TY - JOUR

T1 - Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction

AU - Do, Ron

AU - Stitziel, Nathan O

AU - Won, Hong-Hee

AU - Jørgensen, Anders Berg

AU - Duga, Stefano

AU - Angelica Merlini, Pier

AU - Kiezun, Adam

AU - Farrall, Martin

AU - Goel, Anuj

AU - Zuk, Or

AU - Guella, Illaria

AU - Asselta, Rosanna

AU - Lange, Leslie A

AU - Peloso, Gina M

AU - Auer, Paul L

AU - Girelli, Domenico

AU - Martinelli, Nicola

AU - Farlow, Deborah N

AU - DePristo, Mark A

AU - Roberts, Robert

AU - Stewart, Alexander F R

AU - Saleheen, Danish

AU - Danesh, John

AU - Epstein, Stephen E

AU - Sivapalaratnam, Suthesh

AU - Hovingh, G Kees

AU - Kastelein, John J

AU - Samani, Nilesh J

AU - Schunkert, Heribert

AU - Erdmann, Jeanette

AU - Shah, Svati H

AU - Kraus, William E

AU - Davies, Robert

AU - Nikpay, Majid

AU - Johansen, Christopher T

AU - Wang, Jian

AU - Hegele, Robert A

AU - Hechter, Eliana

AU - Marz, Winfried

AU - Kleber, Marcus E

AU - Huang, Jie

AU - Johnson, Andrew D

AU - Li, Mingyao

AU - Burke, Greg L

AU - Gross, Myron

AU - Liu, Yongmei

AU - Assimes, Themistocles L

AU - Heiss, Gerardo

AU - Lange, Ethan M

AU - Tybjaerg-Hansen, Anne

AU - NHLBI Exome Sequencing Project

PY - 2015/2/5

Y1 - 2015/2/5

N2 - 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.

AB - 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.

KW - Age Factors

KW - Age of Onset

KW - Alleles

KW - Apolipoproteins A

KW - Case-Control Studies

KW - Cholesterol, LDL

KW - Coronary Artery Disease

KW - Exome

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetics, Population

KW - Heterozygote

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Myocardial Infarction

KW - National Heart, Lung, and Blood Institute (U.S.)

KW - Receptors, LDL

KW - Triglycerides

KW - United States

U2 - 10.1038/nature13917

DO - 10.1038/nature13917

M3 - Letter

C2 - 25487149

VL - 518

SP - 102-6, 4 unpag. pages

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7537

ER -