Influence of common genetic variation on blood lipid levels, cardiovascular risk, and coronary events in two British prospective cohort studies

Abstract

Aims: The aim of this study was to quantify the collective effect of common lipid-associated single nucleotide polymorphisms (SNPs) on blood lipid levels, cardiovascular risk, use of lipid-lowering medication, and risk of coronary heart disease (CHD) events.

Methods and results: Analysis was performed in two prospective cohorts: Whitehall II (WHII; N = 5059) and the British Women's Heart and Health Study (BWHHS; N = 3414). For each participant, scores were calculated based on the cumulative effect of multiple genetic variants influencing total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Compared with the bottom quintile, individuals in the top quintile of the LDL-C genetic score distribution had higher LDL-C {mean difference of 0.85 [95% confidence interval, (CI) = 0.76-0.94] and 0.63 [95% CI = 0.50-0.76] mmol/l in WHII and BWHHS, respectively}. They also tended to have greater odds of having 'high-risk' status (Framingham 10-year cardiovascular disease risk >20%) [WHII: odds ratio (OR) = 1.36 (0.93-1.98), BWHHS: OR = 1.49 (1.14-1.94)]; receiving lipid-lowering treatment [WHII: OR = 2.38 (1.57-3.59), BWHHS: OR = 2.24 (1.52-3.29)]; and CHD events [WHII: OR = 1.43 (1.02-2.00), BWHHS: OR = 1.31 (0.99-1.72)]. Similar associations were observed for the TC score in both studies. The TG score was associated with high-risk status and medication use in both studies. Neither HDL nor TG scores were associated with the risk of coronary events. The genetic scores did not improve discrimination over the Framingham risk score.

Conclusion: At the population level, common SNPs associated with LDL-C and TC contribute to blood lipid variation, cardiovascular risk, use of lipid-lowering medications and coronary events. However, their effects are too small to discriminate future lipid-lowering medication requirements or coronary events.

Figure 1

Association of lipid genetic scores with actual lipid medication use. Odds ratio of using lipid-modifying drugs in top vs. bottom quintiles of the genetic score distribution. (A) Unadjusted odds ratios and (B) adjusted for the respective lipid fraction.

Figure 2

Association of lipid genetic scores with coronary heart disease. Odds ratio of coronary heart disease for individuals in the top quintile of the lipid genetic score distribution compared with individuals in the bottom quintile. Odds ratios and P values are shown for (A) unadjusted analyses and (B) adjusted for the respective lipid fraction.

Figure 3

Prediction of lipid drug usage and coronary heart disease events in Whitehall II using lipid genetic scores area under the receiver operating characteristic for discriminating between high-risk individuals based on a Framingham risk >20% in (A) the Whitehall II study and (B) the British Women's Heart and Health Study, actual use of lipid medication in (C) the Whitehall II and (D) the British Women's Heart and Health Study, and coronary heart disease in (E) the Whitehall II and (F) the British Women's Heart and Health Study.