TY - JOUR
T1 - Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction
AU - AUTHOR GROUP
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 - Folsom, Aaron R.
PY - 2015
Y1 - 2015
N2 - 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 inindividual families(3-8), whereas common variants at more than 45 loci have been associated with MI risk in the population(9-15). 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 inmales 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
AB - 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 inindividual families(3-8), whereas common variants at more than 45 loci have been associated with MI risk in the population(9-15). 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 inmales 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
U2 - https://doi.org/10.1038/nature13917
DO - https://doi.org/10.1038/nature13917
M3 - Article
C2 - 25487149
SN - 0028-0836
VL - 518
SP - 102-+
JO - NATURE
JF - NATURE
IS - 7537
ER -