title: Genetic variation in WRN and ischemic stroke: General population studies and meta-analyses.
abstract: Werner syndrome, a premature genetic aging syndrome, shares many clinical features reminiscent of normal physiological aging, and ischemic vascular disease is a frequent cause of death. We tested the hypothesis that genetic variation in the WRN gene was associated with risk of ischemic vascular disease in the general population.
  
  
  
  We included 58,284 participants from two general population cohorts, the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS). Of these, 6,312 developed ischemic vascular disease during follow-up. In the CCHS (n=10,250), we genotyped all non-synonymous variants in WRN with reported minor allele frequencies ≥0.5% in Caucasians. Second, variants which were associated with ischemic vascular disease in the CCHS or in previous studies, were genotyped in the CGPS (n=48,034).
  
  
  
  A total of 11 non-synonymous variants were identified in the CCHS. In C1367R (rs1346044) TT homozygotes versus CC/CT, hazard ratios for ischemic stroke were 1.09 (95% confidence interval: 0.95-1.24; P=0.22) in the CCHS, 1.16 (1.00-1.33; P=0.04) in the CGPS, and 1.12 (1.01-1.23; P=0.02) in studies combined (CCHS+CGPS), with similar trends for ischemic cerebrovascular disease (P=0.06). In meta-analyses including 59,190 individuals in 5 studies, the hazard ratio for ischemic stroke for C1367R TT homozygotes versus CC/CT was 1.14 (1.04-1.25; P=0.008).
  
  
  
  This study suggests that common genetic variation in WRN is associated with increased risk of ischemic stroke in the general population.
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: mette.christoffersen.02@regionh.dk.
authors.forename: Mette
authors.initials: M
authors.lastname: Christoffersen
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: ruth.frikke-schmidt@regionh.dk.
authors.forename: Ruth
authors.initials: R
authors.lastname: Frikke-Schmidt
authors.affiliation: The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Nordre Fasanvej 57, DK-2000 Frederiksberg, Denmark; Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: boerge.nordestgaard@regionh.dk.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Nordre Fasanvej 57, DK-2000 Frederiksberg, Denmark; Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: anne.tybjaerg.hansen@regionh.dk.
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjærg-Hansen
mesh_terms: D000328:Adult; D000368:Aged; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012307:Risk Factors; D020521:Stroke / Q000235:genetics* / Q000401:mortality; D000071657:Werner Syndrome Helicase / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: C098785:WRN protein, human; D000071657:Werner Syndrome Helicase
keywords: Cardiovascular disease; Epidemiology; Genetics