Association Between Genetically Proxied Inhibition of HMG-CoA Reductase and Epithelial Ovarian Cancer

Abstract

IMPORTANCE Preclinical and epidemiological studies indicate a potential chemopreventive role of statins in epithelial ovarian cancer risk. OBJECTIVE To evaluate the association of genetically proxied inhibition of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase (ie, genetic variants related to lower function of HMG-CoA reductase, target of statins) with epithelial ovarian cancer among the general population and in BRCA1/2 mutation carriers. DESIGN, SETTING, AND PARTICIPANTS Single-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with low-density lipoprotein (LDL) cholesterol in a genome-wide association study (GWAS) meta-analysis (N Յ196 475) were used to proxy therapeutic inhibition of HMG-CoA reductase, Niemann-Pick C1-Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Summary statistics were obtained for these SNPs from a GWAS meta-analysis of case-control analyses of invasive epithelial ovarian cancer in the Ovarian Cancer Association Consortium (OCAC; N = 63 347) and from a GWAS meta-analysis of retrospective cohort analyses of epithelial ovarian cancer among BRCA1/2 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA; N = 31 448). Across the 2 consortia, participants were enrolled between 1973 and 2014 and followed up through 2015. OCAC participants came from 14 countries and CIMBA participants came from 25 countries. SNPs were combined into multi-allelic models and mendelian randomization estimates representing lifelong inhibition of targets were generated using inverse-variance weighted random-effects models. EXPOSURES Primary exposure was genetically proxied inhibition of HMG-CoA reductase and secondary exposures were genetically proxied inhibition of NPC1L1 and PCSK9 and genetically proxied circulating LDL cholesterol levels. MAIN OUTCOMES AND MEASURES Overall and histotype-specific invasive epithelial ovarian cancer (general population) and epithelial ovarian cancer (BRCA1/2 mutation carriers), measured as ovarian cancer odds (general population) and hazard ratio (BRCA1/2 mutation carriers). RESULTS The OCAC sample included 22 406 women with invasive epithelial ovarian cancer and 40 941 control individuals and the CIMBA sample included 3887 women with epithelial ovarian cancer and 27 561 control individuals. Median ages for the cohorts ranged from 41.5 to 59.0 years and all participants were of European ancestry. In the primary analysis, genetically proxied HMG-CoA reductase inhibition equivalent to a 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol was associated with lower odds of epithelial ovarian cancer (odds ratio [OR], 0.60 [95% CI, 0.43-0.83]; P = .002). In BRCA1/2 mutation carriers, genetically proxied HMG-CoA reductase inhibition was associated with lower ovarian cancer risk (hazard ratio, 0.69 [95% CI, 0.51-0.93]; P = .01). In secondary analyses, there were no significant associations of genetically proxied inhibition of NPC1L1 (OR, 0.97 [95% CI, 0.53-1.75]; P = .91), PCSK9 (OR, 0.98 [95% C...

Predicting the effect of statins on cancer risk using genetic variants from a Mendelian randomization study in the UK Biobank

“…We found that genetic variants in the HMGCR region, serving as proxies for targets of statin therapy, were associated with a 26% decrease in risk of overall cancer per standard deviation (around 39 mg/dL or 1.0 mmol/L) reduction in genetically-predicted LDL-cholesterol. Our result replicates protective associations previously observed for prostate cancer ( PRACTICAL consortium et al, 2016 ), colorectal cancer ( Rodriguez-Broadbent et al, 2017 ), breast cancer ( Orho-Melander et al, 2018 ; Nowak and Ärnlöv, 2018 ), and ovarian cancer ( Yarmolinsky et al, 2020 ), although with a stronger weight of statistical evidence due to the additional number of cases analyzed here. For coronary artery disease, the short-term impact of statins in trials is around one-third of the genetic estimate, which represents the impact of lifelong reduced levels of LDL-cholesterol ( Ference et al, 2012 ).…”

“…Mendelian randomization studies also have the potential to predict the outcomes of trials for specific therapeutic interventions. A limited number of Mendelian randomization studies have investigated the relationship between HMGCR inhibition and cancer ( PRACTICAL consortium et al, 2016 ; Rodriguez-Broadbent et al, 2017 ; Orho-Melander et al, 2018 ; Nowak and Ärnlöv, 2018 ; Yarmolinsky et al, 2020 ), with protective associations observed for prostate cancer ( PRACTICAL consortium et al, 2016 ), colorectal cancer ( Rodriguez-Broadbent et al, 2017 ), breast cancer ( Orho-Melander et al, 2018 ; Nowak and Ärnlöv, 2018 ), and ovarian cancer ( Yarmolinsky et al, 2020 ). However, no comprehensive Mendelian randomization investigation has evaluated the predicted impact of HMGCR inhibition or the causal role of specific lipid fractions on the risk of many of the most common site-specific cancers.…”

Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: a Mendelian randomization study

“…In contrast to previous MR studies assessing overall cancer risk [29] and ovarian specific risk [30], the MR carried out here in relation to OC and OPC showed no effect using genetic instruments for HMGCR (statins). There was also limited evidence for a causal effect of NPC1L1 (ezetimibe), CETP (CETP inhibitors) as well as a number of other circulating lipid traits on OC or OPC.…”

“…The authors found little indication that statin therapy influences cancer incidence, which was consistent with the analyses of randomised trials (with a 10-year cancer-free survival difference of −0.3% 95%CI −1.5%, 0.5%) [19]. Nonetheless, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint recent MR studies [29,30] have identified an association between variants in HMGCR with cancer risk, but not alternative cholesterol-lowering treatments or genetically-predicted LDL-C, suggesting that statins may reduce cancer risk through a cholesterol independent pathway.…”

Predicting the effect of statins on cancer risk using genetic variants: a Mendelian randomization study in UK Biobank

“…A limited number of Mendelian randomization studies have investigated the relationship between HMGCR inhibition and cancer [37][38][39][40][41] , with protective associations observed for prostate cancer 37 , colorectal cancer 38 , breast cancer 39,40 , and ovarian cancer 41 . However, no comprehensive Mendelian randomization investigation has evaluated the predicted impact of HMGCR inhibition or the causal role of specific lipid fractions on the risk of many of the most common site-specific cancers.…”