AUTHOR=Norton Nadine , Crook Julia E. , Wang Liwei , Olson Janet E. , Kachergus Jennifer M. , Serie Daniel J. , Necela Brian M. , Borgman Paul G. , Advani Pooja P. , Ray Jordan C. , Landolfo Carolyn , Di Florio Damian N. , Hill Anneliese R. , Bruno Katelyn A. , Fairweather DeLisa 

TITLE=Association of Genetic Variants at TRPC6 With Chemotherapy-Related Heart Failure

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=7

YEAR=2020

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2020.00142

DOI=10.3389/fcvm.2020.00142

ISSN=2297-055X

ABSTRACT=<p><bold>Background:</bold> Our previous GWAS identified genetic variants at six novel loci that were associated with a decline in left ventricular ejection fraction (LVEF), <italic>p</italic> &lt; 1 × 10<sup>−5</sup> 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.</p><p><bold>Methods:</bold> 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 (<italic>N</italic> = 12) and control groups of patients treated with anthracycline +/– trastuzumab without HF (<italic>N</italic> = 282) and patients with HF that were never treated with anthracycline or trastuzumab (<italic>N</italic> = 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.</p><p><bold>Results:</bold><italic>TRPC6 5</italic>′ flanking variant rs57242572-T was significantly more frequent in cases compared to controls, <italic>p</italic> = 0.031, and rs61918162-T showed a trend for association, <italic>p</italic> = 0.065. The rs61918162 T-allele was associated with higher <italic>TRPC6</italic> expression in the heart left ventricle. We identified a single <italic>TRPC6</italic> 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.</p><p><bold>Conclusions:</bold> Genetic variants that are associated with increased <italic>TRPC6</italic> expression in the heart and rare <italic>TRPC6</italic> missense variants may be clinically useful as risk factors for CRHF. GsMTx-4 may be a cardioprotective agent in patients with <italic>TRPC6</italic> risk variants. Replication of the genetic associations in larger well-characterized samples and functional studies are required.</p>