2 research outputs found
Loss-of-function mutations in APOC3, triglycerides, and coronary disease
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+1GโA and IVS3+1GโT). 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<1ร10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8ร10(-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=4ร10(-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.)
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this
association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent
of non-genetic confounding, and are unmodifi ed by disease processes, mendelian random isation can be used to test
the hypothesis that the association of a plasma biomarker with disease is causal.
Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide
polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies
(20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of
14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of
myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs
exclusively associated with LDL cholesterol.
Findings Carriers of the LIPG 396Ser allele (2ยท6% frequency) had higher HDL cholesterol (0ยท14 mmol/L higher,
p=8ร10โ
ยนยณ) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers.
This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio
[OR] 0ยท87, 95% CI 0ยท84โ0ยท91). However, we noted that the 396Ser allele was not associated with risk of myocardial
infarction (OR 0ยท99, 95% CI 0ยท88โ1ยท11, p=0ยท85). From observational epidemiology, an increase of 1 SD in HDL
cholesterol was associated with reduced risk of myocardial infarction (OR 0ยท62, 95% CI 0ยท58โ0ยท66). However, a 1 SD
increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0ยท93,
95% CI 0ยท68โ1ยท26, p=0ยท63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in
LDL cholesterol associated with OR 1ยท54, 95% CI 1ยท45โ1ยท63) was concordant with that from genetic score (OR 2ยท13,
95% CI 1ยท69โ2ยท69, p=2ร10โ
ยนโฐ).
Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial
infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into
reductions in risk of myocardial infarction.
Funding US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the
German Federal Ministry of Education and Research