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 Roberts; Alexander 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; Anne Tybjaerg-Hansen; NHLBI Exome Sequencing Project

doi:10.1038/nature13917

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, Anne Tybjaerg-Hansen, NHLBI Exome Sequencing Project

Department of Clinical Medicine

391 Citations (Scopus)

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 language	English
Journal	Nature
Volume	518
Issue number	7537
Pages (from-to)	102-6, 4 unpag. pages
Number of pages	9
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature13917
Publication status	Published - 5 Feb 2015

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

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Do, R., Stitziel, N. O., Won, H-H., Jørgensen, A. B., Duga, S., Angelica Merlini, P., Kiezun, A., Farrall, M., Goel, A., Zuk, O., Guella, I., Asselta, R., Lange, L. A., Peloso, G. M., Auer, P. L., Girelli, D., Martinelli, N., Farlow, D. N., DePristo, M. A., ... NHLBI Exome Sequencing Project (2015). Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature, 518(7537), 102-6, 4 unpag. pages. https://doi.org/10.1038/nature13917

Do, R, Stitziel, NO, Won, H-H, Jørgensen, AB, Duga, S, Angelica Merlini, P, 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, Hovingh, GK, Kastelein, JJ, Samani, NJ, Schunkert, H, Erdmann, J, Shah, SH, Kraus, WE, Davies, R, Nikpay, M, Johansen, CT, Wang, J, Hegele, RA, Hechter, E, Marz, W, Kleber, ME, Huang, J, Johnson, AD, Li, M, Burke, GL, Gross, M, Liu, Y, Assimes, TL, Heiss, G, Lange, EM, Tybjaerg-Hansen, A & NHLBI Exome Sequencing Project 2015, 'Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction', Nature, vol. 518, no. 7537, pp. 102-6, 4 unpag. pages. https://doi.org/10.1038/nature13917

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title = "Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction",

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.",

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",

author = "Ron Do and Stitziel, {Nathan O} and Hong-Hee Won and J{\o}rgensen, {Anders Berg} and Stefano Duga and {Angelica Merlini}, Pier and Adam Kiezun and Martin Farrall and Anuj Goel and Or Zuk and Illaria Guella and Rosanna Asselta and Lange, {Leslie A} and Peloso, {Gina M} and Auer, {Paul L} and Domenico Girelli and Nicola Martinelli and Farlow, {Deborah N} and DePristo, {Mark A} and Robert Roberts and Stewart, {Alexander F R} and Danish Saleheen and John Danesh and Epstein, {Stephen E} and Suthesh Sivapalaratnam and Hovingh, {G Kees} and Kastelein, {John J} and Samani, {Nilesh J} and Heribert Schunkert and Jeanette Erdmann and Shah, {Svati H} and Kraus, {William E} and Robert Davies and Majid Nikpay and Johansen, {Christopher T} and Jian Wang and Hegele, {Robert A} and Eliana Hechter and Winfried Marz and Kleber, {Marcus E} and Jie Huang and Johnson, {Andrew D} and Mingyao Li and Burke, {Greg L} and Myron Gross and Yongmei Liu and Assimes, {Themistocles L} and Gerardo Heiss and Lange, {Ethan M} and Anne Tybjaerg-Hansen and {NHLBI Exome Sequencing Project}",

year = "2015",

month = feb,

day = "5",

doi = "10.1038/nature13917",

language = "English",

volume = "518",

pages = "102--6, 4 unpag. pages",

journal = "Nature",

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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

SN - 0028-0836

VL - 518

SP - 102-6, 4 unpag. pages

JO - Nature

JF - Nature

IS - 7537

ER -

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

Abstract

Keywords

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