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


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Mark Gormley, James Yarmolinsky, Tom Dudding, Kimberley Burrows, Richard Martin, Steven Thomas, Jessica Tyrrell, Miranda Pring, Danny Legge, Andrew Ness, George Davey Smith, Emma Vincent, Rebecca Richmond

Abstract

Background

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, confers substantial global morbidity and mortality. Strategies to reduce disease burden include the discovery of novel therapies as well as the repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR), with some observational studies suggesting statin use reduces the risk of HNSCC, but the evidence is inconclusive.  Our aim was to appraise the relationship of genetically proxied cholesterol-lowering drug targets with oral (OC) and oropharyngeal (OPC) cancer.

Method

We conducted two-sample Mendelian randomization (MR) using genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR which were robustly associated with low-density lipoprotein cholesterol (LDL-C) and other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. The second sample was taken from a GWAS of 6,034 OC/OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank data, using 839 OC/OPC cases and 372,016 controls and the results combined in a fixed-effects meta-analysis.

Results

We found limited evidence of a causal effect of genetically proxied HMGCR, NPC1L1, CETP and other circulating lipid traits on OC/OPC risk. Genetically proxied PCSK9 inhibition equivalent to a 1mmol/L (38.7mg/dL) reduction in LDL-C was associated with an increased risk of combined OC/OPC (OR 1.8 95%CI 1.2, 2.8), with good concordance between studies. Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). A series of pleiotropy-robust and outlier detection methods were applied and the findings were not found to be biased as a result of pleiotropy.

Conclusion

There was little evidence for a protective effect of genetic inhibition of HMGCR, NPC1L1 and CETP with circulating lipid traits on OPC/OC risk, suggesting previous observational studies may have been confounded. There was however, some evidence that genetically proxied inhibition of PCSK9 increased OPC/OC risk. This indicates that the mechanisms of action of PCSK9 on OPC/OC risk may be independent of its cholesterol lowering effects.

Impact statement

MR can help identify metabolic targets common to all HNSCC tumours which could simplify a preventative or therapeutic approach.