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

Ron Do, Nathan O. Stitziel, Hong Hee Won, Anders Berg Jørgensen, Stefano Duga, Pier Angelica Merlini, Adam Kiezun, Martin Farrall, Anuj Goel, Or Zuk, Illaria Guella, Rosanna Asselta, Leslie A. Lange, Gina M. Peloso, Paul L. Auer, Domenico Girelli, Nicola Martinelli, Deborah N. Farlow, Mark A. DePristo, Robert RobertsAlexander F R Stewart, Danish Saleheen, John Danesh, Stephen E. Epstein, Suthesh Sivapalaratnam, G. Kees Hovingh, John J. Kastelein, Nilesh J. Samani, Heribert Schunkert, Jeanette Erdmann, Svati H. Shah, William E. Kraus, Robert Davies, Majid Nikpay, Christopher T. Johansen, Jian Wang, Robert A. Hegele, Eliana Hechter, Winfried Marz, Marcus E. Kleber, Jie Huang, Andrew D. Johnson, Mingyao Li, Greg L. Burke, Myron Gross, Yongmei Liu, Themistocles L. Assimes, Gerardo Heiss, Ethan M. Lange, Aaron R. Folsom, Herman A. Taylor, Oliviero Olivieri, Anders Hamsten, Robert Clarke, Dermot F. Reilly, Wu Yin, Manuel A. Rivas, Peter Donnelly, Jacques E. Rossouw, Bruce M. Psaty, David M. Herrington, James G. Wilson, Stephen S. Rich, Michael J. Bamshad, Russell P. Tracy, L. Adrienne Cupples, Daniel J. Rader, Muredach P. Reilly, John A. Spertus, Sharon Cresci, Jaana Hartiala, W. H Wilson Tang, Stanley L. Hazen, Hooman Allayee, Alex P. Reiner, Christopher S. Carlson, Charles Kooperberg, Rebecca D. Jackson, Eric Boerwinkle, Eric S. Lander, Stephen M. Schwartz, David S. Siscovick, Ruth McPherson, Anne Tybjaerg-Hansen, Goncalo R. Abecasis, Hugh Watkins, Deborah A. Nickerson, Diego Ardissino, Shamil R. Sunyaev, Christopher J. O'Donnell, David Altshuler, Stacey Gabriel, Sekar Kathiresan

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380 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)102-106
Number of pages5
JournalNature
Volume518
Issue number7537
DOIs
StatePublished - Feb 5 2015

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