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Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction

Abstract

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, genetic inheritance is a major component to risk1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3,4,5,6,7,8, whereas common variants at more than 45 loci have been associated with MI risk in the population9,10,11,12,13,14,15. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol16. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl−1. At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

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Figure 1: Overall design for the early-onset myocardial infarction study within the US National Heart, Lung, and Blood Institute’s exome sequencing project (ESP).
Figure 2: Apolipoprotein A-V (APOA5) mutations discovered after sequencing of 13,432 individuals.
Figure 3: Low-density lipoprotein receptor (LDLR) mutations discovered after sequencing 9,793 individuals.

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Data deposits

DNA sequences have been deposited with the NIH dbGAP repository under accession numbers phs000279 and phs000814.

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Acknowledgements

The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the National Human Genome Research Institute (NHGRI) of the US National Institutes of Health (NIH) and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. Funding for the exome sequencing project (ESP) was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO) and RC2 HL-102924 (WHISP). Exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Exome sequencing in the ATVB, PROCARDIS, and Ottawa studies was supported by NHGRI 5U54HG003067-11 to E.S.L. and S.G. Cleveland Clinic GeneBank was supported by NIH grants P01 HL076491 and P01 HL098055. S.K. is supported by a Research Scholar award from the Massachusetts General Hospital (MGH), the Howard Goodman Fellowship from MGH, the Donovan Family Foundation, R01HL107816, and a grant from Fondation Leducq. R.D. is supported by a Banting Fellowship from the Canadian Institutes of Health Research. N.O.S. is supported, in part, by a career development award from the NIH/NHLBI K08HL114642 and by The Foundation for Barnes-Jewish Hospital. N.O.S. was supported by award number T32HL007604 from the NHLBI. G.M.P was supported by award number T32HL007208 from the NHLBI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI, NHGRI, or NIH. The Italian ATVB Study was supported by a grant from RFPS-2007-3-644382. A full listing of acknowledgements is provided in the Supplementary Information.

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R.Do, N.O.S., H.-H.W., A.B.J., and A.K. carried out the primary data analyses. R.Do, N.O.S., L.A.L., G.M.P., P.L.A., J.E.R., B.M.P., D.M.H., J.G.W., S.S.R., M.J.B., R.P.T., L.A.C., S.L.H., H.A., J.A.S., S.C., C.S.C., C.K., R.D.J., E.B., G.R.A., S.M.S., D.S.S., D.A.N., S.R.S., C.J.O., D. Altshuler, S.G., and S.K. contributed to the design and conduct of the discovery exome sequencing study. S.G., D.N.F., and M.A.D. enabled the exome sequencing, variant calling, and annotation. R.Do, N.O.S., H.-H.W., A.B.J., S.D., P.A.M., M.F., A.G., I.G., R.A., D.G., N.M., O.O., R.R., A.F.R.S., D.S., J.D., S.E.E., S.S., G.K.H., J.J.K., N.J.S., H.S., J.E., S.H.S., W.E.K., C.T.J., R.A.H., O.Z, E.H., W.M., M.N., J.W., A.H., R.C., D.F.R, W.Y., M.E.K., J.H., A.D.J., M.L., G.L.B., M.G., Y.L., T.L.A., G.H., E.M.L., A.R.F., H.A.T., M.A.R., P.D., D.J.R., M.P.R., J.H., W.W.H.T., A.P.R., D. Ardissino, D. Altshuler, R.M., A.T.-H., H.W., and S.K. contributed to the design and conduct of the imputation-based validation, genotyping-based validation, and/or the re-sequencing based validation study. S.S. supervised the analysis of exome sequencing data and power analysis. R.Do, N.O.S., H.-H.W., S.D., P.A.M., M.F., A.G., R.A., E.S.L., R.M., H.W., D. Ardissino, S.G., and S.K. contributed to the design and conduct of the replication exome sequencing study. S.G., E.S.L., S.K., D.A.N., and D. Altshuler obtained funding. D. Altshuler, D.A.N., S.S.R., R.D.J., and M.J.B. comprised the executive committee of the NHLBI Exome Sequencing Project. C.J.O. and S.K. led the Early-Onset Myocardial Infarction study team within the NHLBI Exome Sequencing Project. R.Do, N.O.S., H.-H.W. and S.K. wrote the manuscript.

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This file contains a list of acknowledgements, Supplementary Figures 1-32, Supplementary Tables 1-26 and Supplementary References. (PDF 6382 kb)

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Do, R., Stitziel, N., Won, HH. et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518, 102–106 (2015). https://doi.org/10.1038/nature13917

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