Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Nov 27;11(1):6071.
doi: 10.1038/s41467-020-19822-6.

A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer

Mark Gormley  1   2   3 , Tom Dudding  4   5   6 , Eleanor Sanderson  4   6 , Richard M Martin  4   6   7 , Steven Thomas  5   7 , Jessica Tyrrell  8 , Andrew R Ness  7 , Paul Brennan  9 , Marcus Munafò  4   6   10 , Miranda Pring  5 , Stefania Boccia  11   12 , Andrew F Olshan  13 , Brenda Diergaarde  14 , Rayjean J Hung  15   16 , Geoffrey Liu  16   17 , George Davey Smith  4   6 , Rebecca C Richmond  4   6
Affiliations

A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer

Mark Gormley et al. Nat Commun. .

Abstract

The independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication. The authors alone are responsible for the views expressed in this article.

Figures

Fig. 1
Fig. 1. Scatter and leave one out plots demonstrating influential outliers in univariable MR of alcohol consumption and oral and oropharyngeal cancer risk.
a Scatter plot showing ADH1B (rs1229984), an outlier single nucleotide polymorphism in the analysis of alcohol consumption (drinks per week, n = 941,280) and oral and oropharyngeal cancer risk (n = 6034 cases and 6585 controls). b Leave one out plot again demonstrating the ADH1B (rs1229984) influential outlier. Consistent evidence for a causal effect of alcohol on oral and oropharyngeal cancer risk was found even when this variant was excluded from the analysis. Effect estimates are reported per SD increase in the exposure and error bars represent 95% confidence intervals.
Fig. 2
Fig. 2. Univariable Mendelian randomisation of smoking initiation, lifetime smoke exposure and drinks per week on oral and oropharyngeal cancer subsites.
Univariable effects displayed were obtained using summary-level data from the GWAS of (a) smoking initiation (n = 1,232,091), (b) comprehensive smoking index (n = 462,690) and (c) drinks per week (n = 941,280) on oral and oropharyngeal cancer risk (n = 6034 cases and 6585 controls). Smoking initiation estimates are reported per log odds increase, while comprehensive smoking index and drinks per week are reported per SD increase in drinks per week. Error bars represent 95% confidence intervals. All statistical tests were two-sided.
Fig. 3
Fig. 3. Multivariable Mendelian randomisation of lifetime smoke exposure and drinks per week on oral and oropharyngeal subsites.
Effect estimates (ORs) are reported per SD increase in the exposure of drinks per week (n = 226,223) and the comprehensive smoking index (n = 226,223) on oral and oropharyngeal cancer risk (n = 6034 cases and 6585 controls). Error bars represent 95% confidence intervals. Genetic instrument for drinks per week excludes outlying variant, ADH1B (rs1229984). Univariable and multivariable effects displayed were obtained using summary-level data from the GWAS of comprehensive smoking index in UK Biobank and summary-level data from a GWAS of drinks per week in GSCAN, excluding UK Biobank and 23andMe. All statistical tests were two-sided.
Fig. 4
Fig. 4. Univariable Mendelian randomisation of risk tolerance and number of sexual partners on oral and oropharyngeal cancer subsites.
Effect estimates (log odds) are reported per SD increase in (a) risk tolerance (n = 508,782) and (b) number of sexual partners (n = 370,711). There was some evidence for a causal effect of number of sexual partners specific to the oropharyngeal subsite. Error bars represent 95% confidence intervals. All statistical tests were two-sided.
See this image and copyright information in PMC

References

    1. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral. Oncol. 2009;45:309–316. doi: 10.1016/j.oraloncology.2008.06.002. - DOI - PubMed
    1. Cancer Research UK. Head and Neck Cancer Statistics.https://www.cancerresearchuk.org/health-professional/cancer-statistics/s... (2019).
    1. Ang KK, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 2010;363:24–35. doi: 10.1056/NEJMoa0912217. - DOI - PMC - PubMed
    1. Heck JE, et al. Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int. J. Epidemiol. 2010;39:166–181. doi: 10.1093/ije/dyp350. - DOI - PMC - PubMed
    1. Thomas SJ, Penfold CM, Waylen A, Ness AR. The changing aetiology of head and neck squamous cell cancer: A tale of three cancers? Clin. Otolaryngol. 2018;43:999–1003. doi: 10.1111/coa.13144. - DOI - PubMed

Publication types