Antihypertensive Drug Target Genes and Epithelial Ovarian Cancer Risk: A Two-Sample Mendelian Randomization Study

Purpose: Findings on the relationship between the use of antihypertensive drugs and the risk of epithelial ovarian cancer (EOC) have been inconsistent. We performed a two-sample Mendelian randomization (MR) using gene expression of target genes as genetic proxies for antihypertensive drug action to interrogate this. Methods: Genetic instruments for expression of antihypertensive medication target genes were identified with expression quantitative trait loci (eQTLs) in blood. Summary statistics for overall EOC and high-grade serous ovarian cancer (HGSOC) were obtained from genome wide association study (GWAS) datasets. The inverse variance weighted (IVW) method was used as the primary model. Sensitivity analysis based on different statistical assumptions was used to evaluate whether the results were robust. Bonferroni Corrections were used to identify significant associations due to multiple testing. Results: CACNA2D3 is a target of calcium channel blockers (CCBs). The MR analysis demonstrated that CACNA2D3 gene expression was associated with a lower risk of overall EOC (IVW OR = 0.919, 95% CI: 0.881– 0.958, P = 7.186 × 10 − 5 ) and HGSOC (IVW OR = 0.902, 95% CI: 0.858– 0.948, P = 4.562 × 10 − 5 ) at a Bonferroni-corrected threshold. In addition, there may be a suggestive causal association between SLC12A3 and overall EOC risk (IVW P = 0.011) and may also between AHR, TNNC1 and HGSOC risk (IVW P = 0.048, P = 0.029). We detected no evidence of horizontal pleiotropy for these associations. No significant association was observed between other target gene expressions and EOC risk. Conclusion: This study supports potential protective effects of genetically proxied CACNA2D3 expression on EOC risk, which may be consistent with the beneficial effects of CCBs, while further validation is required.