A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy

TY - JOUR

T1 - A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy

AU - Villard, Eric

AU - Perret, Claire

AU - Gary, Françoise

AU - Proust, Carole

AU - Dilanian, Gilles

AU - Hengstenberg, Christian

AU - Ruppert, Volker

AU - Arbustini, Eloisa

AU - Wichter, Thomas

AU - Germain, Marine

AU - Dubourg, Olivier

AU - Tavazzi, Luigi

AU - Aumont, Marie-Claude

AU - DeGroote, Pascal

AU - Fauchier, Laurent

AU - Trochu, Jean-Noël

AU - Gibelin, Pierre

AU - Aupetit, Jean-François

AU - Stark, Klaus

AU - Erdmann, Jeanette

AU - Hetzer, Roland

AU - Roberts, Angharad M

AU - Barton, Paul J R

AU - Regitz-Zagrosek, Vera

AU - Aslam, Uzma

AU - Duboscq-Bidot, Laëtitia

AU - Meyborg, Matthias

AU - Maisch, Bernhard

AU - Madeira, Hugo

AU - Waldenström, Anders

AU - Galve, Enrique

AU - Cleland, John G

AU - Dorent, Richard

AU - Roizes, Gerard

AU - Zeller, Tanja

AU - Blankenberg, Stefan

AU - Goodall, Alison H

AU - Cook, Stuart

AU - Tregouet, David A

AU - Tiret, Laurence

AU - Isnard, Richard

AU - Komajda, Michel

AU - Charron, Philippe

AU - Cambien, François

AU - CardioGenics Consortium

PY - 2011/5

Y1 - 2011/5

N2 - AIMS: Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM.METHODS AND RESULTS: One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P < 5.0 10(-7)), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease.CONCLUSION: This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM.

AB - AIMS: Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM.METHODS AND RESULTS: One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P < 5.0 10(-7)), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease.CONCLUSION: This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM.

KW - Adaptor Proteins, Signal Transducing/genetics

KW - Adult

KW - Apoptosis Regulatory Proteins

KW - Cardiomyopathy, Dilated/genetics

KW - Chloride Channels/genetics

KW - Chromosomes, Human, Pair 1/genetics

KW - Chromosomes, Human, Pair 10/genetics

KW - Female

KW - Genetic Loci/genetics

KW - Genome-Wide Association Study

KW - HSP27 Heat-Shock Proteins/genetics

KW - Heart Failure/genetics

KW - Heterozygote

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation, Missense/genetics

KW - Polymorphism, Single Nucleotide/genetics

U2 - 10.1093/eurheartj/ehr105

DO - 10.1093/eurheartj/ehr105

M3 - SCORING: Journal article

C2 - 21459883

VL - 32

SP - 1065

EP - 1076

JO - EUR HEART J

JF - EUR HEART J

SN - 0195-668X

IS - 9

ER -