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

Publication ,  Journal Article
Do, R; Stitziel, NO; Won, H-H; Jørgensen, AB; Duga, S; Angelica Merlini, P; Kiezun, A; Farrall, M; Goel, A; Zuk, O; Guella, I; Asselta, R ...
Published in: Nature
February 5, 2015

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. 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 cholesterol. 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 lipase 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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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

February 5, 2015

Volume

518

Issue

7537

Start / End Page

102 / 106

Location

England

Related Subject Headings

  • United States
  • Triglycerides
  • Receptors, LDL
  • National Heart, Lung, and Blood Institute (U.S.)
  • Myocardial Infarction
  • Mutation
  • Middle Aged
  • Male
  • Humans
  • Heterozygote
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Do, R., Stitziel, N. O., Won, H.-H., Jørgensen, A. B., Duga, S., Angelica Merlini, P., … Kathiresan, S. (2015). Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature, 518(7537), 102–106. https://doi.org/10.1038/nature13917
Do, Ron, Nathan O. Stitziel, Hong-Hee Won, Anders Berg Jørgensen, Stefano Duga, Pier Angelica Merlini, Adam Kiezun, et al. “Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.Nature 518, no. 7537 (February 5, 2015): 102–6. https://doi.org/10.1038/nature13917.
Do R, Stitziel NO, Won H-H, Jørgensen AB, Duga S, Angelica Merlini P, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015 Feb 5;518(7537):102–6.
Do, Ron, et al. “Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.Nature, vol. 518, no. 7537, Feb. 2015, pp. 102–06. Pubmed, doi:10.1038/nature13917.
Do R, Stitziel NO, Won H-H, Jørgensen AB, Duga S, Angelica Merlini P, Kiezun A, Farrall M, Goel A, Zuk O, Guella I, Asselta R, Lange LA, Peloso GM, Auer PL, NHLBI Exome Sequencing Project, Girelli D, Martinelli N, Farlow DN, DePristo MA, Roberts R, Stewart AFR, Saleheen D, Danesh J, Epstein SE, Sivapalaratnam S, Hovingh GK, Kastelein JJ, Samani NJ, Schunkert H, Erdmann J, Shah SH, Kraus WE, Davies R, Nikpay M, Johansen CT, Wang J, Hegele RA, Hechter E, Marz W, Kleber ME, Huang J, Johnson AD, Li M, Burke GL, Gross M, Liu Y, Assimes TL, Heiss G, Lange EM, Folsom AR, Taylor HA, Olivieri O, Hamsten A, Clarke R, Reilly DF, Yin W, Rivas MA, Donnelly P, Rossouw JE, Psaty BM, Herrington DM, Wilson JG, Rich SS, Bamshad MJ, Tracy RP, Cupples LA, Rader DJ, Reilly MP, Spertus JA, Cresci S, Hartiala J, Tang WHW, Hazen SL, Allayee H, Reiner AP, Carlson CS, Kooperberg C, Jackson RD, Boerwinkle E, Lander ES, Schwartz SM, Siscovick DS, McPherson R, Tybjaerg-Hansen A, Abecasis GR, Watkins H, Nickerson DA, Ardissino D, Sunyaev SR, O’Donnell CJ, Altshuler D, Gabriel S, Kathiresan S. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015 Feb 5;518(7537):102–106.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

February 5, 2015

Volume

518

Issue

7537

Start / End Page

102 / 106

Location

England

Related Subject Headings

  • United States
  • Triglycerides
  • Receptors, LDL
  • National Heart, Lung, and Blood Institute (U.S.)
  • Myocardial Infarction
  • Mutation
  • Middle Aged
  • Male
  • Humans
  • Heterozygote