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

Abstract

Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. We here assess the potential effect of statin therapy on cancer risk in Mendelian randomization analyses. We obtained genetic associations with the risk of overall and 22 site-specific cancers for 367,703 individuals in UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (OR per 1 standard deviation increase in LDL-cholesterol 1.32, 95% CI 1.13-1.53, p=0.0003), but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically-predicted LDL-cholesterol was not associated with overall cancer risk (OR 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk, but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.

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, 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.…”

“…Despite the lack of consistent evidence for a role of cholesterol-lowering on risk of OC or OPC in this study, individual effects of both PCSK9 and LDLR were demonstrated which may implicate a role for these drug targets in the development of OC or OPC via other mechanisms. The effects identified in the present study are directionally consistent with a recent MR analysis of 1,615 combined head and neck cancer cases from UK Biobank, which also found that a 1 SD unit increase in LDL-C proxied by PCSK9 and LDLR was associated with a reduction (OR 0.7 95%CI 0.4, 1.4, p= 0.35) and increase in odds (OR 1.6 95%CI 1.0, 2.4, p= 0.05) of head and neck cancer, respectively [29]. The opposing effects of PCSK9 and LDLR in this study also suggests that cholesterol lowering is unlikely to be the main mechanism of action.…”

“…MR has previously demonstrated the protective effect of cholesterol-lowering drugs on cardiovascular disease risk [27] , but also that inhibition of HMGCR and PCSK9 may have an adverse effect on diabetes risk [28]. Of relevance to cancer, some recent MR studies have shown that genetically-proxied inhibition of HMGCR may be protective against overall cancer [29] and epithelial ovarian cancer [30] [13,27,32], diabetes [28] and ovarian cancer [30]. In secondary analyses, SNPs were used to proxy circulating levels of LDL-C, HDL-C, total triglyceride, total cholesterol, apolipoprotein A and B. Betas represented the change in lipid trait levels per copy of the effect allele.…”

“…MR has previously demonstrated the protective effect of cholesterol-lowering drugs on cardiovascular disease risk [27], but also that inhibition of HMGCR and PCSK9 may have an adverse effect on diabetes risk [28]. Of relevance to cancer, some recent MR studies have shown that genetically-proxied inhibition of HMGCR may be protective against overall cancer [29] and epithelial ovarian cancer [30] risk. Our aim was to use MR to appraise the causal nature and mechanistic basis of the relationship between cholesterol-lowering and risk of oral and oropharyngeal cancer by investigating germline variation in HMGCR, NPC1L1, CETP, PCSK9 and LDLR, and other related lipid traits such as circulating LDL-C.…”