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.

Genome wide association analysis in dilated cardiomyopathy revealed two new susceptibility loci for systolic heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Garnier ◽  
M Harakalova ◽  
S Weiss ◽  
M Mokry ◽  
J Van Setten ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Meta Analysis ◽  
Systolic Heart Failure ◽  
Genome Wide Association ◽  
Research Centre ◽  
Funding Source ◽  
Chromosome 3P ◽  
Risk Alleles ◽  
Genome Wide

Abstract   We conducted the largest Genome Wide Association Study performed so far in Dilated Cardiomyopathy (DCM), a leading cause of systolic heart failure and cardiovascular death. Using a discovery phase of 2,719 cases and 4,440 controls and a replication phase of 584 independent cases and 966 controls, we identified and replicated two new DCM-associated loci, one on chromosome 3p (meta-analysis OR = 1.36 [1.25 - 1.48], p=5.3 10–13) and the second on chromosome 22q (meta-analysis OR = 1.33 [1.22 - 1.46], p=5.0 10–10), while confirming the two previously identified DCM loci on chromosome 10 and 1, BAG3 and HSPB7. We estimated the global heritability to 31% ± 8%. The genetic risk score constructed from the number of lead risk-alleles at these 4 loci revealed a 27% risk increased in individuals with 8 risk-alleles compared to the 5 risk alleles reference group (OR = 1.27 [1.14–1.42]). The two association signals were then fine-mapped by combining in silico and functional genomics investigations (as 4C-sequencing on iPSC-derived cardiomyocytes). While a few genes remain candidates at the second locus and deserve further investigations, our work clearly identified one gene as responsible for the association at the first locus whose role in the pathophysiology of DCM is supported by recent observations in human and mice. As the biological pathway in which this gene is involved is a potential target for pharmacological agents, our finding opens novel therapeutic perspectives for treating or preventing heart failure. We are convinced that these results provide new findings that add both on the understanding of the genetic architecture of heart failure and on potential new players involved in the pathophysiology of this devastating disease. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): GENMED Laboratory of Excellence on Medical Genomics, DETECTIN-HF project (ERA-CVD framework), Assistance Publique-Hôpitaux de Paris, Délégation à la recherche clinique, the “Fondation LEDUCQ”, the PROMEX charitable foundation, the Société Française de Cardiologie/Fédération Française de Cardiologie, the Deutsche Forschungsgemeinschaft, The Federal Ministry of Education and Research and the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania, The German Center for Cardiovascular Research (DZHK), Hospitals NIHR Biomedical Research Centre, NWO VENI grant (no. 016.176.136)

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 A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy

2011 ◽  
Vol 32 (9) ◽  
pp. 1065-1076 ◽  
Author(s):  
Eric Villard ◽  
Claire Perret ◽  
Françoise Gary ◽  
Carole Proust ◽  
Gilles Dilanian ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

scholarly journals Temporal trends in outcome and patient characteristics in dilated cardiomyopathy, data from the Swedish Heart Failure Registry 2003–2015

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Helen Sjöland ◽  
Jonas Silverdal ◽  
Entela Bollano ◽  
Aldina Pivodic ◽  
Ulf Dahlström ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Temporal Trends ◽  
Physical Symptoms ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Continuous Change ◽  
Ventricular Ejection Fraction ◽  
Increased Risk ◽  
Over Time

Abstract Background Temporal trends in clinical composition and outcome in dilated cardiomyopathy (DCM) are largely unknown, despite considerable advances in heart failure management. We set out to study clinical characteristics and prognosis over time in DCM in Sweden during 2003–2015. Methods DCM patients (n = 7873) from the Swedish Heart Failure Registry were divided into three calendar periods of inclusion, 2003–2007 (Period 1, n = 2029), 2008–2011 (Period 2, n = 3363), 2012–2015 (Period 3, n = 2481). The primary outcome was the composite of all-cause death, transplantation and hospitalization during 1 year after inclusion into the registry. Results Over the three calendar periods patients were older (p = 0.022), the proportion of females increased (mean 22.5%, 26.4%, 27.6%, p = 0.0001), left ventricular ejection fraction was higher (p = 0.0014), and symptoms by New York Heart Association less severe (p < 0.0001). Device (implantable cardioverter defibrillator and/or cardiac resynchronization) therapy increased by 30% over time (mean 11.6%, 12.3%, 15.1%, p < 0.0001). The event rates for mortality, and hospitalization were consistently decreasing over calendar periods (p < 0.0001 for all), whereas transplantation rate was stable. More advanced physical symptoms correlated with an increased risk of a composite outcome over time (p = 0.0043). Conclusions From 2003 until 2015, we observed declining mortality and hospitalizations in DCM, paralleled by a continuous change in both demographic profile and therapy in the DCM population in Sweden, towards a less affected phenotype.

Prevalence and prognostic impact of somatic mutations in patients with heart failure and reduced ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D.J Vazquez Andres ◽  
A Hernandez Vicente ◽  
M Diez Diez ◽  
M Gomez Molina ◽  
A Quintas ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Somatic Mutations ◽  
Myocardial Dysfunction ◽  
Study Endpoint ◽  
Prognostic Impact ◽  
Reduced Ejection Fraction ◽  
Increased Risk ◽  
Patients With Heart Failure

Abstract Introduction Somatic mutations in hematopoietic cells are associated with age and have been associated with higher mortality in apparently healthy adults, especially due to atherosclerotic disease. In animal models, somatic mutations are associated with atherosclerosis progression and myocardial dysfunction, especially when gene TET2 is affected. Preliminary clinical data, referred to ischemic heart failure (HF), have associate the presence of these acquired mutations with impaired prognosis. Purpose To study the prevalence of somatic mutations in patients with heart failure with reduced ejection fraction (HFrEF) and their impact on long-term prognosis. Methods We studied a cohort of elderly patients (more than 60 years old) hospitalized with HFrEF (LVEF&lt;45%). The presence of somatic mutations was assessed using next generation sequencing (Illumina HiSeq 2500), with a mutated allelic fraction of at least 2% and a panel of 55 genes related with clonal hematopoiesis. Patients were followed-up for a median of three years. The study endpoint was a composite of death or readmission for worsening HF. Kaplan-Meier analysis (log-rank test) and Cox proportional hazards regression models were performed adjusting for age, sex and LVEF. Results A total of 62 patients (46 males (74.2%), age 74±7.5 years) with HFrEF (LVEF 29.7±7.8%) were enrolled in the study. The ischemic etiology was present in 54% of patients. Somatic mutations in Dnmt3a or Tet2 were present in 11 patients (17.7%). No differences existed in baseline characteristics except for a higher prevalence of atrial fibrillation in patients with somatic mutations (70% vs. 40%, p=0.007). During the follow-up period, 40 patients (64.5%) died and 38 (61.3%) had HF re-admission. The KM survival analysis for the combined event is shown in Figure 1. Compared with patients without somatic mutations and after adjusting for covariates, there was an increased risk of adverse outcomes when the somatic mutations were present (HR 3.6, 95% CI [1.6, 7.8], p=0.0014). This results remains considering death as a competing risk (Gray's test p=0.0097) and adjusting for covariates (HR = 2.21 95% CI [0.98, 5], p=0.0556). Conclusions Somatic mutation are present in patients with HFrEF and determine a higher risk of adverse events in the follow-up. Further studies are needed to assess the clinical implications of these findings. Figure 1 Funding Acknowledgement Type of funding source: None

Abstract 34: Genome-wide Association Study Identified New Susceptibility Loci To Coronary Artery Aneurysm-related In Kawasaki Disease

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Kyu Yeun Kim ◽  
Mo Kyung Jung ◽  
Yoon-Sun Bae ◽  
Woohyuk Ji ◽  
Dongjik Shin ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Kawasaki Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Coronary Artery Aneurysm ◽  
Artery Aneurysm ◽  
Genome Wide Association ◽  
Korean Children ◽  
Genome Wide ◽  
Increased Risk

Kawasaki disease (KD) is an acute systemic vasculitis syndrome that predominantly affects children younger than 5 years of age, and may causes serious, sometimes life-threatening, cardiac sequela associated with coronary artery aneurysm (CAA). To identify genetic variants that confers a highly increased risk of coronary artery aneurysm-related in Kawasaki disease. In this study, we carried out genome-wide association study (GWAS) in a Korean children population including 102 CAA-related KD cases and 126 controls. Fifteen genetic loci were found to be significantly correlated with KD risk (P<1.0X10(-7)). Our case-control study revealed that rs4236089 C allele in chloride intracellular channel 5 (CLIC5) gene at 6p21.1 was significantly associated with KD patients with CAA (odds ratio (OR)=4.6, P=7.53X10(-7)). These findings suggest that the CLIC5 gene may play a crucial role in CAA development pathway of KD.

Abstract 18599: Clinical Assessment of Hemodynamic Profiles Predict Readmission and Mortality in Diastolic Heart Failure Patients

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Mohammed Siddiqui ◽  
Salpy V Pamboukian ◽  
Jose A Tallaj ◽  
Michael Falola ◽  
Sula Mazimba
Keyword(s):  
Heart Failure ◽  
Clinical Assessment ◽  
Diastolic Heart Failure ◽  
Clinical Care ◽  
Systolic Heart Failure ◽  
Health Care Expenditures ◽  
Left Ventricular ◽  
Readmission Rates ◽  
Heart Failure Patients ◽  
Increased Risk

Background: Reducing 30 day readmission rates for patients with heart failure (HF) has been a recent focus of lowering health care expenditures. Hemodynamic profiles (HP) have been associated with clinical outcomes in chronic systolic HF. The relationship of HP to outcomes in acute decompensated diastolic HF (DHF) has not been defined. Methods: This case-control study of 1892 DHF patients discharged alive from an academic hospital between 2002-2012 with left ventricular function greater or equal to 45% were categorized into 4 groups: Profile A, no evidence of congestion and hypoperfusion (dry-warm); Profile B, congestion with adequate perfusion (wet-warm); Profile C, congestion with hypoperfusion (wet-cold); and Profile L, hypoperfusion without congestion (dry-cold). All cause readmissions at 30 days and 1 year and mortality at 30 days and 1 year were examined. Statistical analysis using multivariable Cox Proportional hazard model was performed adjusting for demographic, clinical, care and hospital characteristics. Results: Of the 1892 patients, 1196 (63%) were females; mean age was 68 (±14) years. There were 724(38%), 1000 (53%), 88(5%) and 80 (4%) patients in the hemodynamic profiles A, B, C and L respectively. Profiles B and C were associated with an increased risk for 30-day all-cause HF readmission compared to profiles A and L: Hazard ratio (HR) [1.38 (95% C.I 1.17-1.61)], [1.39 (95% C.I 1.18-1.62)] for B and C profiles respectively. Profiles C and L were associated with increased mortality at 1 year: HR [1.46 (95% CI 1.06-1.89)] and [1.31 (95% CI 1.01-1.64)] for A and L profiles respectively (Table). Conclusions: Clinical assessment of HP can help identify DHF patients at increased risk of readmission and mortality, similar to systolic heart failure patients.

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