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

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 prescrib...

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Autores principales: Gormley, Mark, Yarmolinsky, James, Dudding, Tom, Burrows, Kimberley, Martin, Richard M., Thomas, Steven, Tyrrell, Jessica, Brennan, Paul, Pring, Miranda, Boccia, Stefania, Olshan, Andrew F., Diergaarde, Brenda, Hung, Rayjean J., Liu, Geoffrey, Legge, Danny, Tajara, Eloiza H., Severino, Patricia, Lacko, Martin, Ness, Andrew R., Davey Smith, George, Vincent, Emma E., Richmond, Rebecca C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096036/
https://www.ncbi.nlm.nih.gov/pubmed/33886544
http://dx.doi.org/10.1371/journal.pgen.1009525
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author Gormley, Mark
Yarmolinsky, James
Dudding, Tom
Burrows, Kimberley
Martin, Richard M.
Thomas, Steven
Tyrrell, Jessica
Brennan, Paul
Pring, Miranda
Boccia, Stefania
Olshan, Andrew F.
Diergaarde, Brenda
Hung, Rayjean J.
Liu, Geoffrey
Legge, Danny
Tajara, Eloiza H.
Severino, Patricia
Lacko, Martin
Ness, Andrew R.
Davey Smith, George
Vincent, Emma E.
Richmond, Rebecca C.
author_facet Gormley, Mark
Yarmolinsky, James
Dudding, Tom
Burrows, Kimberley
Martin, Richard M.
Thomas, Steven
Tyrrell, Jessica
Brennan, Paul
Pring, Miranda
Boccia, Stefania
Olshan, Andrew F.
Diergaarde, Brenda
Hung, Rayjean J.
Liu, Geoffrey
Legge, Danny
Tajara, Eloiza H.
Severino, Patricia
Lacko, Martin
Ness, Andrew R.
Davey Smith, George
Vincent, Emma E.
Richmond, Rebecca C.
author_sort Gormley, Mark
collection PubMed
description 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.
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spelling pubmed-80960362021-05-13 Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study Gormley, Mark Yarmolinsky, James Dudding, Tom Burrows, Kimberley Martin, Richard M. Thomas, Steven Tyrrell, Jessica Brennan, Paul Pring, Miranda Boccia, Stefania Olshan, Andrew F. Diergaarde, Brenda Hung, Rayjean J. Liu, Geoffrey Legge, Danny Tajara, Eloiza H. Severino, Patricia Lacko, Martin Ness, Andrew R. Davey Smith, George Vincent, Emma E. Richmond, Rebecca C. PLoS Genet 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 (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. Public Library of Science 2021-04-22 /pmc/articles/PMC8096036/ /pubmed/33886544 http://dx.doi.org/10.1371/journal.pgen.1009525 Text en © 2021 Gormley et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Gormley, Mark
Yarmolinsky, James
Dudding, Tom
Burrows, Kimberley
Martin, Richard M.
Thomas, Steven
Tyrrell, Jessica
Brennan, Paul
Pring, Miranda
Boccia, Stefania
Olshan, Andrew F.
Diergaarde, Brenda
Hung, Rayjean J.
Liu, Geoffrey
Legge, Danny
Tajara, Eloiza H.
Severino, Patricia
Lacko, Martin
Ness, Andrew R.
Davey Smith, George
Vincent, Emma E.
Richmond, Rebecca C.
Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study
title Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study
title_full Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study
title_fullStr Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study
title_full_unstemmed Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study
title_short Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study
title_sort using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: a mendelian randomization study
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096036/
https://www.ncbi.nlm.nih.gov/pubmed/33886544
http://dx.doi.org/10.1371/journal.pgen.1009525
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