Genome-wide association for heart failure: from discovery to clinical use

2021 ◽  
Author(s):  
Dominic E Fullenkamp ◽  
Megan J Puckelwartz ◽  
Elizabeth M McNally
Keyword(s):  
Heart Failure ◽  
Genome Wide Association ◽  
Clinical Use ◽  
Genome Wide

Abstract 16003: Genetic Variation Associated With Favorable Exercise Response in Patients With Systolic Heart Failure: A Hf-action Trial Substudy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Sara Coles ◽  
Stephanie Giamberardino ◽  
Carol Haynes ◽  
Ruicong She ◽  
Hongsheng Gui ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Trial ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Systolic Heart Failure ◽  
Genome Wide Association ◽  
Supervised Exercise ◽  
Genome Wide ◽  
A Genome ◽  
Response To Exercise

Background: Exercise has shown benefit in patients with systolic heart failure, including in the clinical trial Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION). There is heterogeneity in who derives benefit from exercise, and the biologic mechanisms of favorable response to exercise in systolic heart failure are not well understood. Hypothesis: Genetic variation is an underlying factor influencing heterogeneity in response to exercise in patients with systolic heart failure. Methods: The HF-ACTION trial randomized individuals with systolic heart failure (left ventricular ejection fraction <35%) to supervised exercise versus usual care. In this study, we performed a genome wide association study (GWAS) in the HF-ACTION biorepository using the Axiom Biobank1 genotyping array (13,403,591 single nucleotide polymorphisms [SNPs] after quality control on directly genotyped and 1000 genomes imputed data), in N=377 study subjects who completed the supervised exercise arm. Using change in peak VO2 as our outcome, we ran within-ancestry GWASes, modeling SNP effects as both additive and dominant, and conducted across-ancestry meta-analysis within each genetic model. Results: Five loci met genome-wide significance in the European ancestry analyses, 5 loci in the African ancestry, and 8 in the meta-analyses. The two most significantly associated loci across both additive and dominant meta-analysis models were rs111577308 located in the histone acetylation for transcription elongator complex 3 gene ( ELP3, p=1.212x10 -9 ) and rs75444785 located in the phosphodiesterase 4D gene ( PDE4D , p=1.565x10 -9 ). ELP3 is responsible for histone modifications related to DNA transcription factor complexes, and PDE4D is involved in cyclic AMP cell signaling. In silico analysis of these loci showed that they are in linkage with regions associated with skeletal muscle and peripheral vascular disease phenotypes. Conclusions: Using a genome-wide association study in a well-phenotyped clinical trial of exercise in systolic heart failure, we found common genetic variants in genes involved in DNA transcription histone modification and cyclic AMP cell signaling that are associated with a more favorable response to exercise.

scholarly journals Genome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Marios Arvanitis ◽  
◽  
Emmanouil Tampakakis ◽  
Yanxiao Zhang ◽  
Wei Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Genome Wide Association ◽  
Genome Wide

scholarly journals Genome-wide association and multi-omic analyses reveal new mechanisms for Heart Failure

2019 ◽  
Author(s):  
Marios Arvanitis ◽  
Yanxiao Zhang ◽  
Wei Wang ◽  
Adam Auton ◽  
Ali Keramati ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Muscle ◽  
Association Studies ◽  
Meta Analysis ◽  
Regulatory Region ◽  
Causal Variant ◽  
Left Ventricular ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractHeart failure is a major medical and economic burden in the healthcare system affecting over 23 million people worldwide. Although recent pedigree studies estimate heart failure heritability around 26%, genome-wide association studies (GWAS) have had limited success in explaining disease pathogenesis. We conducted the largest meta-analysis of heart failure GWAS to-date and replicated our findings in a comparable sized cohort to identify one known and two novel variants associated with heart failure. Leveraging heart failure sub-phenotyping and fine-mapping, we reveal a putative causal variant found in a cardiac muscle specific regulatory region that binds to the ACTN2 cardiac sarcolemmal gene and affects left ventricular adverse remodeling and clinical heart failure in response to different initial cardiac muscle insults. Via genetic correlation, we show evidence of broadly shared heritability between heart failure and multiple musculoskeletal traits. Our findings extend our understanding of biological mechanisms underlying heart failure.

scholarly journals Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonia Shah ◽  
◽  
Albert Henry ◽  
Carolina Roselli ◽  
Honghuang Lin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Cardiac Development ◽  
Association Studies ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Genome Wide Association ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractHeart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

scholarly journals Genome wide association analysis in dilated cardiomyopathy reveals two new key players in systolic heart failure on chromosome 3p25.1 and 22q11.23

2020 ◽  
Author(s):  
Sophie Garnier ◽  
Magdalena Harakalova ◽  
Stefan Weiss ◽  
Michal Mokry ◽  
Vera Regitz-Zagrosek ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Myocardial Dysfunction ◽  
Genetic Risk Score ◽  
Systolic Heart Failure ◽  
Genome Wide Association ◽  
Sequencing Analysis ◽  
Risk Alleles ◽  
Genome Wide ◽  
Increased Risk

SummaryWe present the results of the largest genome wide association study (GWAS) performed so far in dilated cardiomyopathy (DCM), a leading cause of systolic heart failure and cardiovascular death, with 2,719 cases and 4,440 controls in the discovery population. We identified and replicated two new DCM-associated loci, one on chromosome 3p25.1 (lead SNP rs62232870, p = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication step, respectively) and the second on chromosome 22q11.23 (lead SNP rs7284877, p = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication step, respectively) while confirming two previously identified DCM loci on chromosome 10 and 1, BAG3 and HSPB7. The genetic risk score constructed from the number of lead risk-alleles at these four DCM loci revealed that individuals with 8 risk-alleles were at a 27% increased risk of DCM compared to individuals with 5 risk alleles (median of the referral population). We estimated the genome wide heritability at 31% ± 8%.In silico annotation and functional 4C-sequencing analysis on iPSC-derived cardiomyocytes strongly suggest SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine and beta-alanine transporter whose involvement in myocardial dysfunction and DCM is supported by recent observations in humans and mice. Although less easy to discriminate the better candidate at the 22q11.23 locus, SMARCB1 appears as the strongest one.This study provides both a better understanding of the genetic architecture of DCM and new knowledge on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective.

scholarly journals Genome-wide association study provides new insights into the genetic architecture and pathogenesis of heart failure

2019 ◽  
Author(s):  
Sonia Shah ◽  
Albert Henry ◽  
Carolina Roselli ◽  
Honghuang Lin ◽  
Garðar Sveinbjörnsson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Genome Wide Association ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractHeart failure (HF) is a leading cause of morbidity and mortality worldwide1. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.

scholarly journals Genome-Wide Association Study for Anthracycline-Induced Congestive Heart Failure

2016 ◽  
Vol 23 (1) ◽  
pp. 43-51 ◽  
Author(s):  
Bryan P. Schneider ◽  
Fei Shen ◽  
Laura Gardner ◽  
Milan Radovich ◽  
Lang Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide

scholarly journals Genetic Architecture of Heart Failure with Preserved versus Reduced Ejection Fraction

2021 ◽  
Author(s):  
Jacob Joseph ◽  
Qin Hui ◽  
Chang Liu ◽  
Krishna Aragam ◽  
Zeyuan Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Clinical Trials ◽  
Ejection Fraction ◽  
Genetic Association ◽  
Genetic Architecture ◽  
Genome Wide Association ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Genome Wide

AbstractBackgroundPharmacologic clinical trials for heart failure (HF) with preserved ejection fraction (HFpEF) have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction (HFrEF). Whether differences in the genetic underpinnings of these HF subtypes may provide insights into the disparate outcomes of these clinical trials remains unknown.ObjectivesWe pursued genetic association analyses to compare the genetic architecture of HFpEF with that of HFrEF.MethodsWe created a non-Hispanic White cohort including 19,495 HFrEF and 19,589 HFpEF cases among 43,344 unclassified HF cases, and 258,943 controls without HF in the Veterans Health Administration Million Veteran Program. We then conducted genome-wide association studies of unclassified HF, HFrEF and HFpEF, followed by genetic correlation analyses and Mendelian randomization analyses of established HF risk factors with HFrEF and HFpEF.ResultsWe found 13 loci associated with HFrEF at genome-wide significance, but only one associated with HFpEF. Among genome-wide significant loci for HFrEF, four loci were not associated with any HF risk factor. The single locus identified for HFpEF (FTO) is a known marker for obesity. Genetically determined associations were widely different between HFrEF and HFpEF for several risk factors including coronary artery disease, lipid levels, and pulse pressure.ConclusionsThe modest genetic discovery for HFpEF compared to HFrEF despite a robust sample size indicates that HFpEF, as currently defined, likely represents the amalgamation of several, distinct pathobiological entities. Development of consensus sub-phenotyping of HFpEF is paramount to better dissect the underlying genetic signals and contributors to HFpEF.Condensed AbstractWe utilized a large, uniformly phenotyped, single cohort of heart failure sub-classified into heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF) based on current clinical definitions, to conduct detailed genetic analyses of the two HF sub-types. We found different genetic architectures and distinct genetic association profiles of HFrEF and HFpEF suggesting differences in underlying pathobiology. Furthermore, the low yield of HFpEF genome-wide association study (GWAS) compared to similarly powered HFrEF GWAS underscores the heterogeneity of HFpEF and the urgent need for developing consensus sub-phenotyping of HFpEF to improve the discovery in genetic mechanisms and therapeutic interventions.

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