A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy

Benjamin Meder, Frank Rühle, Tanja Weis, Georg Homuth, Andreas Keller, Jennifer Franke, Barbara Peil, Justo Lorenzo Bermejo, Karen Frese, Andreas Huge, Anika Witten, Britta Vogel, Jan Haas, Uwe Völker, Florian Ernst, Alexander Teumer, Philipp Ehlermann, Christian Zugck, Frauke Friedrichs, Heyo Kroemer & 36 others Marcus Dörr, Wolfgang Hoffmann, Bernhard Maisch, Sabine Pankuweit, Volker Ruppert, Thomas Scheffold, Uwe Kühl, Hans Peter Schultheiss, Reinhold Kreutz, Georg Ertl, Christiane Angermann, Philippe Charron, Eric Villard, Françoise Gary, Richard Isnard, Michel Komajda, Matthias Lutz, Thomas Meitinger, Moritz F. Sinner, H. Erich Wichmann, Michael Krawczak, Boris Ivandic, Dieter Weichenhan, Goetz Gelbrich, Nour Eddine El-Mokhtari, Stefan Schreiber, Stephan B. Felix, Gerd Hasenfuß, Arne Pfeufer, Norbert Hübner, Stefan Kääb, Eloisa Arbustini, Wolfgang Rottbauer, Norbert Frey, Monika Stoll, Hugo A. Katus

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Aims Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM. Methods and results Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10-9) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. Conclusion The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.

Original languageEnglish
Pages (from-to)1069-1077
Number of pages9
JournalEuropean Heart Journal
Volume35
Issue number16
DOIs
Publication statusPublished - Apr 21 2014

Fingerprint

Genome-Wide Association Study
Dilated Cardiomyopathy
Genetic Loci
Quantitative Trait Loci
MHC Class I Genes
Heart Transplantation
Genetic Predisposition to Disease
Major Histocompatibility Complex
Age of Onset
Single Nucleotide Polymorphism
Heart Failure
Chromosomes
Phenotype

Keywords

  • DCM
  • Dilated cardiomyopathy
  • Genome-wide association study

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Meder, B., Rühle, F., Weis, T., Homuth, G., Keller, A., Franke, J., ... Katus, H. A. (2014). A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy. European Heart Journal, 35(16), 1069-1077. https://doi.org/10.1093/eurheartj/eht251

A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy. / Meder, Benjamin; Rühle, Frank; Weis, Tanja; Homuth, Georg; Keller, Andreas; Franke, Jennifer; Peil, Barbara; Bermejo, Justo Lorenzo; Frese, Karen; Huge, Andreas; Witten, Anika; Vogel, Britta; Haas, Jan; Völker, Uwe; Ernst, Florian; Teumer, Alexander; Ehlermann, Philipp; Zugck, Christian; Friedrichs, Frauke; Kroemer, Heyo; Dörr, Marcus; Hoffmann, Wolfgang; Maisch, Bernhard; Pankuweit, Sabine; Ruppert, Volker; Scheffold, Thomas; Kühl, Uwe; Schultheiss, Hans Peter; Kreutz, Reinhold; Ertl, Georg; Angermann, Christiane; Charron, Philippe; Villard, Eric; Gary, Françoise; Isnard, Richard; Komajda, Michel; Lutz, Matthias; Meitinger, Thomas; Sinner, Moritz F.; Wichmann, H. Erich; Krawczak, Michael; Ivandic, Boris; Weichenhan, Dieter; Gelbrich, Goetz; El-Mokhtari, Nour Eddine; Schreiber, Stefan; Felix, Stephan B.; Hasenfuß, Gerd; Pfeufer, Arne; Hübner, Norbert; Kääb, Stefan; Arbustini, Eloisa; Rottbauer, Wolfgang; Frey, Norbert; Stoll, Monika; Katus, Hugo A.

In: European Heart Journal, Vol. 35, No. 16, 21.04.2014, p. 1069-1077.

Research output: Contribution to journalArticle

Meder, B, Rühle, F, Weis, T, Homuth, G, Keller, A, Franke, J, Peil, B, Bermejo, JL, Frese, K, Huge, A, Witten, A, Vogel, B, Haas, J, Völker, U, Ernst, F, Teumer, A, Ehlermann, P, Zugck, C, Friedrichs, F, Kroemer, H, Dörr, M, Hoffmann, W, Maisch, B, Pankuweit, S, Ruppert, V, Scheffold, T, Kühl, U, Schultheiss, HP, Kreutz, R, Ertl, G, Angermann, C, Charron, P, Villard, E, Gary, F, Isnard, R, Komajda, M, Lutz, M, Meitinger, T, Sinner, MF, Wichmann, HE, Krawczak, M, Ivandic, B, Weichenhan, D, Gelbrich, G, El-Mokhtari, NE, Schreiber, S, Felix, SB, Hasenfuß, G, Pfeufer, A, Hübner, N, Kääb, S, Arbustini, E, Rottbauer, W, Frey, N, Stoll, M & Katus, HA 2014, 'A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy', European Heart Journal, vol. 35, no. 16, pp. 1069-1077. https://doi.org/10.1093/eurheartj/eht251
Meder, Benjamin ; Rühle, Frank ; Weis, Tanja ; Homuth, Georg ; Keller, Andreas ; Franke, Jennifer ; Peil, Barbara ; Bermejo, Justo Lorenzo ; Frese, Karen ; Huge, Andreas ; Witten, Anika ; Vogel, Britta ; Haas, Jan ; Völker, Uwe ; Ernst, Florian ; Teumer, Alexander ; Ehlermann, Philipp ; Zugck, Christian ; Friedrichs, Frauke ; Kroemer, Heyo ; Dörr, Marcus ; Hoffmann, Wolfgang ; Maisch, Bernhard ; Pankuweit, Sabine ; Ruppert, Volker ; Scheffold, Thomas ; Kühl, Uwe ; Schultheiss, Hans Peter ; Kreutz, Reinhold ; Ertl, Georg ; Angermann, Christiane ; Charron, Philippe ; Villard, Eric ; Gary, Françoise ; Isnard, Richard ; Komajda, Michel ; Lutz, Matthias ; Meitinger, Thomas ; Sinner, Moritz F. ; Wichmann, H. Erich ; Krawczak, Michael ; Ivandic, Boris ; Weichenhan, Dieter ; Gelbrich, Goetz ; El-Mokhtari, Nour Eddine ; Schreiber, Stefan ; Felix, Stephan B. ; Hasenfuß, Gerd ; Pfeufer, Arne ; Hübner, Norbert ; Kääb, Stefan ; Arbustini, Eloisa ; Rottbauer, Wolfgang ; Frey, Norbert ; Stoll, Monika ; Katus, Hugo A. / A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy. In: European Heart Journal. 2014 ; Vol. 35, No. 16. pp. 1069-1077.
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abstract = "Aims Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM. Methods and results Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10-9) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. Conclusion The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.",
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T1 - A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy

AU - Meder, Benjamin

AU - Rühle, Frank

AU - Weis, Tanja

AU - Homuth, Georg

AU - Keller, Andreas

AU - Franke, Jennifer

AU - Peil, Barbara

AU - Bermejo, Justo Lorenzo

AU - Frese, Karen

AU - Huge, Andreas

AU - Witten, Anika

AU - Vogel, Britta

AU - Haas, Jan

AU - Völker, Uwe

AU - Ernst, Florian

AU - Teumer, Alexander

AU - Ehlermann, Philipp

AU - Zugck, Christian

AU - Friedrichs, Frauke

AU - Kroemer, Heyo

AU - Dörr, Marcus

AU - Hoffmann, Wolfgang

AU - Maisch, Bernhard

AU - Pankuweit, Sabine

AU - Ruppert, Volker

AU - Scheffold, Thomas

AU - Kühl, Uwe

AU - Schultheiss, Hans Peter

AU - Kreutz, Reinhold

AU - Ertl, Georg

AU - Angermann, Christiane

AU - Charron, Philippe

AU - Villard, Eric

AU - Gary, Françoise

AU - Isnard, Richard

AU - Komajda, Michel

AU - Lutz, Matthias

AU - Meitinger, Thomas

AU - Sinner, Moritz F.

AU - Wichmann, H. Erich

AU - Krawczak, Michael

AU - Ivandic, Boris

AU - Weichenhan, Dieter

AU - Gelbrich, Goetz

AU - El-Mokhtari, Nour Eddine

AU - Schreiber, Stefan

AU - Felix, Stephan B.

AU - Hasenfuß, Gerd

AU - Pfeufer, Arne

AU - Hübner, Norbert

AU - Kääb, Stefan

AU - Arbustini, Eloisa

AU - Rottbauer, Wolfgang

AU - Frey, Norbert

AU - Stoll, Monika

AU - Katus, Hugo A.

PY - 2014/4/21

Y1 - 2014/4/21

N2 - Aims Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM. Methods and results Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10-9) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. Conclusion The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.

AB - Aims Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM. Methods and results Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10-9) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. Conclusion The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.

KW - DCM

KW - Dilated cardiomyopathy

KW - Genome-wide association study

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