Genetic inhibition of HMG-CoA reductase and epithelial ovarian cancer risk: a Mendelian randomization analysis


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James Yarmolinsky1,Caroline Bull1,Emma Vincent1,Jamie Robinson1,Axel Walther1,George Davey Smith1,Sarah Lewis1,Caroline Relton1,Richard Martin1
1University of Bristol

Abstract

Background

Preclinical and epidemiological studies indicate a potential chemopreventive role of statins in epithelial ovarian cancer (EOC) risk. We aimed to evaluate the association of genetically-proxied pharmacological inhibition of HMG-CoA reductase (a target of statins) with risk of EOC among the general population and in BRCA1/2 mutation carriers. In secondary analyses, we also aimed to evaluate the association of genetically-proxied Niemann-Pick C1-like protein (NPC1L1; a target of ezetimibe), proprotein convertase subtilisin/kexin type 9 (PCSK9; a target of PCSK9 inhibitors), and circulating low-density lipoprotein cholesterol (LDL-C) with EOC to examine whether risk-lowering effects of HMG-CoA reductase inhibition are a consequence of LDL-C lowering or are mechanism-specific.

Method

We obtained summary statistics on SNPs in HMGCR, NPC1L1, and PCSK9 associated (P<5x10-8) with LDL-cholesterol in a GWAS meta-analysis (N≤188,577 individuals). Summary statistics were also obtained for the association of these SNPs with EOC risk in up to 25,509 cases and 40,941 controls in the OCAC Consortium and EOC risk among BRCA1/2 mutation carriers in 3,887 cases and 27,561 controls in the CIMBA consortium. SNPs were combined into multi-allelic models and causal estimates were generated using inverse-variance weighted random-effects models.

Results

Genetically-proxied HMG-CoA reductase inhibition equivalent to a 1-mmol/L reduction in LDL-cholesterol was associated with a lower EOC risk (OR:0.60,95%CI:0.43-0.83;P=0.002). In analyses among BRCA1/2 mutation carriers, genetically-proxied HMG-CoA reductase inhibition was likewise associated with lower risk (OR:0.69,95%CI:0.51-0.93,P=0.014). There was little evidence of association of genetically-proxied inhibition of NPC1L1 (OR:0.97,95%CI:0.53-1.75;P=0.91) or PCSK9 (OR:0.98,95%CI:0.85-1.13;P=0.80) or of circulating LDL-cholesterol (OR:0.98,95%CI:0.91-1.05;P=0.55) with EOC risk.

Conclusion

Genetic evidence supports a chemopreventive role of long-term HMG-CoA reductase inhibition in risk of epithelial ovarian cancer in the general population and among BRCA1/2 mutation carriers.