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Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.
Friday,2015-04-17 14:24 America/Los_Angeles — zdrager
| Title | Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. |
| Publication Type | Journal Article |
| Year of Publication | 2015 |
| Authors | Do, R, Stitziel, NO, Won, H-H, Jørgensen, ABerg, Duga, S, Merlini, PAngelica, Kiezun, A, Farrall, M, Goel, A, Zuk, O, Guella, I, Asselta, R, Lange, LA, Peloso, GM, Auer, PL, Girelli, D, Martinelli, N, Farlow, DN, DePristo, MA, Roberts, R, Stewart, AFR, Saleheen, D, Danesh, J, Epstein, SE, Sivapalaratnam, S, G Hovingh, K, Kastelein, JJ, Samani, NJ, Schunkert, H, Erdmann, J, Shah, SH, Kraus, WE, Davies, R, Nikpay, M, Johansen, CT, Wang, J, Hegele, RA, Hechter, E, März, 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, AL, Rader, DJ, Reilly, MP, Spertus, JA, Cresci, S, Hartiala, J, Tang, WHWilson, 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 |
| Corporate/Institutional Authors | NHLBI Exome Sequencing Project, |
| Journal | Nature |
| Volume | 518 |
| Issue | 7537 |
| Pagination | 102-6 |
| Date Published | 2015 Feb 5 |
| ISSN | 1476-4687 |
| Keywords | Age Factors, Age of Onset, Alleles, Apolipoproteins A, Case-Control Studies, Cholesterol, LDL, Coronary Artery Disease, Exome, Female, Genetic Predisposition to Disease, Genetics, Population, Heterozygote, Humans, Male, Middle Aged, Mutation, Myocardial Infarction, National Heart, Lung, and Blood Institute (U.S.), Receptors, LDL, Triglycerides, United States |
| Abstract | <p>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.</p> |
| DOI | 10.1038/nature13917 |
| Alternate Journal | Nature |
| PubMed ID | 25487149 |
| PubMed Central ID | PMC4319990 |
| Grant List | 090532 / / Wellcome Trust / United Kingdom 095552 / / Wellcome Trust / United Kingdom 5U54HG003067-11 / HG / NHGRI NIH HHS / United States G-0907 / / Parkinson's UK / United Kingdom K08 HL114642 / HL / NHLBI NIH HHS / United States K08HL114642 / HL / NHLBI NIH HHS / United States MR/L003120/1 / / Medical Research Council / United Kingdom P01 HL076491 / HL / NHLBI NIH HHS / United States P01 HL076491 / HL / NHLBI NIH HHS / United States P01 HL098055 / HL / NHLBI NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States R01 HL107816 / HL / NHLBI NIH HHS / United States R01HL107816 / HL / NHLBI NIH HHS / United States RC2 HL-102923 / HL / NHLBI NIH HHS / United States RC2 HL-102924 / HL / NHLBI NIH HHS / United States RC2 HL-102925 / HL / NHLBI NIH HHS / United States RC2 HL-102926 / HL / NHLBI NIH HHS / United States RC2 HL-103010 / HL / NHLBI NIH HHS / United States RG/08/014/24067 / / British Heart Foundation / United Kingdom T32 HL007208 / HL / NHLBI NIH HHS / United States T32HL00720 / HL / NHLBI NIH HHS / United States T32HL007604 / HL / NHLBI NIH HHS / United States UL1 TR000439 / TR / NCATS NIH HHS / United States / / Canadian Institutes of Health Research / Canada |