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  • 201.
    Nordlund, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Epigenetics in pediatric acute lymphoblastic leukemia2018In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 51, p. 129-138Article, review/survey (Refereed)
    Abstract [en]

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

  • 202.
    Nordmark, Gunnel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Imgenberg-Kreuz, Juliana
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Almlöf, Jonas Carlsson
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Nordlund, Jessica
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Omdal, Roald
    Norheim, Katrine B.
    Eloranta, Maija-Leena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sandling, Johanna K.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Genome-Wide DNA Methylation Analysis of CD19+B Cells in Primary Sjogren's Syndrome2014In: Arthritis & Rheumatology, ISSN 2326-5191, Vol. 66, no S10, p. S1303-S1303, article id 2980Article in journal (Other academic)
  • 203.
    Nordmark, Gunnel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kristjansdottir, Gudlaug
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Theander, E.
    Appel, S.
    Eriksson, P.
    Vasaitis, Lilian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Kvarnström, M.
    Delaleu, N.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sjöwall, C.
    Brun, J. G.
    Jonsson, M. V.
    Harboe, E.
    Gøransson, L. G.
    Johnsen, S. J.
    Söderkvist, P.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Alm, G.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wahren-Herlenius, M.
    Omdal, R.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jonsson, R.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome2011In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 12, no 2, p. 100-109Article in journal (Refereed)
    Abstract [en]

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

  • 204.
    Nordmark, Gunnel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kristjansdottir, Gudlaug
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Theander, E.
    Eriksson, P.
    Brun, J. G.
    Wang, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Padyukov, L.
    Truedsson, L.
    Alm, Gunnar
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jonsson, R.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome2009In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 10, no 1, p. 68-76Article in journal (Refereed)
    Abstract [en]

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

  • 205.
    Nordmark, Gunnel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wang, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vasaitis, Lilian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eriksson, Per
    Theander, Elke
    Kvarnström, Marika
    Forsblad-d'Elia, Helena
    Jazebi, Helmi
    Sjöwall, Christopher
    Reksten, Tove Ragna
    Brun, Johan G
    Jonsson, Malin V
    Johnsen, Svein J
    Wahren-Herlenius, Marie
    Omdal, Roald
    Jonsson, Roland
    Bowman, Simon
    Ng, Wan-Fai
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Association of genes in the NF-κB pathway with antibody positive primary Sjögren's syndrome2013In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 78, no 5, p. 447-454Article in journal (Refereed)
    Abstract [en]

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

  • 206.
    Norheim, Katrine B.
    et al.
    Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Imgenberg-Kreuz, Juliana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jonsdottir, Kristin
    Stavanger Univ Hosp, Dept Pathol, Stavanger, Norway..
    Janssen, Emiel
    Stavanger Univ Hosp, Dept Pathol, Stavanger, Norway..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Omdal, Roald
    Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Epigenome-Wide DNA Methylation Patterns Associated with Fatigue in Primary Sjogren's Syndrome2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no Suppl. 10, article id 1262Article in journal (Other academic)
  • 207.
    Norheim, Katrine Braekke
    et al.
    Stavanger Univ Hosp, Clin Immunol Unit, Dept Internal Med, Pb 8100 Forus, N-4068 Stavanger, Norway..
    Imgenberg-Kreuz, Juliana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Jonsdottir, Kristin
    Stavanger Univ Hosp, Dept Pathol, N-4068 Stavanger, Norway..
    Janssen, Emiel A. M.
    Stavanger Univ Hosp, Dept Pathol, N-4068 Stavanger, Norway..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Omdal, Roald
    Stavanger Univ Hosp, Clin Immunol Unit, Dept Internal Med, Pb 8100 Forus, N-4068 Stavanger, Norway..
    Epigenome-wide DNA methylation patterns associated with fatigue in primary Sjogren's syndrome2016In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 55, no 6, p. 1074-1082Article in journal (Refereed)
    Abstract [en]

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

  • 208. Norheim, Katrine Braekke
    et al.
    Imgenberg-Kreuz, Juliana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jonsdottir, Kristin
    Sandling, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvanen, Ann-Christine
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Omdal, Roald
    Genome-Wide DNA Methylation Patterns Associated with Fatigue in Primary Sjogren's Syndrome2015In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 81, no 5, p. 413-413Article in journal (Other academic)
  • 209. Ofverholm, I. Ivanov
    et al.
    Olsson, L.
    Noren-Nystrom, U.
    Forestier, E.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sjogren, H.
    Golovleva, I.
    Heyman, M.
    Zachariadis, V.
    Nordgren, A.
    Johansson, B.
    Barbany, G.
    Prognostic Impact of IKZF1 Deletions in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia Treated According to Nopho Protocols - the Swedish Experience2014In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no S1, p. 9-9Article in journal (Other academic)
  • 210.
    Olsson, Charlotta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Waldenström, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Westermark, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Determination of the frequencies of ten allelic variants of the Wilson disease gene (ATP7B), in pooled DNA samples2000In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 8, no 12, p. 933-938Article in journal (Refereed)
    Abstract [en]

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

  • 211.
    Olsson, Linda
    et al.
    Lund Univ, Dept Lab Med, Div Clin Genet, SE-22184 Lund, Sweden..
    Oefverholm, Ingegerd Ivanov
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    Noren-Nystroem, Ulrika
    Umea Univ, Dept Clin Sci, Paediat, Umea, Sweden..
    Zachariadis, Vasilios
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjoegren, Helene
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Clin Chem & Transfus Med, Gothenburg, Sweden..
    Golovleva, Irina
    Umea Univ, Dept Med Biosci Med & Clin Genet, Umea, Sweden..
    Nordgren, Ann
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    Paulsson, Kajsa
    Lund Univ, Dept Lab Med, Div Clin Genet, SE-22184 Lund, Sweden..
    Heyman, Mats
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Barbany, Gisela
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden..
    Johansson, Bertil
    Lund Univ, Dept Lab Med, Div Clin Genet, SE-22184 Lund, Sweden.;Univ & Reg Labs Reg Skane, Dept Clin Genet, Lund, Sweden..
    The clinical impact of IKZF1 deletions in paediatric B-cell precursor acute lymphoblastic leukaemia is independent of minimal residual disease stratification in Nordic Society for Paediatric Haematology and Oncology treatment protocols used between 1992 and 20132015In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 170, no 6, p. 847-858Article in journal (Refereed)
    Abstract [en]

    Paediatric B-cell precursor acute lymphoblastic leukaemias (BCP ALL) with IKZF1 deletions (IKZF1) are associated with a poor outcome. However, there are conflicting data as to whether IKZF1 is an independent risk factor if minimal residual disease (MRD) and other copy number alterations also are taken into account. We investigated 334 paediatric BCP ALL, diagnosed 1992-2013 and treated according to Nordic Society for Paediatric Haematology and Oncology ALL protocols, with known IKZF1 status based on either single nucleotide polymorphism array (N=218) or multiplex ligation-dependent probe amplification (N=116) analyses. IKZF1, found in 15%, was associated with inferior 10-year probabilities of event-free (60% vs. 83%; P<0001) and overall survival (pOS; 73% vs. 89%; P=0001). Adjusting for known risk factors, including white blood cell (WBC) count and MRD, IKZF1 was the strongest independent factor for relapse and death. IKZF1 was present in 27% of cases with non-informative cytogenetics (BCP-other') and a poor 10-year pOS was particularly pronounced in this group (58% vs. 90%; P<0001). Importantly, neither MRD nor WBC count predicted events in the IKZF1-positive cases. Co-occurrence of pseudoautosomal region 1 (PAR1) deletions in Xp22.33/Yp11.32 (P2RY8-CRLF2) and IKZF1 increased the risk of relapse (75% vs. 30% for cases with only IKZF1; P=0045), indicating that BCP-other ALL with both P2RY8-CRLF2 and IKZF1 constitutes a particularly high-risk group.

  • 212. Orentas, Rimas J
    et al.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    He, Jianbin
    Sindiri, Sivasish
    Mackall, Crystal
    Fry, Terry J
    Khan, Javed
    Bioinformatic description of immunotherapy targets for pediatric T-cell leukemia and the impact of normal gene sets used for comparison2014In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 4, article id 134Article in journal (Refereed)
    Abstract [en]

    Pediatric lymphoid leukemia has the highest cure rate of all pediatric malignancies, yet due to its prevalence, still accounts for the majority of childhood cancer deaths and requires long-term highly toxic therapy. The ability to target B-cell ALL with immunoglobulin-like binders, whether anti-CD22 antibody or anti-CD19 CAR-Ts, has impacted treatment options for some patients. The development of new ways to target B-cell antigens continues at rapid pace. T-cell ALL accounts for up to 20% of childhood leukemia but has yet to see a set of high-value immunotherapeutic targets identified. To find new targets for T-ALL immunotherapy, we employed a bioinformatic comparison to broad normal tissue arrays, hematopoietic stem cells (HSC), and mature lymphocytes, then filtered the results for transcripts encoding plasma membrane proteins. T-ALL bears a core T-cell signature and transcripts encoding TCR/CD3 components and canonical markers of T-cell development predominate, especially when comparison was made to normal tissue or HSC. However, when comparison to mature lymphocytes was also undertaken, we identified two antigens that may drive, or be associated with leukemogenesis; TALLA-1 and hedgehog interacting protein. In addition, TCR subfamilies, CD1, activation and adhesion markers, membrane-organizing molecules, and receptors linked to metabolism and inflammation were also identified. Of these, only CD52, CD37, and CD98 are currently being targeted clinically. This work provides a set of targets to be considered for future development of immunotherapies for T-ALL.

  • 213.
    Parmar, Priyanka
    et al.
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Univ Oulu, Bioctr Oulu, Oulu, Finland.
    Lowry, Estelle
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Univ Oulu, Bioctr Oulu, Oulu, Finland.
    Cugliari, Giovanni
    Univ Turin, Dept Med Sci, Turin, Italy;IIGM, Turin, Italy.
    Suderman, Matthew
    Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Populat Hlth Sci, Bristol, Avon, England.
    Wilson, Rory
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany.
    Karhunen, Ville
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
    Andrew, Toby
    Imperial Coll London, Dept Med, Genom Common Dis, London, England.
    Wiklund, Petri
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla, Finland.
    Wielscher, Matthias
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
    Guarrera, Simonetta
    Univ Turin, Dept Med Sci, Turin, Italy;IIGM, Turin, Italy.
    Teumer, Alexander
    Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany.
    Lehne, Benjamin
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
    Milani, Lili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    de Klein, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
    Mishra, Pashupati P.
    Fimlab Labs, Dept Clin Chem, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Melton, Phillip E.
    Curtin Univ, Sch Pharm & Biomed Sci, Bentley, WA, Australia;Univ Western Australia, Curtin UWA Ctr Genet Origins Hlth & Dis, Sch Biomed Sci, Crawley, Australia.
    Mandaviya, Pooja R.
    Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands.
    Kasela, Silva
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Nano, Jana
    Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands.
    Zhang, Weihua
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England.
    Zhang, Yan
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Uitterlinden, Andre G.
    Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands;Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands.
    Peters, Annette
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
    Schoettker, Ben
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany;Heidelberg Univ, Network Aging Res, Bergheimer Str, Heidelberg, Germany.
    Gieger, Christian
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
    Anderson, Denise
    Univ Western Australia, Telethon Kids Inst, Perth, WA, Australia.
    Boomsma, Dorret, I
    Vrije Univ Amsterdam, Sch Publ Hlth, Dept Biol Psychol, Amsterdam, Netherlands.
    Grabe, Hans J.
    Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany;German Ctr Neurodegenerat Dis DZNF, Site Rostock Greifswald, Greifswald, Germany.
    Panico, Salvatore
    Univ Naples Federico II, Dept Clin Med & Surg, Naples, Italy.
    Veldink, Jan H.
    Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands.
    van Meurs, Joyce B. J.
    Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands.
    van den Berg, Leonard
    Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands.
    Beilin, Lawrence J.
    Univ Western Australia, Med Sch, Perth, WA, Australia.
    Franke, Lude
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
    Loh, Marie
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;ASTAR, TLGM, 8A Biomed Grove,Level 5, Singapore, Singapore;Univ Oulu, Inst Hlth Sci, Oulu, Finland.
    van Greevenbroek, Marleen M. J.
    Maastricht Univ, Dept Internal Med, Med Ctr, Maastricht, Netherlands;Maastricht Univ, Sch Cardiovasc Dis CARIM, Med Ctr, Maastricht, Netherlands.
    Nauck, Matthias
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany;Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany.
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Dept Clin Physiol, Tampere, Finland.
    Hurme, Mikko A.
    Fac Med & Life Sci Univ Tampere, Dept Microbiol & Immunol, Tampere, Finland.
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.
    Franco, Oscar H.
    Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands.
    Slagboom, P. Eline
    Leiden Univ, Dept Biomed Data Sci, Mol Epidemiol, Med Ctr, Leiden, Netherlands.
    van der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands;Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.
    Kunze, Sonja
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany.
    Felix, Stephan B.
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.
    Zhang, Tao
    Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA;Shandong Univ, Sch Publ Hlth, Dept Biostat, Jinan, Shandong, Peoples R China.
    Chen, Wei
    Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA.
    Mori, Trevor A.
    Univ Western Australia, Med Sch, Perth, WA, Australia.
    Bonnefond, Amelie
    Imperial Coll London, Dept Med, Genom Common Dis, London, England;Univ Lille, EGID, Inst Pasteur Lille, CMS UMR 8199, Lille, France.
    Heijmans, Bastiaan T.
    Leiden Univ, Dept Biomed Data Sci, Mol Epidemiol, Med Ctr, Leiden, Netherlands.
    Muka, Taulant
    Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands.
    Kooner, Jaspal S.
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England;Imperial Coll London, Natl Heart & Lung Inst, London, England;Childrens Minnesota Res Inst, Childrens Hosp & Clin, Minneapolis, MN 55404 USA.
    Fischer, Krista
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Waldenberger, Melanie
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;Helmholtz Zentrum Munchen, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Bavaria, Germany;German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany.
    Froguel, Philippe
    Imperial Coll London, Dept Med, Genom Common Dis, London, England;Univ Lille, EGID, Inst Pasteur Lille, CMS UMR 8199, Lille, France.
    Huang, Rae-Chi
    Univ Western Australia, Telethon Kids Inst, Perth, WA, Australia.
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Rathmann, Wolfgang
    Heine Univ, Inst Biometr & Epidemiol, Leibniz Ctr Diabet Res Heinrich, German Diabet Ctr, Dusseldorf, Germany.
    Relton, Caroline L.
    Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Populat Hlth Sci, Bristol, Avon, England.
    Matullo, Giuseppe
    Univ Turin, Dept Med Sci, Turin, Italy;IIGM, Turin, Italy.
    Brenner, Hermann
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany;Heidelberg Univ, Network Aging Res, Bergheimer Str, Heidelberg, Germany.
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Li, Shengxu
    Childrens Minnesota Res Inst, Childrens Hosp & Clin, Minneapolis, MN 55404 USA.
    Chambers, John C.
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England;Imperial Coll Healthcare NHS Trust, London, England;Nanyang Technol Univ Singapore, Lee Kong Chian Sch Med, Singapore, Singapore.
    Jarvelin, Marjo-Riitta
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Univ Oulu, Bioctr Oulu, Oulu, Finland;Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England;Brunel Univ London, Dept Life Sci, Coll Hlth & Life Sci, Uxbridge, Middx, England.
    Sebert, Sylvain
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland;Univ Oulu, Bioctr Oulu, Oulu, Finland;Univ Oulu, Med Res Ctr MRC Oulu, Oulu Univ Hosp, Oulu, Finland.
    Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults2018In: EBioMedicine, E-ISSN 2352-3964, Vol. 38, p. 206-216Article in journal (Refereed)
    Abstract [en]

    Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n= 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0.012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 x 10(-7) < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 x 10(-8) < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. Interpretation: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. Fund: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.

  • 214. Paré, Guillaume
    et al.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lehr, Thorsten
    Connolly, Stuart
    Eikelboom, John
    Ezekowitz, Michael D
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Haertter, Sebastian
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Reilly, Paul
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Zimdahl-Gelling, Heike
    Yusuf, Salim
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding2013In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 127, no 13, p. 1404-Article in journal (Refereed)
    Abstract [en]

    Background

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

    Methods and Results

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

    Conclusions

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

  • 215. Pastinen, Tomi
    et al.
    Raitio, Mirja
    Lindroos, Katarina
    Tainola, Päivi
    Peltonen, Leena
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    A system for specific, high-throughput genotyping by allele-specific primer extension on microarrays2000In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 10, no 7, p. 1031-1042Article in journal (Refereed)
    Abstract [en]

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

  • 216. Peden, John F.
    et al.
    Hopewell, Jemma C.
    Saleheen, Danish
    Chambers, John C.
    Hager, Jorg
    Soranzo, Nicole
    Collins, Rory
    Danesh, John
    Elliott, Paul
    Farrall, Martin
    Stirrups, Kathy
    Zhang, Weihua
    Hamsten, Anders
    Parish, Sarah
    Lathrop, Mark
    Watkins, Hugh
    Clarke, Robert
    Deloukas, Panos
    Kooner, Jaspal S.
    Goel, Anuj
    Ongen, Halit
    Strawbridge, Rona J.
    Heath, Simon
    Mälarstig, Anders
    Helgadottir, Anna
    Öhrvik, John
    Murtaza, Muhammed
    Potter, Simon
    Hunt, Sarah E.
    Delepine, Marc
    Jalilzadeh, Shapour
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Gwilliam, Rhian
    Bumpstead, Suzannah
    Gray, Emma
    Edkins, Sarah
    Folkersen, Lasse
    Kyriakou, Theodosios
    Franco-Cereceda, Anders
    Gabrielsen, Anders
    Seedorf, Udo
    Eriksson, Per
    Offer, Alison
    Bowman, Louise
    Sleight, Peter
    Armitage, Jane
    Peto, Richard
    Abecasis, Goncalo
    Ahmed, Nabeel
    Caulfield, Mark
    Donnelly, Peter
    Froguel, Philippe
    Kooner, Angad S.
    McCarthy, Mark I.
    Samani, Nilesh J.
    Scott, James
    Sehmi, Joban
    Silveira, Angela
    Hellenius, Mai-Lis
    van't Hooft, Ferdinand M.
    Olsson, Gunnar
    Rust, Stephan
    Assmann, Gerd
    Barlera, Simona
    Tognoni, Gianni
    Franzosi, Maria Grazia
    Linksted, Pamela
    Green, Fiona R.
    Rasheed, Asif
    Zaidi, Moazzam
    Shah, Nabi
    Samuel, Maria
    Mallick, Nadeem H.
    Azhar, Muhammad
    Zaman, Khan S.
    Samad, Abdus
    Ishaq, Mohammad
    Gardezi, Ali R.
    Memon, Fazal-ur-Rehman
    Frossard, Philippe M.
    Spector, Tim
    Peltonen, Leena
    Nieminen, Markku S.
    Sinisalo, Juha
    Salomaa, Veikko
    Ripatti, Samuli
    Bennett, Derrick
    Leander, Karin
    Gigante, Bruna
    de Faire, Ulf
    Pietri, Silvia
    Gori, Francesca
    Marchioli, Roberto
    Sivapalaratnam, Suthesh
    Kastelein, John J. P.
    Trip, Mieke D.
    Theodoraki, Eirini V.
    Dedoussis, George V.
    Engert, Jamie C.
    Yusuf, Salim
    Anand, Sonia S.
    A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease2011In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, no 4, p. 339-344Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD)(1-7), a modest number considering the apparent heritability of CAD(8). All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with similar to 575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 x 10(-8) in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility.

  • 217.
    Penell, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morris, Andrew P
    Lindgren, Cecilia
    Mahajan, Anubha
    Salihovic, Samira
    van Bavel, Bert
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, P Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Genetic variation in the CYP2B6 Gene is related to circulating 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) concentrations: an observational population-based study2014In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 13, p. 34-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

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

    METHODS:

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

    RESULTS:

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

    CONCLUSION:

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

  • 218.
    Peterson, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Engler, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    PET-scan shows peripherally increased neurokinin 1 receptor availability in chronic tennis elbow: a picture of neurogenic inflammation?2011In: Pain, ISSN 0304-3959, E-ISSN 1872-6623Article in journal (Refereed)
    Abstract [en]

    In response to pain, neurokinin 1 (NK1) receptor availability in the central nervous system is altered in the dorsal horn of the spinal cord as well as in the brain. But the NK1 receptor and its primary agonist, substance P, also play a crucial role in peripheral tissue in response to pain, as part of neurogenic inflammation. However, little is known about alterations in NK1 receptor availability in peripheral tissue in chronic pain conditions and very few studies have been performed on human beings. We therefore performed positron emission tomography (PET) with the NK1 specific radioligand [11C]GR205171 in ten subjects with chronic tennis elbow. We demonstrated increased NK1 receptor availability in the affected arm as compared with the unaffected arm, measured as differences between the arms in number and volume of pixels > 2.5 SD above reference as well as signal intensity of this volume. We conclude that in addition to alteration of the NK1 receptor in the CNS, there is also activation, or up-regulation of the NK1 receptor in the peripheral, painful tissue in a chronic pain condition. We interpret this increased NK1 receptor availability as part of ongoing neurogenic inflammation and suggest that this is part of the cause of chronic tennis elbow.

  • 219. Pielberg, Gerli
    et al.
    Olsson, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Andersson, L
    Unexpectedly High Allelic Diversity at the KIT Locus Causing DominantWhite Color in the Domestic Pig2002In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 160, no 1, p. 305-311Article in journal (Refereed)
    Abstract [en]

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

  • 220. Prokopenko, Inga
    et al.
    Poon, Wenny
    Mägi, Reedik
    Prasad B, Rashmi
    Salehi, S Albert
    Almgren, Peter
    Osmark, Peter
    Bouatia-Naji, Nabila
    Wierup, Nils
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stančáková, Alena
    Barker, Adam
    Lagou, Vasiliki
    Osmond, Clive
    Xie, Weijia
    Lahti, Jari
    Jackson, Anne U
    Cheng, Yu-Ching
    Liu, Jie
    O'Connell, Jeffrey R
    Blomstedt, Paul A
    Fadista, Joao
    Alkayyali, Sami
    Dayeh, Tasnim
    Ahlqvist, Emma
    Taneera, Jalal
    Lecoeur, Cecile
    Kumar, Ashish
    Hansson, Ola
    Hansson, Karin
    Voight, Benjamin F
    Kang, Hyun Min
    Levy-Marchal, Claire
    Vatin, Vincent
    Palotie, Aarno
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mari, Andrea
    Weedon, Michael N
    Loos, Ruth J F
    Ong, Ken K
    Nilsson, Peter
    Isomaa, Bo
    Tuomi, Tiinamaija
    Wareham, Nicholas J
    Stumvoll, Michael
    Widen, Elisabeth
    Lakka, Timo A
    Langenberg, Claudia
    Tönjes, Anke
    Rauramaa, Rainer
    Kuusisto, Johanna
    Frayling, Timothy M
    Froguel, Philippe
    Walker, Mark
    Eriksson, Johan G
    Ling, Charlotte
    Kovacs, Peter
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    McCarthy, Mark I
    Shuldiner, Alan R
    Silver, Kristi D
    Laakso, Markku
    Groop, Leif
    Lyssenko, Valeriya
    A Central Role for GRB10 in Regulation of Islet Function in Man2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 4, article id e1004235Article in journal (Refereed)
    Abstract [en]

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

  • 221.
    Raine, Amanda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Data quality of whole genome bisulfite sequencing on Illumina platforms2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0195972Article in journal (Refereed)
    Abstract [en]

    The powerful HiSeq X sequencers with their patterned flowcell technology and fast turnaround times are instrumental for many large-scale genomic and epigenomic studies. However, assessment of DNA methylation by sodium bisulfite treatment results in sequencing libraries of low diversity, which may impact data quality and yield. In this report we assess the quality of WGBS data generated on the HiSeq X system in comparison with data generated on the HiSeq 2500 system and the newly released NovaSeq system. We report a systematic issue with low basecall quality scores assigned to guanines in the second read of WGBS when using certain Real Time Analysis (RTA) software versions on the HiSeq X sequencer, reminiscent of an issue that was previously reported with certain HiSeq 2500 software versions. However, with the HD.3.4.0 /RTA 2.7.7 software upgrade for the HiSeq X system, we observed an overall improved quality and yield of the WGBS data generated, which in turn empowers cost-effective and high quality DNA methylation studies.

  • 222.
    Raine, Amanda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Manlig, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wahlberg, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    SPlinted Ligation Adapter Tagging (SPLAT), a novel library preparation method for whole genome bisulphite sequencing2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 6, article id e36Article in journal (Refereed)
    Abstract [en]

    Sodium bisulphite treatment of DNA combined with next generation sequencing (NGS) is a powerful combination for the interrogation of genome-wide DNA methylation profiles. Library preparation for whole genome bisulphite sequencing (WGBS) is challenging due to side effects of the bisulphite treatment, which leads to extensive DNA damage. Recently, a new generation of methods for bisulphite sequencing library preparation have been devised. They are based on initial bisulphite treatment of the DNA, followed by adaptor tagging of single stranded DNA fragments, and enable WGBS using low quantities of input DNA. In this study, we present a novel approach for quick and cost effectiveWGBS library preparation that is based on splinted adaptor tagging (SPLAT) of bisulphite-converted single-stranded DNA. Moreover, we validate SPLAT against three commercially available WGBS library preparation techniques, two of which are based on bisulphite treatment prior to adaptor tagging and one is a conventional WGBS method.

  • 223. Raitio, Mirja
    et al.
    Lindroos, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Laukkanen, Minna
    Pastinen, Tomi
    Sistonen, Pertti
    Sajantila, Antti
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Y-chromosomal SNPs in Finno-Ugric-speaking populations analyzed by minisequencing on microarrays2001In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 11, no 3, p. 471-482Article in journal (Refereed)
    Abstract [en]

    An increasing number of single nucleotide polymorphisms (SNPs) on the Y chromosome are being identified. To utilize the full potential of the SNP markers in population genetic studies, new genotyping methods with high throughput are required. We describe a microarray system based on the minisequencing single nucleotide primer extension principle for multiplex genotyping of Y-chromosomal SNP markers. The system was applied for screening a panel of 25 Y-chromosomal SNPs in a unique collection of samples representing five Finno--Ugric populations. The specific minisequencing reaction provides 5-fold to infinite discrimination between the Y-chromosomal genotypes, and the microarray format of the system allows parallel and simultaneous analysis of large numbers of SNPs and samples. In addition to the SNP markers, five Y-chromosomal microsatellite loci were typed. Altogether 10,000 genotypes were generated to assess the genetic diversity in these population samples. Six of the 25 SNP markers (M9, Tat, SRY10831, M17, M12, 92R7) were polymorphic in the analyzed populations, yielding six distinct SNP haplotypes. The microsatellite data were used to study the genetic structure of two major SNP haplotypes in the Finns and the Saami in more detail. We found that the most common haplotypes are shared between the Finns and the Saami, and that the SNP haplotypes show regional differences within the Finns and the Saami, which supports the hypothesis of two separate settlement waves to Finland.

  • 224.
    Reid, Sarah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frodlund, Martina
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Sandling, Johanna K.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Jonsen, Andreas
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden..
    Bengtsson, Christine
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Bengtsson, Anders A.
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden..
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden..
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjowall, Christopher
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    High Genetic Risk Score Is Associated with Increased Organ Damage in SLE2017In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 1638Article in journal (Other academic)
  • 225.
    Reisberg, Sulev
    et al.
    Univ Tartu, Inst Comp Sci, Tartu, Estonia;STACC, Tartu, Estonia;Quretec, Tartu, Estonia.
    Krebs, Kristi
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia;Univ Tartu, Inst Mol & Cell Biol, Tartu, Estonia.
    Lepamets, Maarja
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia;Univ Tartu, Inst Mol & Cell Biol, Tartu, Estonia.
    Kals, Mart
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Metsalu, Kristjan
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Lauschke, Volker M.
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacogenet, Stockholm, Sweden.
    Vilo, Jaak
    Univ Tartu, Inst Comp Sci, Tartu, Estonia;STACC, Tartu, Estonia;Quretec, Tartu, Estonia.
    Milani, Lili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia.
    Translating genotype data of 44,000 biobank participants into clinical pharmacogenetic recommendations: challenges and solutions2019In: Genetics in Medicine, ISSN 1098-3600, E-ISSN 1530-0366, Vol. 21, no 6, p. 1345-1354Article in journal (Refereed)
    Abstract [en]

    Purpose: Biomedical databases combining electronic medical records and phenotypic and genomic data constitute a powerful resource for the personalization of treatment. To leverage the wealth of information provided, algorithms are required that systematically translate the contained information into treatment recommendations based on existing genotype-phenotype associations. Methods: We developed and tested algorithms for translation of preexisting genotype data of over 44,000 participants of the Estonian biobank into pharmacogenetic recommendations. We compared the results obtained by genome sequencing, exome sequencing, and genotyping using microarrays, and evaluated the impact of pharmacogenetic reporting based on drug prescription statistics in the Nordic countries and Estonia. Results: Our most striking result was that the performance of genotyping arrays is similar to that of genome sequencing, whereas exome sequencing is not suitable for pharmacogenetic predictions. Interestingly, 99.8% of all assessed individuals had a genotype associated with increased risks to at least one medication, and thereby the implementation of pharmacogenetic recommendations based on genotyping affects at least 50 daily drug doses per 1000 inhabitants. Conclusion: We find that microarrays are a cost-effective solution for creating preemptive pharmacogenetic reports, and with slight modifications, existing databases can be applied for automated pharmacogenetic decision support for clinicians.

  • 226.
    Roos, Leonie
    et al.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;MRC London Inst Med Sci, London, England.;Imperial Coll London, Inst Clin Sci, Fac Med, Du Cane Rd, London W12 0NN, England..
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bell, Christopher G.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England.;Univ Southampton, Human Dev & Hlth Acad Unit, Inst Dev Sci, Southampton, Hants, England.;Univ Southampton, Fac Environm & Nat Sci, Ctr Biol Sci, Epigen Med, Southampton, Hants, England..
    Glass, Daniel
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Spector, Tim D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, London, England..
    Bataille, Veronique
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Bell, Jordana T.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Higher Nevus Count Exhibits a Distinct DNA Methylation Signature in Healthy Human Skin: Implications for Melanoma2017In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 137, no 4, p. 910-920Article in journal (Refereed)
    Abstract [en]

    High nevus count is the strongest risk factor for melanoma, and although gene variants have been discovered for both traits, epigenetic variation is unexplored. We investigated 322 healthy human skin DNA methylomes associated with total body nevi count, incorporating genetic and transcriptomic variation. DNA methylation changes were identified at genes involved in melanocyte biology, such as RAF1 (P = 1.2x10(-6)) and CTC1 (region: P = 6.3 x 10(-4)), and other genes including ARRDC1 (P = 3.1 x 10(-7)). A subset exhibited coordinated methylation and transcription changes within the same biopsy. The total analysis was also enriched for melanoma-associated DNA methylation variation (P = 6.33 x 10(-6)). In addition, we show that skin DNA methylation is associated in cis with known genome-wide association study single nucleotide polymorphisms for nevus count, at PLA2G6 (P = 1.7 x 10(-49)) and NID1 (P = 6.4 x 10(-14)), as well as melanoma risk, including in or near MC1R, MX2, and TERT/CLPTM1L (P < 1 x 10(-10)). Our analysis using a uniquely large dataset comprising healthy skin DNA methylomes identified known and additional regulatory loci and pathways in nevi and melanoma biology. This integrative study improves our understanding of predisposition to nevi and their potential contribution to melanoma pathogenesis.

  • 227.
    Roshanbin, Sahar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindberg, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lekholm, Emilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Eriksson, Mikaela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Åhlund, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Raine, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Histological characterization of orphan transporter MCT14 (SLC16A14) shows abundant expression in mouse CNS and kidney2016In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 17, article id 43Article in journal (Refereed)
    Abstract [en]

    Background: MCT14 (SLC16A14) is an orphan member of the monocarboxylate transporter (MCT) family, also known as the SLC16 family of secondary active transmembrane transporters. Available expression data for this transporter is limited, and in this paper we aim to characterize MCT14 with respect to tissue distribution and cellular localization in mouse brain. Results: Using qPCR, we found that Slc16a14 mRNA was highly abundant in mouse kidney and moderately in central nervous system, testis, uterus and liver. Using immunohistochemistry and in situ hybridization, we determined that MCT14 was highly expressed in excitatory and inhibitory neurons as well as epithelial cells in the mouse brain. The expression was exclusively localized to the soma of neurons. Furthermore, we showed with our phylogenetic analysis that MCT14 most closely relate to the aromatic amino acid- and thyroid-hormone transporters MCT8 (SLC16A2) and MCT10 (SLC16A10), in addition to the carnitine transporter MCT9 (SLC16A9). Conclusions: We provide here the first histological mapping of MCT14 in the brain and our data are consistent with the hypothesis that MCT14 is a neuronal aromatic-amino-acid transporter.

  • 228.
    Rönn, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Analysis of Nucleotide Variations in Non-human Primates2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Many of our closest relatives, the primates, are endangered and could be extinct in a near future. To increase the knowledge of non-human primate genomes, and at the same time acquire information on our own genomic evolution, studies using high-throughput technologies are applied, which raises the demand for large amounts of high quality DNA.

    In study I and II, we evaluated the multiple displacement amplification (MDA) technique, a whole genome amplification method, on a wide range of DNA sources, such as blood, hair and semen, by comparing MDA products to genomic DNA as templates for several commonly used genotyping methods. In general, the genotyping success rate from the MDA products was in concordance with the genomic DNA. The quality of sequences of the mitochondrial control region obtained from MDA products from blood and non-invasively collected semen samples was maintained. However, the readable sequence length was shorter for MDA products.

    Few studies have focused on the genetic variation in the nuclear genes of non-human primates. In study III, we discovered 23 new single nucleotide polymorphisms (SNPs) in the Y-chromosome of the chimpanzee. We designed a tag-microarray minisequencing assay for genotyping the SNPs together with 19 SNPs from the literature and 45 SNPs in the mitochondrial DNA. Using the microarray, we were able to analyze the population structure of wild-living chimpanzees.

    In study IV, we established 111 diagnostic nucleotide positions for primate genera determination. We used sequence alignments of the nuclear epsilon globin gene and apolipoprotein B gene to identify positions for determination on the infraorder and Catarrhini subfamily level, respectively, and sequence alignments of the mitochondrial 12S rRNA (MT-RNR1) to identify positions to distinguish between genera. We designed a microarray assay for immobilized minisequencing primers for genotyping these positions to aid in the forensic determination of an unknown sample.

    List of papers
    1. Multiple displacement amplification for generating an unlimited source of DNA for genotyping in nonhuman primate species
    Open this publication in new window or tab >>Multiple displacement amplification for generating an unlimited source of DNA for genotyping in nonhuman primate species
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    2006 (English)In: International journal of primatology, ISSN 0164-0291, E-ISSN 1573-8604, Vol. 27, no 4, p. 1145-1169Article in journal (Refereed) Published
    Abstract [en]

    We evaluated a whole genome amplification method-multiple displacement amplification (MDA)-as a means to conserve valuable nonhuman primate samples. We tested 148 samples from a variety of species and sample sources, including blood, tissue, cell-lines, plucked hair and noninvasively collected semen. To evaluate genotyping success and accuracy of MDA, we used routine genotyping methods, including short tandem repeat (STR) analysis, denaturing gradient gel electrophoresis (DGGE), Alu repeat analysis, direct sequencing, and nucleotide detection by tag-array minisequencing. We compared genotyping results from MDA products to genotypes generated from the original (non-MD amplified) DNA samples. All genotyping methods showed good results with the MDA products as a DNA template, and for some samples MDA improved genotyping success. We show that the MDA procedure has the potential to provide a long-lasting source of DNA for genetic studies, which would be highly valuable for the primate research field, in which genetic resources are limited and for other species in which similar sampling constraints apply.

    Keywords
    Alu-SINE, minisequencing, multiple displacement amplification, short tandem repeat, single nucleotide polymorphism
    National Category
    Medical and Health Sciences Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-95932 (URN)10.1007/s10764-006-9067-7 (DOI)000241400100012 ()
    Available from: 2007-05-10 Created: 2007-05-10 Last updated: 2017-12-14Bibliographically approved
    2. Sequence quality is maintained after multiple displacement amplification of non-invasively obtained macaque semen DNA
    Open this publication in new window or tab >>Sequence quality is maintained after multiple displacement amplification of non-invasively obtained macaque semen DNA
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    2006 In: Biotechnology Journal, ISSN 1860-7314, Vol. 1, no 4, p. 466-469Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95933 (URN)
    Available from: 2007-05-10 Created: 2007-05-10Bibliographically approved
    3. A microarray system for Y chromosomal and mitochondrial single nucleotide polymorphism analysis in chimpanzee populations
    Open this publication in new window or tab >>A microarray system for Y chromosomal and mitochondrial single nucleotide polymorphism analysis in chimpanzee populations
    Show others...
    2008 (English)In: Molecular Ecology Notes, ISSN 1471-8278, E-ISSN 1471-8286, Vol. 8, no 3, p. 529-539Article in journal (Refereed) Published
    Abstract [en]

    Chimpanzee populations are diminishing as a consequence of human activities, and as a result this species is now endangered. In the context of conservation programmes, genetic data can add vital information, for instance on the genetic diversity and structure of threatened populations. Single nucleotide polymorphisms (SNP) are biallelic markers that are widely used in human molecular studies and can be implemented in efficient microarray systems. This technology offers the potential of robust, multiplexed SNP genotyping at low reagent cost in other organisms than humans, but it is not commonly used yet in wild population studies. Here, we describe the characterization of new SNPs in Y-chromosomal intronic regions in chimpanzees and also identify SNPs from mitochondrial genes, with the aim of developing a microarray system that permits the simultaneous study of both paternal and maternal lineages. Our system consists of 42 SNPs for the Y chromosome and 45 SNPs for the mitochondrial genome. We demonstrate the applicability of this microarray in a captive population where genotypes accurately reflected its large pedigree. Two wild-living populations were also analysed and the results show that the microarray will be a useful tool alongside microsatellite markers, since it supplies complementary information about population structure and ecology. SNP genotyping using microarray technology, therefore, is a promising approach and may become an essential tool in conservation genetics to help in the management and study of captive and wild-living populations. Moreover, microarrays that combine SNPs from different genomic regions could replace microsatellite typing in the future.

    Keywords
    chimpanzee, conservation genetics, microarray, minisequencing, population genetics, sex-linked SNPs
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-110437 (URN)10.1111/j.1471-8286.2007.02000.x (DOI)000254810300007 ()
    Available from: 2009-11-16 Created: 2009-11-16 Last updated: 2017-12-12Bibliographically approved
    4. A microarray-system for forensic identification of primate species subject to bushmeat trade
    Open this publication in new window or tab >>A microarray-system for forensic identification of primate species subject to bushmeat trade
    Show others...
    (English)Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-95935 (URN)10.3354/esr00191 (DOI)
    Available from: 2007-05-10 Created: 2007-05-10 Last updated: 2012-02-29
  • 229.
    Rönn, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Andrés, Olga
    Bruford, Michael W.
    Crouau-Roy, Brigitte
    Doxiadis, Gaby
    Domingo-Roura, Xavier
    Roeder, Amy D.
    Verschoor, Ernst
    Zischler, Hans
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Multiple displacement amplification for generating an unlimited source of DNA for genotyping in nonhuman primate species2006In: International journal of primatology, ISSN 0164-0291, E-ISSN 1573-8604, Vol. 27, no 4, p. 1145-1169Article in journal (Refereed)
    Abstract [en]

    We evaluated a whole genome amplification method-multiple displacement amplification (MDA)-as a means to conserve valuable nonhuman primate samples. We tested 148 samples from a variety of species and sample sources, including blood, tissue, cell-lines, plucked hair and noninvasively collected semen. To evaluate genotyping success and accuracy of MDA, we used routine genotyping methods, including short tandem repeat (STR) analysis, denaturing gradient gel electrophoresis (DGGE), Alu repeat analysis, direct sequencing, and nucleotide detection by tag-array minisequencing. We compared genotyping results from MDA products to genotypes generated from the original (non-MD amplified) DNA samples. All genotyping methods showed good results with the MDA products as a DNA template, and for some samples MDA improved genotyping success. We show that the MDA procedure has the potential to provide a long-lasting source of DNA for genetic studies, which would be highly valuable for the primate research field, in which genetic resources are limited and for other species in which similar sampling constraints apply.

  • 230.
    Rönn, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Andrés, Olga
    López-Giráldez, Franscesc
    Johnsson-Glans, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Verschoor, Ernst
    Domingo-Roura, Xavier
    Bruford, Michael, W.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Bosch, Montserrat
    A microarray-system for forensic identification of primate species subject to bushmeat tradeManuscript (Other academic)
  • 231. Saetre, Peter
    et al.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Wang, August
    Hansen, Thomas
    Rasmussen, Henrik B.
    Djurovic, Srdjan
    Melle, Ingrid
    Andreassen, Ole A.
    Werge, Thomas
    Agartz, Ingrid
    Hall, Håkan
    Terenius, Lars
    Jönsson, Erik G.
    The Tryptophan Hydroxylase 1 (TPH1) Gene, Schizophrenia Susceptibility, and Suicidal Behavior: A Multi-Centre Case-Control Study and Meta-Analysis2010In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, ISSN 1552-4841, Vol. 153B, no 2, p. 387-396Article in journal (Refereed)
    Abstract [en]

    Serotonin (5-hydroxytryptamin; 5-HT) alternations has since long been suspected in the pathophysiology of schizophrenia. Tryptophan hydroxylase (tryptophan 5-monooxygenase; TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT, and sequence variation in intron 6 of the TPH1 gene has been associated with schizophrenia. The minor allele (A) of this polymorphism (A218C) is also more frequent in patients who have attempted suicide and individuals who died by suicide, than in healthy control individuals. In an attempt to replicate previous findings, five single nucleotide polymorphisms (SNPs) were genotyped in 837 Scandinavian schizophrenia patients and 1,473 controls. Three SNPs spanning intron 6 and 7, including the A218C and A779C polymorphisms, were associated with schizophrenia susceptibility (P = 0.019). However there were no differences in allele frequencies of these loci between affected individuals having attempted suicide at least once and patients with no history of suicide attempts (P=0.84). A systematic literature review and meta-analysis support the A218C polymorphism as a susceptibility locus for schizophrenia (odds ratio 1.17, 95% confidence interval 1.07-1.29). Association studies on suicide attempts are however conflicting (heterogeneity index I-2 = 0.54) and do not support the A218C/A779C polymorphisms being a susceptibility locus for suicidal behavior among individuals diagnosed with a psychiatric disorder (OR = 0.96 [0.80-1.16]). We conclude that the TPH1 A218/A779 locus increases the susceptibility of schizophrenia in Caucasian and Asian populations. In addition, the data at hand suggest that the locus contributes to the liability of psychiatric disorders characterized by elevated suicidal rates, rather than affecting suicidal behavior of individuals suffering from a psychiatric disorder.

  • 232.
    Sandling, Johanna K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Genetic Analyses of Multiple Sclerosis and Systemic Lupus Erythematosus: From Single Markers to Genome-Wide Data2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In autoimmune diseases an individual’s immune system becomes targeted at the body’s own healthy cells. The aim of this thesis was to identify genetic risk factors for the two autoimmune diseases multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In Study I, we found that genetic variation in the interferon regulatory factor 5 gene (IRF5), previously shown to be associated with SLE, rheumatoid arthritis and inflammatory bowel diseases, was associated also with MS. An insertion/deletion polymorphism in the first intron of IRF5 is as a good functional candidate for this association. IRF5, together with the signal transducer and activator of transcription 4 gene (STAT4), are the most important genetic risk factors for SLE, outside the HLA region. In Study II we showed using a family-based study design that genetic variation in STAT4 is associated with SLE also in the Finnish population. In Study III, we investigated a STAT4 risk allele for SLE for its association with cardiovascular disease in SLE