Genetic variants in eleven telomere-associated genes and the risk of incident cardio/cerebrovascular disease: The Women's Genome Health Study

Background: Candidate genes associated with telomere length maintenance, an important molecular marker for biological aging, represent potential risk predictors for cardiovascular disease (CVD). To date, no prospective data are available.

Methods: The associations between 154 tag-single nucleotide polymorphisms (tSNPs) of 11 telomere-associated candidate genes (TERT, POT1, TNKS, TERF1, TNKS2, UCP2, TEP1, ACD, TERF2, TERF2IP, and TERC) were investigated in 23,294 Caucasian participants of the Women's Genome Health Study. All were free of known CVD and cancer at baseline. The primary outcome measure was a composite CVD end point (incident ischemic stroke, myocardial infarction (MI), or death due to ischemic CVD); other measures were incident MI and ischemic stroke. During follow-up, 1178 total incident CVD, 315 incident MI cases, and 323 incident ischemic stroke events were identified. Multivariable Cox regression analysis and a haplotype-based approach were performed to investigate the relationship between genotypes/haplotypes and CVD risk, assuming an additive model.

Results: In a marker-by-marker analysis, 7 (TEP1, TNKS, and ACD), 11 (TEP1, ACD, and TERT), and 24 (TEP1, TNKS, TERT, TERF2IP, TNKS2, and UCP2) SNPs were associated-at the level of p < 0.05-with the total CVD, MI, and ischemic stroke risk, respectively. Further analysis using a haplotype-based approach showed similar findings. Although none remained significant after the correction of multiple testing, the false discovery rate analysis revealed 28% of the nominally significant SNPs with true associations in relation to ischemic stroke risk.

Conclusions: The present large prospective study encourages further investigation of the biological role of telomere-associated pathway genes in the pathogenesis and early assessment of vascular events.