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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  • Gormley, M.
    • Other Affiliation: University of Bristol
  • Yarmolinsky, J.
    • Other Affiliation: University of Bristol
  • Dudding, T.
    • Other Affiliation: University of Bristol
  • Burrows, K.
    • Other Affiliation: University of Bristol
  • Martin, R.M.
    • Other Affiliation: University of Bristol
  • Thomas, S.
    • Other Affiliation: University of Bristol
  • Tyrrell, J.
    • Other Affiliation: University of Exeter
  • Brennan, P.
    • Other Affiliation: World Health Organization
  • Pring, M.
    • Other Affiliation: University of Bristol
  • Boccia, S.
    • Other Affiliation: Università Cattolica del Sacro Cuore
  • Olshan, A.F.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Diergaarde, B.
    • Other Affiliation: University of Pittsburgh
  • Hung, R.J.
    • Other Affiliation: University of Toronto
  • Liu, G.
    • Other Affiliation: University of Toronto
  • Legge, D.
    • Other Affiliation: University of Bristol
  • Tajara, E.H.
    • Other Affiliation: School of Medicine of São José do Rio Preto
  • Severino, P.
    • Other Affiliation: Hospital Israelita Albert Einstein
  • Lacko, M.
    • Other Affiliation: Maastricht University Medical Center
  • Ness, A.R.
    • Other Affiliation: University of Bristol
  • Smith, G.D.
    • Other Affiliation: University of Bristol
  • Vincent, E.E.
    • Other Affiliation: University of Bristol
  • Richmond, R.C.
    • Other Affiliation: University of Bristol
Abstract
  • 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 using 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 x10-05), 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. 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; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.
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  • Article
Rights statement
  • In Copyright
License
  • Attribution 4.0 International
Journal title
  • PLoS Genetics
Journal volume
  • 17
Journal issue
  • 4-Apr-21
Language
  • English
Version
  • Publisher
Funder
  • Division of Cancer Prevention, National Cancer Institute, DCP, NCI
  • World Cancer Research Fund International, WCRF: IIG_2019_2009
  • Wellcome Trust, WT: 15825, 220530/Z/20/Z, 40644
  • World Cancer Research Fund, WCRF
  • National Institute for Health and Care Research, NIHR
  • Academy of Medical Sciences
  • University Hospitals Bristol NHS Foundation Trust, UHBW: RP-PG-0707-10034
  • University of North Carolina Wilmington, UNCW
  • National Cancer Institute, NCI: 17/0005587, P30CA016086, P30CA047904, P50CA097190, R01CA090731
  • University of Pittsburgh
  • National Institutes of Health, NIH
  • Cancer Research UK, CRUK: C18281/A19169
  • Diabetes UK: SBF004\1079
  • National Institute of Dental and Craniofacial Research, NIDCR: 1X01HG007780-0, R01DE025712
  • Medical Research Council, MRC: C68933/ A28534, MC_UU_00011/1, MC_UU_00011/7
  • Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP: 10/51168-0
  • University of Bristol
  • NIHR Bristol Biomedical Research Centre
ISSN
  • 1553-7390
Publisher
  • Public Library of Science

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