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

Author(s):Show less -

Gormley, Mark ^{[1, 2, 3]} ; Yarmolinsky, James ^{[1, 2]} ; Dudding, Tom ^{[1, 2, 3]} ; Burrows, Kimberley ^{[1, 2]} ; Martin, Richard M. ^{[1, 2, 4]} ; Thomas, Steven ^{[3, 4]} ; Tyrrell, Jessica ^[5] ; Brennan, Paul ^[6] ; Pring, Miranda ^[3] ; Boccia, Stefania ^{[7, 8]} ; Olshan, Andrew F. ^[9] ; Diergaarde, Brenda ^{[10, 11]} ; Hung, Rayjean J. ^{[12, 13]} ; Liu, Geoffrey ^{[12, 14]} ; Legge, Danny ^[15] ; Tajara, Eloiza H. ^[16] ; Severino, Patricia ^[17] ; Lacko, Martin ^[18] ; Ness, Andrew R. ^[4] ; Smith, George Davey ^{[1, 2]} ; Vincent, Emma E. ^{[15, 1, 2]} ; Richmond, Rebecca C. ^{[1, 2]}

Affiliation:Show less -

^[1] Univ Bristol, Bristol Med Sch, Dept Populat Hlth Sci, Bristol, Avon - England

^[2] Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Populat Hlth Sci, Bristol, Avon - England

^[3] Univ Bristol, Bristol Dent Hosp & Sch, Bristol, Avon - England

^[4] Univ Bristol, Natl Inst Hlth Res Bristol Biomed Res Ctr, Univ Hosp Bristol & Weston NHS Fdn Trust, Bristol, Avon - England

^[5] Univ Exeter, Med Sch, RD&E Hosp, RILD Bldg, Exeter, Devon - England

^[6] WHO, Int Agcy Res Canc, Genet Epidemiol Grp, Lyon - France

^[7] Univ Cattolica Sacro Cuore, Univ Dept Life Sci & Publ Hlth, Sect Hyg, Rome - Italy

^[8] Fdn Policlin Univ A Gemelli IRCCS, Dept Woman & Child Hlth & Publ Hlth, Publ Hlth Area, Rome - Italy

^[9] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27515 - USA

^[10] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 - USA

^[11] UPMC Hillman Canc Ctr, Pittsburgh, PA - USA

^[12] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON - Canada

^[13] Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Populat Hlth Res, Toronto, ON - Canada

^[14] Princess Margaret Canc Ctr, Toronto, ON - Canada

^[15] Univ Bristol, Sch Cellular & Mol Med, Bristol, Avon - England

^[16] Sch Med Sao Jose do Rio Preto, Sao Paulo - Brazil

^[17] Hosp Israelita Albert Einstein, Albert Einstein Res & Educ Inst, Sao Paulo - Brazil

^[18] Maastricht Univ, Res Inst GROW, Dept Otorhinolaryngol & Head & Neck Surg, Med Ctr, Maastricht - Netherlands

• Document type: Journal article
• Source: PLOS GENETICS; v. 17, n. 4 APR 2021.
• Web of Science Citations: 0

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 (I-2 = 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. Author summary This study aimed to determine if genetically-proxied cholesterol-lowering drugs (such as statins which target HMGCR) and genetically-proxied circulating lipid traits (e.g., lowdensity lipoprotein cholesterol) have a causal effect on oral and oropharyngeal cancer risk. There was little evidence that genetically-proxied inhibition of HMGCR (target of statins), NPC1L1 (target of ezetimibe) and CETP (target of CETP inhibitors) influences oral or oropharyngeal cancer risk. Similarly, there was little evidence of an effect of circulating lipid traits on oral or oropharyngeal cancer risk. We did find some evidence that genetically-proxied inhibition of PCSK9 increases, while lipid-lowering variants in LDLR reduce oral and oropharyngeal cancer risk. Our findings suggest that the results of previous observational studies examining the effect of statins on oral and oropharyngeal risk may have been confounded. The mechanism of action of PCSK9 may be independent of cholesterol-lowering, however further replication of this finding in other head and neck cancer datasets is required. (AU)

• FAPESP's process: 10/51168-0 - Environmental, clinical, histopathological and molecular factors associated with development and prognosis of head and neck squamous cell carcinomas
• Grantee: Eloiza Helena Tajara da Silva
• Support Opportunities: Research Projects - Thematic Grants