Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy

Klaus Stark; Ulrike B. Esslinger; Wibke Reinhard; George Petrov; Thomas Winkler; Michel Komajda; Richard Isnard; Philippe Charron; Eric Villard; François Cambien; Laurence Tiret; Marie Claude Aumont; Olivier Dubourg; Jean Noël Trochu; Laurent Fauchier; Pascal DeGroote; Anette Richter; Bernhard Maisch; Thomas Wichter; Christa Zollbrecht; Martina Grassl; Heribert Schunkert; Patrick Linsel-Nitschke; Jeanette Erdmann; Jens Baumert; Thomas Illig; Norman Klopp; H. Erich Wichmann; Christa Meisinger; Wolfgang Koenig; Peter Lichtner; Thomas Meitinger; Arne Schillert; Inke R. König; Roland Hetzer; Iris M. Heid; Vera Regitz-Zagrosek; Christian Hengstenberg

doi:10.1371/journal.pgen.1001167

Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy

Klaus Stark
, Ulrike B. Esslinger
, Wibke Reinhard
, George Petrov
, Thomas Winkler
, Michel Komajda
, Richard Isnard
, Philippe Charron
, Eric Villard
, François Cambien
, Laurence Tiret
, Marie Claude Aumont
, Olivier Dubourg
, Jean Noël Trochu
, Laurent Fauchier
, Pascal DeGroote
, Anette Richter
, Bernhard Maisch
, Thomas Wichter
, Christa Zollbrecht

Martina Grassl, Heribert Schunkert, Patrick Linsel-Nitschke, Jeanette Erdmann, Jens Baumert, Thomas Illig, Norman Klopp, H. Erich Wichmann, Christa Meisinger, Wolfgang Koenig, Peter Lichtner, Thomas Meitinger, Arne Schillert, Inke R. König, Roland Hetzer, Iris M. Heid, Vera Regitz-Zagrosek, Christian Hengstenberg

Medicine and Health

Klinikum der Universität Regensburg und Medizinische Fakultät
Partner Site Munich Heart Alliance
German Heart Institute Berlin
University of Regensburg
INSERM U70
Hôpital Bichat-Claude Bernard
Versailles Saint Quentin University
Hôpital Laennec
AP-HP
CHRU Roger Salengro
Philipps-Universität Marburg
Universitätsklinikum Münster
University of Lübeck
Institute of Epidemiology
Klinikum Augsburg
University Medical Center Ulm and Center of Excellence 'Metabolic Disorders'
Institute of Human Genetics

Research output: Contribution to journal › Article › peer-review

107 Scopus citations

Abstract

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes preselected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10^-6, OR = 0.67 [95% CI 0.57-0.79] for the minor allele T). Three more SNPs showed p < 2.21×10^-5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10^-3, OR = 0.79 [95% CI 0.67-0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10^-3, OR = 0.74 [95% CI 0.60-0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10^-4, OR = 0.63 [95% CI 0.50-0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10^-13, OR = 0.72 [95% CI 0.65-0.78]). None of the other three SNPs showed significant results in the replication stage. This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility. Copyright:

Original language	English
Article number	e1001167
Pages (from-to)	1-9
Number of pages	9
Journal	PLoS Genetics
Volume	6
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1001167
State	Published - Oct 2010

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10.1371/journal.pgen.1001167

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Stark, K., Esslinger, U. B., Reinhard, W., Petrov, G., Winkler, T., Komajda, M., Isnard, R., Charron, P., Villard, E., Cambien, F., Tiret, L., Aumont, M. C., Dubourg, O., Trochu, J. N., Fauchier, L., DeGroote, P., Richter, A., Maisch, B., Wichter, T., ... Hengstenberg, C. (2010). Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy. PLoS Genetics, 6(10), 1-9. Article e1001167. https://doi.org/10.1371/journal.pgen.1001167

@article{15b7ad18cf0e444e85a8babaeec6f345,

title = "Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy",

abstract = "Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes preselected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39\%) and idiopathic DCM (p = 1.06×10-6, OR = 0.67 [95\% CI 0.57-0.79] for the minor allele T). Three more SNPs showed p < 2.21×10-5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10-3, OR = 0.79 [95\% CI 0.67-0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10-3, OR = 0.74 [95\% CI 0.60-0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10-4, OR = 0.63 [95\% CI 0.50-0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10-13, OR = 0.72 [95\% CI 0.65-0.78]). None of the other three SNPs showed significant results in the replication stage. This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility. Copyright:",

author = "Klaus Stark and Esslinger, \{Ulrike B.\} and Wibke Reinhard and George Petrov and Thomas Winkler and Michel Komajda and Richard Isnard and Philippe Charron and Eric Villard and Fran{\c c}ois Cambien and Laurence Tiret and Aumont, \{Marie Claude\} and Olivier Dubourg and Trochu, \{Jean No{\"e}l\} and Laurent Fauchier and Pascal DeGroote and Anette Richter and Bernhard Maisch and Thomas Wichter and Christa Zollbrecht and Martina Grassl and Heribert Schunkert and Patrick Linsel-Nitschke and Jeanette Erdmann and Jens Baumert and Thomas Illig and Norman Klopp and Wichmann, \{H. Erich\} and Christa Meisinger and Wolfgang Koenig and Peter Lichtner and Thomas Meitinger and Arne Schillert and K{\"o}nig, \{Inke R.\} and Roland Hetzer and Heid, \{Iris M.\} and Vera Regitz-Zagrosek and Christian Hengstenberg",

year = "2010",

month = oct,

doi = "10.1371/journal.pgen.1001167",

language = "English",

volume = "6",

pages = "1--9",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "10",

}

Stark, K, Esslinger, UB, Reinhard, W, Petrov, G, Winkler, T, Komajda, M, Isnard, R, Charron, P, Villard, E, Cambien, F, Tiret, L, Aumont, MC, Dubourg, O, Trochu, JN, Fauchier, L, DeGroote, P, Richter, A, Maisch, B, Wichter, T, Zollbrecht, C, Grassl, M, Schunkert, H, Linsel-Nitschke, P, Erdmann, J, Baumert, J, Illig, T, Klopp, N, Wichmann, HE, Meisinger, C, Koenig, W, Lichtner, P, Meitinger, T, Schillert, A, König, IR, Hetzer, R, Heid, IM, Regitz-Zagrosek, V & Hengstenberg, C 2010, 'Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy', PLoS Genetics, vol. 6, no. 10, e1001167, pp. 1-9. https://doi.org/10.1371/journal.pgen.1001167

TY - JOUR

T1 - Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy

AU - Stark, Klaus

AU - Esslinger, Ulrike B.

AU - Reinhard, Wibke

AU - Petrov, George

AU - Winkler, Thomas

AU - Komajda, Michel

AU - Isnard, Richard

AU - Charron, Philippe

AU - Villard, Eric

AU - Cambien, François

AU - Tiret, Laurence

AU - Aumont, Marie Claude

AU - Dubourg, Olivier

AU - Trochu, Jean Noël

AU - Fauchier, Laurent

AU - DeGroote, Pascal

AU - Richter, Anette

AU - Maisch, Bernhard

AU - Wichter, Thomas

AU - Zollbrecht, Christa

AU - Grassl, Martina

AU - Schunkert, Heribert

AU - Linsel-Nitschke, Patrick

AU - Erdmann, Jeanette

AU - Baumert, Jens

AU - Illig, Thomas

AU - Klopp, Norman

AU - Wichmann, H. Erich

AU - Meisinger, Christa

AU - Koenig, Wolfgang

AU - Lichtner, Peter

AU - Meitinger, Thomas

AU - Schillert, Arne

AU - König, Inke R.

AU - Hetzer, Roland

AU - Heid, Iris M.

AU - Regitz-Zagrosek, Vera

AU - Hengstenberg, Christian

PY - 2010/10

Y1 - 2010/10

N2 - Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes preselected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10-6, OR = 0.67 [95% CI 0.57-0.79] for the minor allele T). Three more SNPs showed p < 2.21×10-5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10-3, OR = 0.79 [95% CI 0.67-0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10-3, OR = 0.74 [95% CI 0.60-0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10-4, OR = 0.63 [95% CI 0.50-0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10-13, OR = 0.72 [95% CI 0.65-0.78]). None of the other three SNPs showed significant results in the replication stage. This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility. Copyright:

AB - Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes preselected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10-6, OR = 0.67 [95% CI 0.57-0.79] for the minor allele T). Three more SNPs showed p < 2.21×10-5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10-3, OR = 0.79 [95% CI 0.67-0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10-3, OR = 0.74 [95% CI 0.60-0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10-4, OR = 0.63 [95% CI 0.50-0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10-13, OR = 0.72 [95% CI 0.65-0.78]). None of the other three SNPs showed significant results in the replication stage. This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility. Copyright:

UR - https://www.scopus.com/pages/publications/78449233578

U2 - 10.1371/journal.pgen.1001167

DO - 10.1371/journal.pgen.1001167

M3 - Article

C2 - 20975947

AN - SCOPUS:78449233578

SN - 1553-7390

VL - 6

SP - 1

EP - 9

JO - PLoS Genetics

JF - PLoS Genetics

IS - 10

M1 - e1001167

ER -

Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy

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