Variation in ANGPTL4 and risk of coronary heart disease: the Atherosclerosis Risk in Communities Study

Abstract

An E40K loss-of-function variant in the ANGPTL4 gene is associated with substantially reduced plasma triglyceride levels in white persons, but its association with cardiovascular disease occurrence has not been reported. The prospective, population-based Atherosclerosis Risk in Communities Study measured the E40K ANGPTL4 variant in approximately 10000 white participants and determined its association with coronary heart disease (CHD) incidence (n = 1318 events) between 1987-1989 and 2004. Compared with noncarriers, carriers of 1 or 2 copies of the 40K variant (3.8% frequency) had a 19-mg/dL lower age- and sex-adjusted mean triglyceride level, 5-mg/dL lower low-density lipoprotein cholesterol, and 4-mg/dL higher high-density lipoprotein cholesterol. The age-, sex-, and field center–adjusted hazard ratio of CHD was 0.63 (95% confidence interval, 0.45-0.89). Adjustment for nonlipid confounding factors did not change this hazard ratio appreciably. Carriers also appeared to have reduced risk of incident stroke, prevalent peripheral artery disease, and carotid atherosclerosis; but these associations were based on few events among 40K carriers and were not statistically significant. In conclusion, in this prospective study, the 40K variant of ANGPTL4 appeared to confer reduced genetic risk for CHD.

Introduction

It is well established that higher blood levels of low-density lipoprotein cholesterol (LDL-C) and lower levels of high-density lipoprotein cholesterol (HDL-C) increase the risk of atherosclerotic cardiovascular disease (CVD). Whether higher blood triglyceride levels increase the risk of atherosclerotic events has been less clear. However, a recent meta-analysis involving 10158 incident coronary heart disease (CHD) cases from 29 studies and corrected for within-person measurement error reported that triglycerides have a moderate independent association with CHD incidence [1]. Comparing the top vs the bottom third of usual log-triglyceride values, the adjusted odds ratio (OR) of CHD was 1.72 (95% confidence interval [CI], 1.56-1.90).

A recent report from 3 cohort studies indicated that an E40K loss-of-function variant in ANGPTL4, a gene involved in partitioning of fatty acids between sites of storage and sites of oxidation, is associated with substantially reduced plasma levels of triglyceride and increased HDL-C in white persons [2]. The E40K polymorphism, which is not currently listed in the Single Nucleotide Polymorphism Database, entails a 118G to A base substitution at codon 40 changing the amino acid from glutamic acid to lysine. In the Atherosclerosis Risk in Communities (ARIC) Study, the 40K variant (1 or 2 copies) was present in 4% of white persons but was very rare in African Americans. Besides lower triglyceride and higher HDL-C, 40K carriers had modestly decreased LDL-C and insulin levels [2]. Whether the ANGPTL4 E40K variant is associated with cardiovascular events has not yet been explored.

We used data from the ARIC Study to determine whether there is an association between the ANGPTL4 E40K variant and incidence of CHD. As secondary analyses, some of which had low statistical power, we also looked at associations with prevalence of carotid atherosclerosis or peripheral artery disease (PAD) and incidence of ischemic stroke.