Abstract 17820: Rare Loss-of-Function Mutations in the Apolipoprotein C-III gene, Plasma Triglycerides, and Risk for Coronary Heart Disease
BACKGROUND: Plasma triglycerides reflect the concentration of circulating triglyceride-rich lipoproteins, and is a heritable factor correlated with risk for coronary heart disease (CHD). Sequencing the protein-coding regions of the human genome (‘the exome’) has the potential to discover rare mutations with a large effect on a phenotype.
METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3,734 participants of European and African-American ancestries from the U.S. National Heart, Lung, and Blood Institute’s Exome Sequencing Project. We tested whether rare coding sequence mutations, individually or aggregated within a gene, were associated with plasma triglycerides. For mutations associated with plasma triglycerides, we subsequently evaluated association with risk for CHD in 110,970 participants.
RESULTS: A burden of rare mutations in the apolipoprotein C-III (APOC3) gene was associated with lower plasma triglycerides. Of four mutations that drove this association result, three were annotated as loss-of-function (R19X, splice site mutation IVS2+1 G>A, and splice site mutation IVS3+1 G>T) and a fourth as missense (A43T). About one in 200 individuals was a heterozygous carrier of at least one of these four mutations. Carriers of any of these four mutations had 38% lower plasma triglycerides (P < 1 x 10-20) and 46% lower concentration of circulating apoC-III protein (P = 8 x 10-10). APOC3 rare mutation carriers were at 40% reduced risk for CHD (OR 0.60, 95% CI 0.47 - 0.75, P=4 x 10-6 among 110,472 non-carriers and 498 carriers)(Figure).
CONCLUSIONS: Rare mutations that disrupt APOC3 gene function protect against clinical CHD, with lower plasma triglycerides and apoC-III protein serving as biomarkers of reduced gene function.
- © 2013 by American Heart Association, Inc.