{"doi":"10.3389/fcvm.2020.00142","title":"Association of Genetic Variants at TRPC6 With Chemotherapy-Related Heart Failure","abstract":"Background: Our previous GWAS identified genetic variants at six novel loci that were associated with a decline in left ventricular ejection fraction (LVEF), p<1x10-5 in 1,191 early breast cancer patients from the N9831 clinical trial of chemotherapy plus trastuzumab. In this study we sought replication of these loci. Methods: We tested the top loci from the GWAS for association with chemotherapy-related heart failure (CRHF) using 26 CRHF cases from N9831 and 984 patients from the Mayo Clinic Biobank which included CRHF cases (N=12) and control groups of patients treated with anthracycline +/- trastuzumab without HF (N=282) and patients with HF that were never treated with anthracycline or trastuzumab (N=690). We further examined associated loci in the context of gene expression and rare coding variants using a TWAS approach in heart left ventricle and Sanger sequencing, respectively. Doxorubicin-induced apoptosis and cardiomyopathy was modelled in human iPSC-derived cardiomyocytes and endothelial cells and a mouse model, respectively, that were pre-treated with GsMTx-4, an inhibitor of TRPC6. Results: TRPC6 5’ flanking variant rs57242572-T was significantly more frequent in cases compared to controls, p=0.031, and rs61918162-T showed a trend for association, p=0.065. The rs61918162 T-allele was associated with higher TRPC6 expression in the heart left ventricle. We identified a single TRPC6 rare missense variant (rs767086724, N338S, prevalence 0.0025% in GnomAD) in one of 38 patients (2.6%) with CRHF. Pre-treatment of cardiomyocytes and endothelial cells with GsMTx4 significantly reduced doxorubicin-induced apoptosis. Similarly, mice treated with GsMTx4 had significantly improved doxorubicin-induced cardiac dysfunction Conclusions: Genetic variants that are associated with increased TRPC6 expression in the heart and rare TRPC6 missense variants may be clinically useful as risk factors for CRHF. GsMTx-4 may be a cardioprotective agent in patients with TRPC6 risk variants. Replication of the genetic associations in larger well characterized samples and functional studies are required.","journal":"Frontiers in Cardiovascular Medicine","year":2020,"id":104154,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.7638,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":308851,"name":"Julia E. Crook","orcid":"0000-0001-9932-925X","position":1,"is_corresponding":false},{"id":49924,"name":"Liwei Wang","orcid":"0000-0001-9970-8604","position":2,"is_corresponding":false},{"id":70827,"name":"Janet E. Olson","orcid":"0000-0003-4944-7789","position":3,"is_corresponding":false},{"id":239292,"name":"Jennifer M. Kachergus","orcid":null,"position":4,"is_corresponding":false},{"id":95810,"name":"Daniel Serie","orcid":null,"position":5,"is_corresponding":false},{"id":506475,"name":"Brian M. Necela","orcid":"0000-0002-4409-1245","position":6,"is_corresponding":false},{"id":507464,"name":"Paul G. Borgman","orcid":null,"position":7,"is_corresponding":false},{"id":506476,"name":"Pooja Advani","orcid":"0009-0007-5470-3149","position":8,"is_corresponding":false},{"id":506477,"name":"Jordan Ray","orcid":"0000-0001-7583-3355","position":9,"is_corresponding":false},{"id":507465,"name":"Carolyn Landolfo","orcid":null,"position":10,"is_corresponding":false},{"id":248039,"name":"Damian N. Di Florio","orcid":"0000-0003-1619-5394","position":11,"is_corresponding":false},{"id":507466,"name":"Anneliese R. Hill","orcid":null,"position":12,"is_corresponding":false},{"id":40577,"name":"Katelyn A. Bruno","orcid":"0000-0001-8980-6059","position":13,"is_corresponding":false},{"id":248042,"name":"DeLisa Fairweather","orcid":"0000-0003-3093-1810","position":14,"is_corresponding":false},{"id":91972,"name":"Nadine Norton","orcid":"0000-0002-3848-4288","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-18T22:43:22.755723Z","pmid":"32903434","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}