67 Anti-hypertensives identified as therapeutic candidates for uterine fibroids using genetically informed drug repurposing approaches

Abstract

Objectives/Goals: We aimed to discover treatment candidates for uterine fibroids, a common benign tumor with adverse impacts on quality of life. Repurposing already approved medications for fibroids can expedite treatment option expansion. Using genetic proxies, we identified novel fibroid drug candidates and estimated their effect on risk of fibroid diagnosis. Methods/Study Population: We performed a genetically predicted gene expression (GPGE) analysis using S-PrediXcan and GTEx tissue models with multi-ancestry genome-wide association study (GWAS) summary statistics of fibroids (cases  =  74,294, controls  =  465). There were 81 genes significantly associated with fibroid risk. Querying drug–gene interaction databases identified 56 approved medications that target these genes, including two antihypertensives, hydralazine, and spironolactone. Using independent multi-ancestry GWAS summary statistics (N  =  635,969) for systolic (SBP) and diastolic blood pressure (DBP), we conducted GPGE analyses. Blood pressure (exposure) and fibroids (outcome) GPGE summary statistics in the same tissues were used for two-sample Mendelian randomization (MR) analyses to proxy medication effects. Results/Anticipated Results: GPGE analyses identified hydralazine/tumor protein P53 (TP53) activity and spironolactone/thyroid hormone receptor beta (THRB) activity as drug-gene candidate pairs. Both drugs increase gene activity of their paired gene. Increased TP53 expression was associated with SBP in four tissues (exposure). The MR results indicated hydralazine use, proxied by increased TP53 expression, may reduce fibroid risk by 42% per standard deviation of gene expression (odds ratio [OR]  =  0.58, p  =  1.43E-12). Increased THRB expression was associated with DBP in eight tissues and were included in the MR (exposure). The MR results suggest spironolactone use, proxied by increased THRB expression, may reduce fibroid risk by 23% per standard deviation of gene expression (OR  =  0.77, p  = 5.94E-6). Discussion/Significance of Impact: We provide biologically plausible evidence for repurposing hydralazine and spironolactone for reducing risk of fibroid diagnosis. Repurposing these hypertension medications could provide novel preventative treatments for fibroids, particularly for individuals disproportionately affected by both conditions.