Literature-Based Genetic Risk Scores and Cardiovascular Disease Events in Women

Risk prevention in cardiovascular disease (CVD) has improved in recent years as genomewide association studies have found possible genetic and molecular markers (especially those in the 9p21 region) that are directly associated with CVD. But the aggregate effect of these possible breakthroughs has not yet been determined. This is particularly the case among women. Clinicians have proposed a multilocus genetic risk score to capture the complex relationship between genetics and CVD.

The objective of this prospective cohort study [JAMA. 2010;303(7):631-637] was to test the predictive ability of a literature-based genetic risk score for CVD. A total of 19,313 initially healthy female health professionals who were part of the Women’s Genome Health Study, an ongoing prospective cohort derived from the Women’s Health Study, were included in the analysis. All women self-reported as white.

The investigators developed 2 genetic risk scores based on a comprehensive literature-based selection of genetic markers known to be associated with CVD or intermediate phenotypes (cholesterol and blood pressure) selected from the database of the National Human Genome Research Institute (NHGRI). Genetic risk scores were derived from the NHGRI’s catalog of genomewide association study results published between 2005 and June 2009. Two scores were utilized; a primary score and a secondary score limited only to those single-nucleotide polymorphisms (SNPs) with a published association with incident CVD. Main outcome measures were incidence of myocardial infarction, stroke, arterial revascularizaton, and CVD death. Patients were followed up for a median of 12.3 years (interquartile range, 11.6-12.8 years).

A total of 157 SNPs that were considered to be associated with CVD or an intermediate phenotype were identified; 101 were ultimately used to compute the primary genetic risk score, and 12 were used to compute the secondary genetic risk score. At baseline, the female participants had a median age of 52.8 years (25th-75th percentile, 48.9-58.9 years), a median systolic blood pressure of 125 mm Hg (25th-75th percentile, 115-135 mm Hg), and a median total cholesterol level of 208 mg/dL (25th-75th percentile, 184-235 mg/dL).

During follow-up, there were 777 CVD events (199 myocardial infarctions, 203 strokes, 63 CVD deaths, and 312 revascularizations). Mean (SD) score using the 101 SNPs was 102.1 (6.4), with a range from 73 to 125. Mean (SD) score using 12 SNPs was 10.7 (1.9), with a range from 4 to 19.

The 101 SNP genetic risk score was positively correlated with total cholesterol, systolic blood pressure, and C-reactive protein, and negatively associated with high-density lipoprotein cholesterol. After adjustment for age, the genetic risk score had a hazard ratio (HR) for CVD of 1.02 per risk allele (95% confidence interval [CI], 1.00-1.03/risk allele; P=.006). This corresponds to an absolute CVD risk of 3% over 10 years in the lowest tertile of genetic risk (73-99 risk alleles) and 3.7% in the highest tertile (106-125 risk alleles).

Even after adjustment, family history of premature myocardial infarction remained an independent risk factor for incident CVD (HR, 1.57; 95% CI, 1.31-1.89). Genetic risk score was not associated with CVD (Adult Treatment Panel III–adjusted HR/allele, 1.00; 95% CI, 0.99-1.01).

The ability of either risk score to discriminate between women at risk for cardiovascular events and those not at risk was minimal; as well, after adjustment for traditional risk factors, neither score was associated with incident CVD and did not have any impact on discrimination or reclassification.—Kevin L. Carter