Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization

Mark Gormley; Tom Dudding; Steven J Thomas; Jessica Tyrrell; Andrew R Ness; Miranda Pring; Danny Legge; George Davey Smith; Rebecca C Richmond; Emma E Vincent; Caroline Bull

doi:10.7554/eLife.82674

Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization

Mark Gormley^*, Tom Dudding, Steven J Thomas, Jessica Tyrrell, Andrew R Ness, Miranda Pring, Danny Legge, George Davey Smith, Rebecca C Richmond, Emma E Vincent, Caroline Bull

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

12 Citations (Scopus)

Abstract

A recent World Health Organization report states that at least 40% of all cancer cases may be preventable, with smoking, alcohol consumption and obesity identified as three of the most important modifiable lifestyle factors. Given the significant decline in smoking rates, particularly within developed countries, other potentially modifiable risk factors for head and neck cancer warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes and hypertension have been associated with head and neck cancer risk in multiple observational studies. However, adiposity has also been correlated with smoking, with bias, confounding or reverse causality possibly explaining these findings. To overcome the challenges of observational studies, we conducted two-sample Mendelian randomization (inverse variance weighted (IVW) method) using genetic variants which were robustly associated with adiposity, glycaemic and blood pressure traits in genome-wide association studies (GWAS). Outcome data was taken from the largest available GWAS of 6,034 oral and oropharyngeal cases, with 6,585 controls. We found limited evidence of a causal effect of genetically proxied body mass index (OR IVW = 0.89, 95%CI 0.72-1.09, p = 0.26 per 1 SD in BMI (4.81 kg/m2)) on oral and oropharyngeal cancer risk. Similarly, there was limited evidence for related traits including type 2 diabetes and hypertension.

Original language	English
Article number	e82674
Journal	eLife
Volume	12
Early online date	12 Apr 2023
DOIs	https://doi.org/10.7554/eLife.82674
Publication status	Published - 28 Apr 2023

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. 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, which is supported by the AMS, the Wellcome Trust, Global Challenges Research Fund (GCRF), the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). A.R.N. was 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 NHS Foundation Trust and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This publication presents data from the Head and Neck 5000 which contributes to international VOYAGER and HEADSpAcE head and neck cancer consortia. The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (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 and Weston Research Capability Funding and the NIHR Senior Investigator award to A.R.N. Human papil-lomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (C18281/A20919). The VOYAGER study was supported in part by the US National Institute of Dental and Craniofacial Research (NIDCR; R01 DE025712). The genotyping of the HNC 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). E.E.V., C.B., and D.L. are supported by Diabetes UK (17/0005587). E.E.V. and C.B. are supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). M.G., T.D., G.D.S., E.E.V., R.C.R., and C.B. are 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_00011/5, MC_UU_00011/6, MC_UU_00011/7).

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. 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, which is supported by the AMS, the Wellcome Trust, Global Challenges Research Fund (GCRF), the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). A.R.N. was 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 NHS Foundation Trust and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This publication presents data from the Head and Neck 5000 which contributes to international VOYAGER and HEADSpAcE head and neck cancer consortia. The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (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 and Weston 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 (C18281/A20919). The VOYAGER study was supported in part by the US National Institute of Dental and Craniofacial Research (NIDCR; R01 DE025712). The genotyping of the HNC 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). E.E.V., C.B., and D.L. are supported by Diabetes UK (17/0005587). E.E.V. and C.B. are supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). M.G., T.D., G.D.S., E.E.V., R.C.R., and C.B. are 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_00011/5, MC_UU_00011/6, MC_UU_00011/7).

Publisher Copyright:
© Gormley et al.

Research Groups and Themes

Bristol Population Health Science Institute
ICEP

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.82674Licence: CC BY

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Persistent link

1 Finished
1 Active

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research
IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Cite this

@article{f9d2179d8fd9414881787c4eee776eae,

title = "Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization",

abstract = "A recent World Health Organization report states that at least 40% of all cancer cases may be preventable, with smoking, alcohol consumption and obesity identified as three of the most important modifiable lifestyle factors. Given the significant decline in smoking rates, particularly within developed countries, other potentially modifiable risk factors for head and neck cancer warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes and hypertension have been associated with head and neck cancer risk in multiple observational studies. However, adiposity has also been correlated with smoking, with bias, confounding or reverse causality possibly explaining these findings. To overcome the challenges of observational studies, we conducted two-sample Mendelian randomization (inverse variance weighted (IVW) method) using genetic variants which were robustly associated with adiposity, glycaemic and blood pressure traits in genome-wide association studies (GWAS). Outcome data was taken from the largest available GWAS of 6,034 oral and oropharyngeal cases, with 6,585 controls. We found limited evidence of a causal effect of genetically proxied body mass index (OR IVW = 0.89, 95%CI 0.72-1.09, p = 0.26 per 1 SD in BMI (4.81 kg/m2)) on oral and oropharyngeal cancer risk. Similarly, there was limited evidence for related traits including type 2 diabetes and hypertension.",

author = "Mark Gormley and Tom Dudding and Thomas, {Steven J} and Jessica Tyrrell and Ness, {Andrew R} and Miranda Pring and Danny Legge and Smith, {George Davey} and Richmond, {Rebecca C} and Vincent, {Emma E} and Caroline Bull",

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. 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, which is supported by the AMS, the Wellcome Trust, Global Challenges Research Fund (GCRF), the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). A.R.N. was 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 NHS Foundation Trust and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This publication presents data from the Head and Neck 5000 which contributes to international VOYAGER and HEADSpAcE head and neck cancer consortia. The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (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 and Weston Research Capability Funding and the NIHR Senior Investigator award to A.R.N. Human papil-lomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (C18281/A20919). The VOYAGER study was supported in part by the US National Institute of Dental and Craniofacial Research (NIDCR; R01 DE025712). The genotyping of the HNC 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). E.E.V., C.B., and D.L. are supported by Diabetes UK (17/0005587). E.E.V. and C.B. are supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). M.G., T.D., G.D.S., E.E.V., R.C.R., and C.B. are 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_00011/5, MC_UU_00011/6, MC_UU_00011/7). 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. 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, which is supported by the AMS, the Wellcome Trust, Global Challenges Research Fund (GCRF), the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). A.R.N. was 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 NHS Foundation Trust and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This publication presents data from the Head and Neck 5000 which contributes to international VOYAGER and HEADSpAcE head and neck cancer consortia. The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (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 and Weston 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 (C18281/A20919). The VOYAGER study was supported in part by the US National Institute of Dental and Craniofacial Research (NIDCR; R01 DE025712). The genotyping of the HNC 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). E.E.V., C.B., and D.L. are supported by Diabetes UK (17/0005587). E.E.V. and C.B. are supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). M.G., T.D., G.D.S., E.E.V., R.C.R., and C.B. are 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_00011/5, MC_UU_00011/6, MC_UU_00011/7). Publisher Copyright: {\textcopyright} Gormley et al.",

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day = "28",

doi = "10.7554/eLife.82674",

language = "English",

volume = "12",

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TY - JOUR

T1 - Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization

AU - Gormley, Mark

AU - Dudding, Tom

AU - Thomas, Steven J

AU - Tyrrell, Jessica

AU - Ness, Andrew R

AU - Pring, Miranda

AU - Legge, Danny

AU - Smith, George Davey

AU - Richmond, Rebecca C

AU - Vincent, Emma E

AU - Bull, Caroline

N1 - 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. 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, which is supported by the AMS, the Wellcome Trust, Global Challenges Research Fund (GCRF), the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). A.R.N. was 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 NHS Foundation Trust and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This publication presents data from the Head and Neck 5000 which contributes to international VOYAGER and HEADSpAcE head and neck cancer consortia. The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (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 and Weston Research Capability Funding and the NIHR Senior Investigator award to A.R.N. Human papil-lomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (C18281/A20919). The VOYAGER study was supported in part by the US National Institute of Dental and Craniofacial Research (NIDCR; R01 DE025712). The genotyping of the HNC 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). E.E.V., C.B., and D.L. are supported by Diabetes UK (17/0005587). E.E.V. and C.B. are supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). M.G., T.D., G.D.S., E.E.V., R.C.R., and C.B. are 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_00011/5, MC_UU_00011/6, MC_UU_00011/7). 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. 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, which is supported by the AMS, the Wellcome Trust, Global Challenges Research Fund (GCRF), the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). A.R.N. was 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 NHS Foundation Trust and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This publication presents data from the Head and Neck 5000 which contributes to international VOYAGER and HEADSpAcE head and neck cancer consortia. The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (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 and Weston 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 (C18281/A20919). The VOYAGER study was supported in part by the US National Institute of Dental and Craniofacial Research (NIDCR; R01 DE025712). The genotyping of the HNC 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). E.E.V., C.B., and D.L. are supported by Diabetes UK (17/0005587). E.E.V. and C.B. are supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). M.G., T.D., G.D.S., E.E.V., R.C.R., and C.B. are 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_00011/5, MC_UU_00011/6, MC_UU_00011/7). Publisher Copyright: © Gormley et al.

PY - 2023/4/28

Y1 - 2023/4/28

N2 - A recent World Health Organization report states that at least 40% of all cancer cases may be preventable, with smoking, alcohol consumption and obesity identified as three of the most important modifiable lifestyle factors. Given the significant decline in smoking rates, particularly within developed countries, other potentially modifiable risk factors for head and neck cancer warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes and hypertension have been associated with head and neck cancer risk in multiple observational studies. However, adiposity has also been correlated with smoking, with bias, confounding or reverse causality possibly explaining these findings. To overcome the challenges of observational studies, we conducted two-sample Mendelian randomization (inverse variance weighted (IVW) method) using genetic variants which were robustly associated with adiposity, glycaemic and blood pressure traits in genome-wide association studies (GWAS). Outcome data was taken from the largest available GWAS of 6,034 oral and oropharyngeal cases, with 6,585 controls. We found limited evidence of a causal effect of genetically proxied body mass index (OR IVW = 0.89, 95%CI 0.72-1.09, p = 0.26 per 1 SD in BMI (4.81 kg/m2)) on oral and oropharyngeal cancer risk. Similarly, there was limited evidence for related traits including type 2 diabetes and hypertension.

AB - A recent World Health Organization report states that at least 40% of all cancer cases may be preventable, with smoking, alcohol consumption and obesity identified as three of the most important modifiable lifestyle factors. Given the significant decline in smoking rates, particularly within developed countries, other potentially modifiable risk factors for head and neck cancer warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes and hypertension have been associated with head and neck cancer risk in multiple observational studies. However, adiposity has also been correlated with smoking, with bias, confounding or reverse causality possibly explaining these findings. To overcome the challenges of observational studies, we conducted two-sample Mendelian randomization (inverse variance weighted (IVW) method) using genetic variants which were robustly associated with adiposity, glycaemic and blood pressure traits in genome-wide association studies (GWAS). Outcome data was taken from the largest available GWAS of 6,034 oral and oropharyngeal cases, with 6,585 controls. We found limited evidence of a causal effect of genetically proxied body mass index (OR IVW = 0.89, 95%CI 0.72-1.09, p = 0.26 per 1 SD in BMI (4.81 kg/m2)) on oral and oropharyngeal cancer risk. Similarly, there was limited evidence for related traits including type 2 diabetes and hypertension.

U2 - 10.7554/eLife.82674

DO - 10.7554/eLife.82674

M3 - Article (Academic Journal)

C2 - 37042641

SN - 2050-084X

VL - 12

JO - eLife

JF - eLife

M1 - e82674

ER -

Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization

Abstract

Bibliographical note

Research Groups and Themes

UN SDGs

Access to Document

Handle.net

Fingerprint

Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Cite this