重新评估肥胖与头颈癌之间的联系：一项孟德尔随机化研究。

Reassessing the link between adiposity and head and neck cancer: a Mendelian randomization study.

作者信息

Morales-Berstein Fernanda, Khouja Jasmine, Gormley Mark, Ebrahimi Elmira, Virani Shama, McKay James, Brennan Paul, Richardson Tom G, Relton Caroline L, Smith George Davey, Borges M Carolina, Dudding Tom, Richmond Rebecca C

机构信息

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

出版信息

medRxiv. 2025 Jan 30:2024.11.21.24317707. doi: 10.1101/2024.11.21.24317707.

DOI:10.1101/2024.11.21.24317707

PMID:39974030

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11838947/

Abstract

BACKGROUND

Adiposity has been associated with an increased risk of head and neck cancer (HNC). Although body mass index (BMI) has been inversely associated with HNC risk among smokers, this is likely due to confounding. Previous Mendelian randomization (MR) studies could not fully discount causality between adiposity and HNC due to limited statistical power. Hence, we aimed to revisit this using the largest genome-wide association study (GWAS) of HNC available, which has more granular data on HNC subsites.

METHODS

We assessed the genetically predicted effects of BMI (N=806,834), waist-to-hip ratio (WHR; N=697,734) and waist circumference (N=462,166) on the risk of HNC (N=12,264 cases and 19,259 controls) and its subsites (oral, laryngeal, hypopharyngeal and oropharyngeal cancers) using a two-sample MR framework. We used the inverse variance weighted (IVW) MR approach and multiple sensitivity analyses including the weighted median, weighted mode, MR-Egger, MR-PRESSO, and CAUSE approaches. We also used multivariable MR (MVMR) to explore the direct effects of the adiposity measures on HNC, while accounting for smoking behaviour, a well-known HNC risk factor.

RESULTS

In univariable MR, higher genetically predicted BMI increased the risk of overall HNC (IVW OR=1.17 per 1 standard deviation [1-SD] higher BMI, 95% CI 1.02-1.34, p=0.03), with no heterogeneity across subsites (Q p=0.78). However, the effect was not consistent in sensitivity analyses. The IVW effect was attenuated when smoking was included in the MVMR model (OR accounting for comprehensive smoking index=0.96 per 1-SD higher BMI, 95% CI 0.80-1.15, p=0.64) and CAUSE indicated the IVW results could be biased by correlated pleiotropy. Furthermore, we did not find a link between genetically predicted WHR (IVW OR=1.05 per 1-SD higher WHR, 95% CI 0.89-1.24, p=0.53) or waist circumference and HNC risk (IVW OR=1.01 per 1-SD higher waist circumference, 95% CI 0.85-1.21, p=0.87).

CONCLUSIONS

Our findings suggest that adiposity does not play a role in HNC risk.

摘要

背景

肥胖与头颈癌（HNC）风险增加有关。尽管体重指数（BMI）与吸烟者的HNC风险呈负相关，但这可能是由于混杂因素所致。先前的孟德尔随机化（MR）研究由于统计效力有限，无法完全排除肥胖与HNC之间的因果关系。因此，我们旨在利用现有的最大规模的HNC全基因组关联研究（GWAS）重新探讨这一问题，该研究拥有关于HNC亚部位的更详细数据。

方法

我们使用两样本MR框架评估了BMI（N = 806,834）、腰臀比（WHR；N = 697,734）和腰围（N = 462,166）的基因预测效应对HNC风险（N = 12,264例病例和19,259例对照）及其亚部位（口腔癌、喉癌、下咽癌和口咽癌）的影响。我们使用了逆方差加权（IVW）MR方法和多种敏感性分析，包括加权中位数、加权众数、MR-Egger、MR-PRESSO和CAUSE方法。我们还使用多变量MR（MVMR）来探讨肥胖指标对HNC的直接影响，同时考虑吸烟行为这一众所周知的HNC风险因素。

结果

在单变量MR中，基因预测的较高BMI增加了总体HNC的风险（IVW比值比[OR]=每1个标准差[1-SD]更高的BMI为1.17，95%置信区间[CI]为1.02-1.34，p = 0.03），各亚部位之间无异质性（Q p = 0.78）。然而，在敏感性分析中该效应并不一致。当在MVMR模型中纳入吸烟因素时，IVW效应减弱（考虑综合吸烟指数的OR =每1-SD更高的BMI为0.96，95% CI为0.80-1.15，p = 0.64），并且CAUSE表明IVW结果可能因相关多效性而存在偏差。此外，我们未发现基因预测的WHR（IVW OR =每1-SD更高的WHR为1.05，95% CI为0.89-1.24，p = 0.53）或腰围与HNC风险之间存在关联（IVW OR =每1-SD更高的腰围为1.01，95% CI为0.85-1.21，p = 0.87）。