholas D.
    Campbell, Harry
    McCarthy, Mark I.
    Rudd, Pauline M.
    Owen, Katharine R.
    Lauc, Gordan
    Wright, Alan F.
    Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile2013Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, nr 4, s. 1329-1337Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A recent genome-wide association study identified hepatocyte nuclear factor 1-alpha (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MOD?) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCE)-MODY (n = 118), hepatocyte nuclear factor 4-alpha (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic >= 0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction.

  • 147.
    Thiblin, Ingemar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Rättsmedicin.
    Wennström, Bo
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Juridiska fakulteten, Centrum för polisforskning. Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Juridiska fakulteten, Juridiska institutionen.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Låt även försvararsidan få tillgång till rättsmedicinsk expertis: [Let the defence have access to forensic expertise, too]2012Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, nr 1-2, s. 39-39Artikel i tidskrift (Refereegranskat)
  • 148. Thomas, Rachael
    et al.
    Borst, Luke
    Rotroff, Daniel
    Motsinger-Reif, Alison
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Modiano, Jaime F.
    Breen, Matthew
    Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine hemangiosarcoma2014Ingår i: Chromosome Research, ISSN 0967-3849, E-ISSN 1573-6849, Vol. 22, nr 3, s. 305-319Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Canine hemangiosarcoma is a highly aggressive vascular neoplasm associated with extensive clinical and anatomical heterogeneity and a grave prognosis. Comprehensive molecular characterization of hemangiosarcoma may identify novel therapeutic targets and advanced clinical management strategies, but there are no published reports of tumor-associated genome instability and disrupted gene dosage in this cancer. We performed genome-wide microarray-based somatic DNA copy number profiling of 75 primary intra-abdominal hemangiosarcomas from five popular dog breeds that are highly predisposed to this disease. The cohort exhibited limited global genomic instability, compared to other canine sarcomas studied to date, and DNA copy number aberrations (CNAs) were predominantly of low amplitude. Recurrent imbalances of several key cancer-associated genes were evident; however, the global penetrance of any single CNA was low and no distinct hallmark aberrations were evident. Copy number gains of dog chromosomes 13, 24, and 31, and loss of chromosome 16, were the most recurrent CNAs involving large chromosome regions, but their relative distribution within and between cases suggests they most likely represent passenger aberrations. CNAs involving CDKN2A, VEGFA, and the SKI oncogene were identified as potential driver aberrations of hemangiosarcoma development, highlighting potential targets for therapeutic modulation. CNA profiles were broadly conserved between the five breeds, although subregional variation was evident, including a near twofold lower incidence of VEGFA gain in Golden Retrievers versus other breeds (22 versus 40 %). These observations support prior transcriptional studies suggesting that the clinical heterogeneity of this cancer may reflect the existence of multiple, molecularly distinct subtypes of canine hemangiosarcoma.

  • 149. Thun, Gian Andri
    et al.
    Imboden, Medea
    Ferrarotti, Ilaria
    Kumar, Ashish
    Obeidat, Ma'en
    Zorzetto, Michele
    Haun, Margot
    Curjuric, Ivan
    Alves, Alexessander Couto
    Jackson, Victoria E.
    Albrecht, Eva
    Ried, Janina S.
    Teumer, Alexander
    Lopez, Lorna M.
    Huffman, Jennifer E.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bosse, Yohan
    Hao, Ke
    Timens, Wim
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Polasek, Ozren
    Wilson, James F.
    Rudan, Igor
    Hayward, Caroline
    Sandford, Andrew J.
    Deary, Ian J.
    Koch, Beate
    Reischl, Eva
    Schulz, Holger
    Hui, Jennie
    James, Alan L.
    Rochat, Thierry
    Russi, Erich W.
    Jarvelin, Marjo-Riitta
    Strachan, David P.
    Hall, Ian P.
    Tobin, Martin D.
    Dahl, Morten
    Nielsen, Sune Fallgaard
    Nordestgaard, Borge G.
    Kronenberg, Florian
    Luisetti, Maurizio
    Probst-Hensch, Nicole M.
    Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels2013Ingår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, nr 8, s. e1003585-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs defined by showing minor allele frequencies (MAFs) >5% reached genome-wide significance all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of beta = 20.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis as well as exon-sequencing in a subsample (N = 410) suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only in particular by the well-documented protein inhibitor S and Z (PI S PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001) as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397) associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.

  • 150.
    Weibrecht, Irene
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lundin, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kiflemariam, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mignardi, Marco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Grundberg, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Larsson, Chatarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Koos, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nilsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Söderberg, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    In situ detection of individual mRNA molecules and protein complexes or post-translational modifications using padlock probes combined with the in situ proximity ligation assay2013Ingår i: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 8, nr 2, s. 355-372Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Analysis at the single-cell level is essential for the understanding of cellular responses in heterogeneous cell populations, but it has been difficult to perform because of the strict requirements put on detection methods with regard to selectivity and sensitivity (i.e., owing to the cross-reactivity of probes and limited signal amplification). Here we describe a 1.5-d protocol for enumerating and genotyping mRNA molecules in situ while simultaneously obtaining information on protein interactions or post-translational modifications; this is achieved by combining padlock probes with in situ proximity ligation assays (in situ PLA). In addition, we provide an example of how to design padlock probes and how to optimize staining conditions for fixed cells and tissue sections. Both padlock probes and in situ PLA provide the ability to directly visualize single molecules by standard microscopy in fixed cells or tissue sections, and these methods may thus be valuable for both research and diagnostic purposes.

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