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

MedStar author(s):
Citation: Nature. 518(7537):102-6, 2015 Feb 5.PMID: 25487149Institution: MedStar Health Research InstituteForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov'tSubject headings: *Alleles | *Apolipoproteins A/ge [Genetics] | *Exome/ge [Genetics] | *Genetic Predisposition to Disease/ge [Genetics] | *Myocardial Infarction/ge [Genetics] | *Receptors, LDL/ge [Genetics] | Age Factors | Age of Onset | Case-Control Studies | Cholesterol, LDL/bl [Blood] | Coronary Artery Disease/ge [Genetics] | Female | Genetics, Population | Heterozygote | Humans | Male | Middle Aged | Mutation/ge [Genetics] | Myocardial Infarction/bl [Blood] | National Heart, Lung, and Blood Institute (U.S.) | Triglycerides/bl [Blood] | United StatesLocal holdings: Available online from MWHC library: 1995 - 2009, Available in print through MWHC library: 1999 - 2006ISSN:
  • 0028-0836
Name of journal: NatureAbstract: 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.All authors: Abecasis GR, Allayee H, Altshuler D, Angelica Merlini P, Ardissino D, Asselta R, Assimes TL, Auer PL, Bamshad MJ, Boerwinkle E, Burke GL, Carlson CS, Clarke R, Cresci S, Cupples LA, Danesh J, Davies R, DePristo MA, Do R, Donnelly P, Duga S, Epstein SE, Erdmann J, Farlow DN, Farrall M, Folsom AR, Gabriel S, Girelli D, Goel A, Gross M, Guella I, Hamsten A, Hartiala J, Hazen SL, Hechter E, Hegele RA, Heiss G, Herrington DM, Hovingh GK, Huang J, Jackson RD, Johansen CT, Johnson AD, Jorgensen AB, Kastelein JJ, Kathiresan S, Kiezun A, Kleber ME, Kooperberg C, Kraus WE, Lander ES, Lange EM, Lange LA, Li M, Liu Y, Martinelli N, Marz W, McPherson R, NHLBI Exome Sequencing Project, Nickerson DA, Nikpay M, O'Donnell CJ, Olivieri O, Peloso GM, Psaty BM, Rader DJ, Reilly DF, Reilly MP, Reiner AP, Rich SS, Rivas MA, Roberts R, Rossouw JE, Saleheen D, Samani NJ, Schunkert H, Schwartz SM, Shah SH, Siscovick DS, Sivapalaratnam S, Spertus JA, Stewart AF, Stitziel NO, Sunyaev SR, Tang WH, Taylor HA, Tracy RP, Tybjaerg-Hansen A, Wang J, Watkins H, Wilson JG, Won HH, Yin W, Zuk ODigital Object Identifier: Date added to catalog: 2016-01-13
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article Available 25487149

Available online from MWHC library: 1995 - 2009, Available in print through MWHC library: 1999 - 2006

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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