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. 2021 Apr 1;6(4):379-386.
doi: 10.1001/jamacardio.2020.6500.

Assessing the Role of Rare Genetic Variation in Patients With Heart Failure

Gundula Povysil  1 , Olympe Chazara  2 , Keren J Carss  2 , Sri V V Deevi  2 , Quanli Wang  2 , Javier Armisen  2 , Dirk S Paul  2 , Christopher B Granger  3 , John Kjekshus  4 , Vimla Aggarwal  1   5 , Carolina Haefliger  2 , David B Goldstein  1
Affiliations

Assessing the Role of Rare Genetic Variation in Patients With Heart Failure

Gundula Povysil et al. JAMA Cardiol. .

Abstract

Importance: Sequencing studies have identified causal genetic variants for distinct subtypes of heart failure (HF) such as hypertrophic or dilated cardiomyopathy. However, the role of rare, high-impact variants in HF, for which ischemic heart disease is the leading cause, has not been systematically investigated.

Objective: To assess the contribution of rare variants to all-cause HF with and without reduced left ventricular ejection fraction.

Design, setting, and participants: This was a retrospective analysis of clinical trials and a prospective epidemiological resource (UK Biobank). Whole-exome sequencing of patients with HF was conducted from the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) and Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) clinical trials. Data were collected from March 1999 to May 2003 for the CHARM studies and September 2003 to July 2007 for the CORONA study. Using a gene-based collapsing approach, the proportion of patients with HF and controls carrying rare and presumed deleterious variants was compared. The burden of pathogenic variants in known cardiomyopathy genes was also investigated to assess the diagnostic yield. Exome sequencing data were generated between January 2018 and October 2018, and analysis began October 2018 and ended April 2020.

Main outcomes and measures: Odds ratios and P values for genes enriched for rare and presumed deleterious variants in either patients with HF or controls and diagnostic yield of pathogenic variants in known cardiomyopathy genes.

Results: This study included 5942 patients with HF and 13 156 controls. The mean (SD) age was 68.9 (9.9) years and 4213 (70.9%) were male. A significant enrichment of protein-truncating variants in the TTN gene (P = 3.35 × 10-13; odds ratio, 2.54; 95% CI, 1.96-3.31) that was further increased after restriction to variants in exons constitutively expressed in the heart (odds ratio, 4.52; 95% CI, 3.10-6.68). Validation using UK Biobank data showed a similar enrichment (odds ratio, 4.97; 95% CI, 3.94-6.19 after restriction). In the clinical trials, 201 of 5916 patients with HF (3.4%) had a pathogenic or likely pathogenic cardiomyopathy variant implicating 21 different genes. Notably, 121 of 201 individuals (60.2%) had ischemic heart disease as the clinically identified etiology for the HF. Individuals with HF and preserved ejection fraction had only a slightly lower yield than individuals with midrange or reduced ejection fraction (20 of 767 [2.6%] vs 15 of 392 [3.8%] vs 166 of 4757 [3.5%]).

Conclusions and relevance: An increased burden of diagnostic mendelian cardiomyopathy variants in a broad group of patients with HF of mostly ischemic etiology compared with controls was observed. This work provides further evidence that mendelian genetic conditions may represent an important subset of complex late-onset diseases such as HF, irrespective of the clinical presentation.

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Conflict of interest statement

Conflict of Interest Disclosures: Drs Chazara, Carss, Deevi, and Paul report personal fees from AstraZeneca during the conduct of the study and outside the submitted work. Mr Wang reports personal fees from AstraZeneca and is a stockholder of AstraZeneca outside the submitted work. Dr Armisen reports personal fees from AstraZeneca during the conduct of the study and outside the submitted work and is a stockholder of AstraZeneca. Dr Granger reports personal fees from AbbVie, Bayer, Boston Scientific, CeleCor, Correvio, Espero BioPharma, Medscape, Medtronic, Merck, National Institutes of Health, Novo Nordisk, Rhoshan, and Roche; grants from Akros, Apple, AstraZeneca, Daiichi Sankyo, US Food and Drug Administration, GlaxoSmithKline, and Medtronic Foundation; grants and personal fees from Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Novartis, and Pfizer; and other support from Duke Clinical Research Institute outside the submitted work. Dr Haefliger reports personal fees from AstraZeneca during the conduct of the study and outside the submitted work and is a stockholder of AstraZeneca. Dr Goldstein reports holding equity in the publicly traded precision medicine company Praxis Precision Medicine, Apostle Inc, and Q-State Biosciences and has in the past been a paid advisor to AstraZeneca, Gilead Sciences, GoldFinch Bio, and Johnson & Johnson. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Quantile-Quantile Plot of Observed vs Expected P Values for the Full Cohort and Protein-Truncating Variants Model
Only TTN reached studywide significance with a P value of 3.35 × 10−13. The orange and light blue lines indicate the 2.5th and 97.5th percentile of expected P values, respectively.
Figure 2.
Figure 2.. Forest Plot Showing an Enrichment of TTN Truncating Variants in Cases Compared With Controls in CHARM/CORONA and the UK Biobank
All subgroups show an enrichment that increases after filtering for a proportion spliced in (PSI) more than 0.9 (odds ratios indicated in yellow). Note that subgroups defined by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes in B are not mutually exclusive (see eTable 16 in the Supplement for more details). CHARM indicates Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity; CORONA, Controlled Rosuvastatin Multinational Trial in Heart Failure; HFmrEF, heart failure with midrange ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.
Figure 3.
Figure 3.. Venn Diagram of Genes With a Diagnostic Variant for the 3 Different Heart Failure Types
All genes implicated in heart failure with preserved ejection fraction are a subgroup of heart failure with reduced ejection fraction genes, and only 1 heart failure with midrange ejection fraction gene is not implicated in heart failure with reduced ejection fraction.
See this image and copyright information in PMC

Comment in

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