Genome-wide association for heart failure: from discovery to clinical use
| Autor: | Megan J. Puckelwartz, Elizabeth M. McNally, Dominic E. Fullenkamp |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Genetics
Cardiomyopathy Dilated business.industry MEDLINE Cardiomyopathy Genome-wide association study medicine.disease Polymorphism Single Nucleotide Chromosomes Polymorphism (computer science) Heart failure Translational Research Medicine Humans Cardiology and Cardiovascular Medicine business Genome-Wide Association Study Heart Failure Systolic |
| Zdroj: | Eur Heart J |
| ISSN: | 1522-9645 |
| Popis: | 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 × 10(−11) and 7.7 × 10(−4) in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10(−8) and 1.4 × 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. |
| Databáze: | OpenAIRE |
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