Genetic variation in WRN and ischemic stroke: General population studies and meta-analyses

BACKGROUND: 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.

METHODS: 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).

RESULTS: 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).

CONCLUSIONS: This study suggests that common genetic variation in WRN is associated with increased risk of ischemic stroke in the general population.