Rare APOC3 loss-of-function variants lower plasma triglycerides and protect against clinical coronary heart disease. J. Crosby1,2, G. M. Peloso3,4, P. Auer5,6, D. R. Crosslin7,8, G. Jarvik7, L. A. Cupples9,10, A. Reiner11, E. Boerwinkle1,2,12, S. Kathiresan3,4,13 On Behalf of the Exome Sequencing Project HDL/TG Working Group 1) Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA; 2) Department of Biostatistics, Bioinformatics, and Systems Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA; 3) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; 4) Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; 5) Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 6) Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA; 7) Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA; 8) Department of Biostatistics, University of Washington, Seattle, WA, USA; 9) Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; 10) Framingham Heart Study, Framingham, MA, USA; 11) Department of Epidemiology, University of Washington, Seattle, WA, USA; 12) Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; 13) Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.

   Plasma concentration of triglycerides is heritable and correlated with risk for coronary heart disease (CHD). Whole exome sequencing has the potential to discover rare mutations with large effects on a phenotype of interest. 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 Institutes Exome Sequencing Project. Using linear regression and SCORE-Seq burden analyses, we tested whether rare mutations, individually or when aggregated within a gene, associated with plasma triglycerides. For mutations significantly associated with plasma triglycerides and replicated in an independent sample, we subsequently evaluated association with risk for CHD in 110,970 individuals. A burden of rare variants in the apolipoprotein C-III (APOC3) gene was associated with lower plasma triglyceride levels. This result could be attributed to four functional variants; 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). Carriers of R19X and splice site IVS2+1 G>A had 46% lower concentration of plasma apoC-III protein, consistent with loss of normal gene function. About 1 in 200 individuals were heterozygous carriers for at least one of the four variants and carriers had 38% lower plasma triglycerides (P < 1 x 10-20). 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). In conclusion, rare APOC3 variants that disrupt gene function lead to lower circulating apoC-III protein level, reduced plasma concentration of triglycerides, and a decreased risk for clinical CHD. These observations based on human knockout alleles highlight pharmacologic inhibition of APOC3 function as a promising strategy to prevent CHD.

You may contact the first author (during and after the meeting) at