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

Autoři: Mark Gormley aff001;  James Yarmolinsky aff001;  Tom Dudding aff001;  Kimberley Burrows aff001;  Richard M. Martin aff001;  Steven Thomas aff002;  Jessica Tyrrell aff005;  Paul Brennan aff006;  Miranda Pring aff002;  Stefania Boccia aff007;  Andrew F. Olshan aff009;  Brenda Diergaarde aff010;  Rayjean J. Hung aff011;  Geoffrey Liu aff012;  Danny Legge aff014;  Eloiza H. Tajara aff015;  Patricia Severino aff016;  Martin Lacko aff017;  Andrew R. Ness aff004;  George Davey Smith aff001;  Emma E. Vincent aff001;  Rebecca C. Richmond aff001
Působiště autorů: MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom aff001;  Bristol Dental Hospital and School, University of Bristol, Bristol, United Kingdom aff002;  Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom aff003;  National Institute for Health Research Bristol Biomedical Research Centre at the University Hospitals Bristol and Weston NHS Foundation Trust, University of Bristol, Bristol, United Kingdom aff004;  University of Exeter Medical School, RILD Building, RD&E Hospital, Exeter, United Kingdom aff005;  Genetic Epidemiology Group, World Health Organization, International Agency for Research on Cancer, Lyon, France aff006;  Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Roma, Italia aff007;  Department of Woman and Child Health and Public Health, Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy aff008;  Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America aff009;  Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, and UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, United States of America aff010;  Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada aff011;  Dalla Lana School of Public Health, University of Toronto, Toronto, Canada aff012;  Princess Margaret Cancer Centre, Toronto, Canada aff013;  School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom aff014;  School of Medicine of São José do Rio Preto, São Paulo, Brazil aff015;  Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, Brazil aff016;  Department of Otorhinolaryngology and Head and Neck Surgery, Research Institute GROW, Maastricht University Medical Center, Maastricht, The Netherlands aff017
Vyšlo v časopise: Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study. PLoS Genet 17(4): e1009525. doi:10.1371/journal.pgen.1009525
Kategorie: Research Article


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.

Klíčová slova:

Statins – Cancer risk factors – Cancers and neoplasms – Genetics – Head and neck cancers – Cholesterol – Lipids – Single nucleotide polymorphisms


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