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Journal or Publication Title: | European Heart Journal | ||||
Publisher: | Oxford Univ. Press | ||||
Place of Publication: | OXFORD | ||||
Volume: | 42 | ||||
Number of Issue or Book Chapter: | 20 | ||||
Page Range: | pp. 2000-2011 | ||||
Date: | 2021 | ||||
Institutions: | Medicine > Lehrstuhl für Innere Medizin II Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie | ||||
Identification Number: |
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Keywords: | Dilated cardiomyopathy; Heart failure; GWAS; Imputation; 4C-sequencing; Genetic risk score | ||||
Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine | ||||
Status: | Published | ||||
Refereed: | Yes, this version has been refereed | ||||
Created at the University of Regensburg: | Partially | ||||
Item ID: | 56763 |
Abstract
Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead ...

Abstract
Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 x 10(-11) and 7.7 x 10(-4) in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 x 10(-8) and 1.4 x 10(-3) in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure. [GRAPHICS]
Metadata last modified: 28 Jun 2024 04:52