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

ABSTRACT: 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.

SUBMITTER: Villard E

PROVIDER: S-EPMC3086901 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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

Villard Eric E Perret Claire C Gary Françoise F Proust Carole C Dilanian Gilles G Hengstenberg Christian C Ruppert Volker V Arbustini Eloisa E Wichter Thomas T Germain Marine M Dubourg Olivier O Tavazzi Luigi L Aumont Marie-Claude MC DeGroote Pascal P Fauchier Laurent L Trochu Jean-Noël JN Gibelin Pierre P Aupetit Jean-François JF Stark Klaus K Erdmann Jeanette J Hetzer Roland R Roberts Angharad M AM Barton Paul J R PJ Regitz-Zagrosek Vera V Aslam Uzma U Duboscq-Bidot Laëtitia L Meyborg Matthias M Maisch Bernhard B Madeira Hugo H Waldenström Anders A Galve Enrique E Cleland John G JG Dorent Richard R Roizes Gerard G Zeller Tanja T Blankenberg Stefan S Goodall Alison H AH Cook Stuart S Tregouet David A DA Tiret Laurence L Isnard Richard R Komajda Michel M Charron Philippe P Cambien François F

European heart journal 20110401 9

<h4>Aims</h4>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.<h4>Methods and results</h4>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 ...[more]

PMID: 21459883

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Project description:AimsThe aims of this paper were to investigate the analytical performance of the nine prognostic scales commonly used in heart failure (HF), in patients with dilated cardiomyopathy (DCM), and to develop a unique prognostic model tailored to DCM patients.Methods and resultsThe hospital and outpatient records of 406 DCM patients were retrospectively analysed. The information on patient status was gathered after 48.2 ± 32.0 months. Tests were carried out to ascertain the prognostic accuracy in DCM using some of the most frequently applied HF prognostic scales (Barcelona Bio-Heart Failure, Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity, Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure, Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, Meta-Analysis Global Group in Chronic Heart Failure, MUerte Subita en Insuficiencia Cardiaca, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure, Seattle Heart Failure Model) and one dedicated to DCM, that of Miura et al. At follow-up, 70 DCM patients (17.2%) died. Most analysed scores substantially overestimated the mortality risk, especially in survivors. The prognostic accuracy of the scales were suboptimal, varying between 60% and 80%, with the best performance from Barcelona Bio-Heart Failure and Seattle Heart Failure Model for 1-5 year mortality [areas under the receiver operating curve 0.792-0.890 (95% confidence interval 0.725-0.918) and 0.764-0.808 (95% confidence interval 0.682-0.934), respectively].Based on our accumulated data, a self-developed DCM prognostic model was constructed. The model consists of age, gender, body mass index, symptoms duration, New York Heart Association class, diabetes mellitus, prior stroke, abnormal liver function, dyslipidaemia, left bundle branch block, left ventricle end-diastolic diameter, ejection fraction, N terminal pro brain natriuretic peptide, haemoglobin, estimated glomerular filtration rate, and pharmacological and resynchronisation therapy. This newly created prognostic model outperformed the analysed HF scales.ConclusionsAn analysis of various HF prognostic models found them to be suboptimal for DCM patients. A self-developed DCM prognostic model showed improved performance over the nine other models studied. However, further validation of the prognostic model in different DCM populations is required.

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

Publications

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

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