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

Mark Gormley, James Yarmolinsky, Tom Dudding, Kimberley Burrows, Richard M Martin, Steven Thomas, Jessica Tyrrell, Paul Brennan, Miranda Pring, Stefania Boccia, Andy F Olshan, Brenda Diergaarde, Rayjean J Hung, Geoffrey Liu, Danny Legge, Eloiza H Tajara, Patricia Severino, Martin Lacko, Andrew R Ness, George Davey SmithEmma E Vincent, Rebecca Richmond

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Introduction: Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk.

Methods and findings: We conducted two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk.

The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis.

We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p= 9.31 ×10−05), with good concordance between GAME-ON and UK Biobank (I2= 22%). 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). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p= 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings.

Conclusion: We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects, but further replication of this finding is required.
Original languageEnglish
Article numbere1009525
Number of pages23
JournalPLoS Genetics
Issue number4 April 2021
Publication statusPublished - 22 Apr 2021

Bibliographical note

Funding Information:
M.G. was a National Institute for Health Research (NIHR) academic clinical fellow and is currently supported by a Wellcome Trust GW4-Clinical Academic Training PhD Fellowship. This research was funded in part, by the Wellcome Trust [Grant number 220530/Z/20/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. UK Biobank approval was given for this project (ID 40644 ?Investigating aetiology, associations and causality in diseases of the head and neck?) and UK Biobank GWAS data was also accessed under the application (ID 15825 ?MR-Base: an online resource for Mendelian randomization using summary data?- Dr Philip Haycock). R.C.R. is a de Pass VC research fellow at the University of Bristol. J.T. is supported by an Academy of Medical Sciences (AMS) Springboard award and Diabetes UK (SBF004\1079). R.M.M. was supported by a Cancer Research UK (C18281/ A19169) programme grant (the Integrative Cancer Epidemiology Programme) and is part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol supported by the Medical Research Council (MC_UU_00011/1, MC_UU_00011/7) and the University of Bristol. JY is supported by a Cancer Research UK Population Research Postdoctoral Fellowship (C68933/ A28534). R.M.M. and A.R.N. are supported by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre which is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the NIHR under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol Research Capability Funding and the NIHR Senior Investigator award to A.R.N. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). B.D. and the University of Pittsburgh head and neck cancer case-control study are supported by US National Institutes of Health (NIH) grants: P50 CA097190, P30 CA047904 and R01 DE025712. The genotyping of the HNSCC cases and controls was performed at the Center for Inherited Disease Research (CIDR) and funded by the US National Institute of Dental and Craniofacial Research (NIDCR; 1X01HG007780-0). A.F.O. and the University of North Carolina (UNC) CHANCE study was supported in part by the Division of Cancer Prevention, National Cancer Institute (R01-CA90731). E.E.V and D.L are supported by Diabetes UK (17/0005587). E.E.V is also supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). E.H.T and P.S. were supported by the GENCAPO/ FAPESP grant (10/51168-0). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2021 Gormley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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