Association Between a Literature-Based Genetic Risk Score and Cardiovascular Events in Women

Abstract

ABSTRACT Genetic markers associated with cardiovascular disease, which may be predictive, have been identified by of genome-wide association studies, but their predictive ability has not been tested. The evaluation of a literature-based genetic risk score for cardiovascular disease is now possible using the online catalog maintained by the National Human Genome Research Institute of all genetic markers identified in genome-wide association studies. This prospective cohort study investigated the predictive ability of literature-based genetic risk scores for cardiovascular disease, and tested their relationship to incident cardiovascular events and their potential to improve prediction. The participants—a cohort of 19,313 initially healthy females enrolled in the Women's Genome Health Study—were followed for a median of 12.3 years. Genetic risk scores were constructed using the online National Human Genome Research Institute catalog of studies published between 2005 and 2009. The scores were based on the selection of single nucleotide polymorphisms (SNPs) that were known markers associated with either cardiovascular disease (myocardial infarction, stroke, coronary disease, or cardiovascular death), or an intermediate phenotype (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, hypertension, and other phenotypes). A total of 101 SNPs were identified with a published risk allele and a P value of less than or equal to 10−7 for the association with cardiovascular disease or at least 1 intermediate phenotype; the addition of risk alleles created the genetic risk score. During the follow-up period, there were 777 incident cardiovascular events (199 myocardial infarctions, 203 strokes, 63 cardiovascular deaths, and 312 revascularizations). Adjustment for age showed that the 101 SNP genetic risk scores were associated with increased risk of cardiovascular disease: the age-adjusted hazard ratio for cardiovascular disease per allele for the101 SNP genetic risk scores was 1.02 per risk allele, with a 95% confidence interval of 1.00 to 1.03 per risk allele; P = 0.006). Over a 10-year study period, this represented an absolute cardiovascular disease risk of 3% in the lowest tertile of genetic risk (73–99 risk alleles) and 3.7% in the highest tertile (106–125 risk alleles). However, after adjusting for traditional risk factors, the ability of the risk score alone to discriminate between women at risk for cardiovascular events and those not at risk was minimal with a c index of 0.52 in the ATP III (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults) risk score; the ATP III–adjusted hazard ratio per allele was 1.00, with a 95% CI of 0.99 to 1.01. In contrast, self-reported family history remained an independent risk factor in multivariate models for incident cardiovascular disease. These findings indicate that a genetic risk score comprised of 101 SNPs is not significantly associated with incident cardiovascular disease, after adjustment for traditional risk factors, and has no significant effect on discrimination or reclassification.