Causal Effects of Hydrophilic Bile Acids on Carfilzomib‐Related Cardiovascular Events in Multiple Myeloma: A Mendelian Randomization Study

Carfilzomib is highly effective in the treatment of multiple myeloma, but it has been associated with cardiovascular adverse events that impact patient outcomes. Our prior global metabolomic analyses indicated an association between hydrophilic bile acids and carfilzomib-cardiotoxicity risk, although a causal relationship remained to be determined. Here, our objective was to validate the previously identified bile acids in an independent cohort and investigate whether these hydrophilic bile acids play a causal role in carfilzomib-cardiotoxicity using Mendelian randomization. Using targeted metabolomics, we validated the association between glycoursodeoxycholic acid and carfilzomib-cardiotoxicity in an independent cohort (n = 61). We then performed two-sample Mendelian randomization analyses, using metabolome-wide association study results to provide the genetic instruments for bile acid levels as exposure and genome-wide association study summary statistics from the UK Biobank (n = 484,598) as the outcome data for cardiovascular adverse events. Causal inference was assessed with the inverse-variance weighted method, followed by multiple sensitivity analyses. Higher glycoursodeoxycholic acid concentration (odds ratio = 0.34, P = 0.032) was associated with lower cardiotoxicity risk after adjusting for hypertension and high levels of brain natriuretic peptides. Mendelian randomization analysis demonstrated a robust causal effect of glycoursodeoxycholic acid on cardiotoxicity risk (β = -0.00065, P = 6.2 × 10^-5). Gene enrichment analysis indicated pathways involving potassium channel regulation and thromboxane signaling to be implicated. This integrative metabolomic and genetic investigation supports a potential protective role of glycoursodeoxycholic acid in cardiovascular vulnerability and motivates larger, carfilzomib-specific studies to evaluate its utility for risk stratification.