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

• Published in: Nature (London) Vol. 518; no. 7537; pp. 102 - 106
• Main Authors: Do, Ron, Stitziel, Nathan O., Won, Hong-Hee, Jørgensen, Anders Berg, Duga, Stefano, Angelica Merlini, Pier, Kiezun, Adam, Farrall, Martin, Goel, Anuj, Zuk, Or, Guella, Illaria, Asselta, Rosanna, Lange, Leslie A., Peloso, Gina M., Auer, Paul L., Girelli, Domenico, Martinelli, Nicola, Farlow, Deborah N., DePristo, Mark A., Roberts, Robert, Stewart, Alexander F. R., Saleheen, Danish, Danesh, John, Epstein, Stephen E., Sivapalaratnam, Suthesh, Kees Hovingh, G., Kastelein, John J., Samani, Nilesh J., Schunkert, Heribert, Erdmann, Jeanette, Shah, Svati H., Kraus, William E., Davies, Robert, Nikpay, Majid, Johansen, Christopher T., Wang, Jian, Hegele, Robert A., Hechter, Eliana, Marz, Winfried, Kleber, Marcus E., Huang, Jie, Johnson, Andrew D., Li, Mingyao, Burke, Greg L., Gross, Myron, Liu, Yongmei, Assimes, Themistocles L., Heiss, Gerardo, Lange, Ethan M., Folsom, Aaron R., Taylor, Herman A., Olivieri, Oliviero, Hamsten, Anders, Clarke, Robert, Reilly, Dermot F., Yin, Wu, Rivas, Manuel A., Donnelly, Peter, Rossouw, Jacques E., Psaty, Bruce M., Herrington, David M., Wilson, James G., Rich, Stephen S., Bamshad, Michael J., Tracy, Russell P., Adrienne Cupples, L., Rader, Daniel J., Reilly, Muredach P., Spertus, John A., Cresci, Sharon, Hartiala, Jaana, Wilson Tang, W. H., Hazen, Stanley L., Allayee, Hooman, Reiner, Alex P., Carlson, Christopher S., Kooperberg, Charles, Jackson, Rebecca D., Boerwinkle, Eric, Lander, Eric S., Schwartz, Stephen M., Siscovick, David S., McPherson, Ruth, Tybjaerg-Hansen, Anne, Abecasis, Goncalo R., Watkins, Hugh, Nickerson, Deborah A., Ardissino, Diego, Sunyaev, Shamil R., O'Donnell, Christopher J., Altshuler, David, Gabriel, Stacey, Kathiresan, Sekar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.02.2015; Nature Publishing Group
• Subjects: 38/23; 631/208/514/1948; 631/208/514/2254; 631/208/727/2000; Age Factors; Age of Onset; Algorithms; Alleles; Apolipoprotein A-V; Apolipoproteins A - genetics; Cardiovascular disease; Case-Control Studies; Cholesterol; Cholesterol, LDL - blood; Coronary Artery Disease - genetics; Diagnosis; Exome - genetics; Exome sequencing; Female; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetics, Population; Heart attack; Heart attacks; Heterozygote; Humanities and Social Sciences; Humans; letter; Low density lipoproteins; Male; Middle Aged; multidisciplinary; Mutation; Mutation - genetics; Myocardial infarction; Myocardial Infarction - blood; Myocardial Infarction - genetics; National Heart, Lung, and Blood Institute (U.S.); Physiological aspects; Proteins; Receptors, LDL - genetics; Risk factors; Science; Studies; Triglycerides; Triglycerides - blood; United States; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature13917

Exome sequence analysis of nearly 10,000 people was carried out to identify alleles associated with early-onset myocardial infarction; mutations in low-density lipoprotein receptor ( LDLR ) or apolipoprotein A-V ( APOA5 ) were associated with disease risk, identifying the key roles of low-density lipoprotein cholesterol and metabolism of triglyceride-rich lipoproteins. Genes associated with myocardial infarction Sekar Kathiresan and colleagues use exome sequencing of nearly 10,000 people to probe the contribution of multiple rare mutations within a gene to risk for myocardial infarction at a population level. They find that mutations in low-density lipoprotein receptor ( LDLR ) or apolipoprotein A-V ( APOA5 ) are associated with disease risk. When compared with non-carriers, LDLR mutation carriers had higher plasma levels of LDL cholesterol, whereas APOA5 mutation carriers had higher plasma levels of triglycerides. As well as confirming that APOA5 is a myocardial infarction gene, this work informs the design and conduct of rare-variant association studies for complex diseases. Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance 1 , 2 . When MI occurs early in life, genetic inheritance is a major component to risk 1 . Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families 3 , 4 , 5 , 6 , 7 , 8 , whereas common variants at more than 45 loci have been associated with MI risk in the population 9 , 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 cholesterol 16 . 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 15 , 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.