Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease

Abstract

Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.

Figure 1

Relationship between the effect of sequence variants on non-HDL cholesterol and their effect on risk of coronary artery disease, (a) Effect on CAD risk of 100 known common (minor allele frequency (MAF) >5%) lipid-associated variants^,, that associate with non-HDL cholesterol in Iceland (P < 0.05). (b) Effect on CAD of the 27 rare and low-frequency lipid-associated variants identified in this study. Previously published variants are colored blue, and new variants are colored red. In both plots, the effect on non-HDL cholesterol (n = 119,146) is given in mmol/L, and the effect on CAD risk (n = 33,090 cases and 236,254 controls) is represented by the odds ratio (OR). Bars represent 95% confidence intervals for the effect on non-HDL cholesterol and risk of CAD. The black line is the line best fitting the common variant, and the gray line is the line best fitting the CAD odds ratio on the log scale transformed back to the original scale.