AUTHOR=Tantawy Marwa , Yang Guang , Algubelli Raghunandan Reddy , DeAvila Gabriel , Rubinstein Samuel M. , Cornell Robert F. , Fradley Michael G. , Siegel Erin M. , Hampton Oliver A. , Silva Ariosto S. , Lenihan Daniel , Shain Kenneth H. , Baz Rachid C. , Gong Yan 

TITLE=Whole-Exome sequencing analysis identified TMSB10/TRABD2A locus to be associated with carfilzomib-related cardiotoxicity among patients with multiple myeloma

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1181806

DOI=10.3389/fcvm.2023.1181806

ISSN=2297-055X

ABSTRACT=<sec><title>Background</title><p>Proteasome inhibitor Carfilzomib (CFZ) is effective in treating patients with refractory or relapsed multiple myeloma (MM) but has been associated with cardiovascular adverse events (CVAE) such as hypertension, cardiomyopathy, and heart failure. This study aimed to investigate the contribution of germline genetic variants in protein-coding genes in CFZ-CVAE among MM patients using whole-exome sequencing (WES) analysis.</p></sec><sec><title>Methods</title><p>Exome-wide single-variant association analysis, gene-based analysis, and rare variant analyses were performed on 603,920 variants in 247 patients with MM who have been treated with CFZ and enrolled in the Oncology Research Information Exchange Network (ORIEN) at the Moffitt Cancer Center. Separate analyses were performed in European Americans and African Americans followed by a trans-ethnic meta-analysis.</p></sec><sec><title>Results</title><p>The most significant variant in the exome-wide single variant analysis was a missense variant rs7148 in the thymosin beta-10/TraB Domain Containing 2A (<italic>TMSB10/TRABD2A</italic>) locus. The effect allele of rs7148 was associated with a higher risk of CVAE [odds ratio (OR) = 9.3 with a 95% confidence interval of 3.9—22.3, <italic>p</italic> = 5.42*10<sup>−7</sup>]. MM patients with rs7148 AG or AA genotype had a higher risk of CVAE (50%) than those with GG genotype (10%). rs7148 is an expression quantitative trait locus (eQTL) for <italic>TRABD2A</italic> and <italic>TMSB10</italic>. The gene-based analysis also showed <italic>TRABD2A</italic> as the most significant gene associated with CFZ-CVAE (<italic>p</italic> = 1.06*10<sup>−6</sup>).</p></sec><sec><title>Conclusions</title><p>We identified a missense SNP rs7148 in the <italic>TMSB10/TRABD2A</italic> as associated with CFZ-CVAE in MM patients. More investigation is needed to understand the underlying mechanisms of these associations.</p></sec>