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 < 1 × 10−5 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 modeled 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.
Highlights
Cardiomyopathy is a major comorbidity for cancer patients treated with anthracyclines and/or trastuzumab [1,2,3,4,5,6,7]
We identified an additional 17 chemotherapy cases with heart failure (HF) from the Mayo Clinic Biobank with an outcome of definite or probable HF determined by the eMERGE algorithm that were assessed by an independent cardiologist (Landolfo) through examination of medical records. 5/17 patients with HF that were determined to have valve or ischemic disease were eliminated from genetic analyses. 12/17 cases were determined to be the result of anthracycline and/or trastuzumab therapy
For TRPC6, we genotyped an additional 11 SNPs, five of which mapped to the 5′ flanking region and were significantly associated at p < 1 × 10−5 in the imputation analysis from the primary genomewide association study (GWAS), four of which were eQTLs in GTEX tissue from heart left ventricle or artery tibial tissue p < 1 × 10−5, two missense variants, and a rare variant identified by Sanger sequencing of 38 patients with chemotherapy-related congestive heart failure (CHF)
Summary
Cardiomyopathy is a major comorbidity for cancer patients treated with anthracyclines and/or trastuzumab [1,2,3,4,5,6,7]. Doxorubicin-related heart failure (CRHF) is dose dependent at doses >250 mg/m2 [8]; even at “safe” doses of
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