Loss-of-Function Mutations inAPOC3,Triglycerides, and Coronary Disease

Abstract

Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10−20), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8×10−10). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4×10−6). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.)

Remnant Lipoprotein Cholesterol and Incident Coronary Heart Disease: The Jackson Heart and Framingham Offspring Cohort Studies

“…Recent Mendelian randomization studies suggested a prominent role of apoCIII activity in atherosclerotic disease by evaluating the effects of lifelong exposure to genetically reduced apoCIII function and reduced TG levels 14, 15. apoCIII is an integral component of RLPs and inhibits the function of lipoprotein lipase and hepatic lipase, while potentially promoting VLDL assembly 44, 45.…”

“…Historically, some studies have suggested that this association is attenuated by the inclusion of other potentially causal factors such as HDL‐C, thus raising the question of whether RLPs may represent a surrogate for other causative factors in atherosclerotic disease 12, 13. Recent Mendelian randomization studies have served as the strongest evidence that RLPs are etiologic for atherosclerosis 6, 14, 15, 16. Further, TGs are predictive of residual risk in statin‐treated individuals 17.…”

“…Further, TGs are predictive of residual risk in statin‐treated individuals 17. However, this extensive recent work relies on surrogate measures of RLP‐C and mainly stems from European populations and thus is not necessarily generalizable to the ethnically diverse US population 8, 14, 15, 16, 18…”

Prediction of Cardiovascular Disease by the Framingham‐REGICOR Equation in the High‐Risk PREDIMED Cohort: Impact of the Mediterranean Diet Across Different Risk Strata

“…Results of noninvasive vascular imaging techniques have been shown to improve cardiovascular risk prediction 38. Newer evidence from large genetic studies39, 40 indicates that triglycerides, the culprit of atherogenic dyslipidemia,41 is causally related to future CVD events, and triglyceride lipoprotein content has been associated with preclinical atherosclerosis 42. Triglycerides, as well as high‐density lipoprotein cholesterol, may contribute to residual cardiovascular risk beyond LDL cholesterol levels 43, 44.…”

APOC3 may not be a predictor of risk of ischemic vascular disease in the Chinese population

“…Most studies have focused on susceptibility factors contributing to an increased risk 1 , while only few studies have identified protective variants conferring reduced risk. Recently, the TG and HDL Working Group and Jørgensen et al reported that loss-of-function mutations in APOC3 are associated with decreased triglyceride levels and a reduced risk of ischemic vascular disease in individuals of European and African ancestry 2, 3 . Approximately 1 in 150 individuals were heterozygous carriers of at least one of the four mutations: R19X, A43T, IVS2+1G→A, and IVS3+1G→T.…”