Causal link between hypothyroidism and gastric cancer risk - insights gained through multivariable Mendelian randomization and mediation analysis

Sep 22, 2026

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Gastric cancer remains a leading cause of cancer mortality worldwide, while hypothyroidism has been proposed as a potential influencing factor. The causal connection between hypothyroidism and gastric cancer, as well as mediators underlying this relationship, has not been clearly defined. This study used univariable and multivariable Mendelian randomization with mediator analysis to evaluate causal effects and pathways involving high cholesterol, chronic hepatitis B, diabetes and endocrine status.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages8

Reading Time20 min

AccessFree to download

Introduction

Methods

Genetic instruments and MR analyses

Confounder and mediator evaluation

Results

Discussion

Conclusion

TYPE Original Research PUBLISHED 06 June 2024 DOI 10.3389/fendo.2024.1388608 OPEN ACCESS EDITED BY Akira Sugawara, Tohoku University, Japan REVIEWED BY Massimo Tusconi, University of Cagliari, Italy Vˆania Gomes, Centro Hospitalar do Tˆamega e Sousa, Portugal *CORRESPONDENCE Jun Wang [wangjunoscar@zju.edu.cn](wangjunoscar@zju.edu.cn) †These authors have contributed equally to this work and share ﬁrst authorship RECEIVED 20 February 2024 ACCEPTED 20 May 2024 PUBLISHED 06 June 2024 CITATION Zhang T, Qiao J, Wang Y, Zhou Y, Jabbar Abdl Sattar Hamoudi H, Hendi MAA and Wang J (2024) Causal link between hypothyroidism and gastric cancer risk: insights gained through multivariable Mendelian randomization and mediation analysis. Front. Endocrinol. 15:1388608 . doi: 10.3389/fendo.2024.1388608 COPYRIGHT © 2024 Zhang, Qiao, Wang, Zhou, Jabbar Abdl Sattar Hamoudi, Hendi and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Causal link between hypothyroidism and gastric cancer risk: insights gained through multivariable Mendelian randomization and mediation analysis Tianyue Zhang 1†, Jie Qiao 1†, Yuanyou Wang 1†, Yinying Zhou 2, Hammza Jabbar Abdl Sattar Hamoudi 1, Mhd Alaa Al Hendi 1 and Jun Wang 3* 1 Department of Endocrinology, The Second Afﬁliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China, 2 Department of Endocrinology, Qingtian People’s Hospital, Lishui, Zhejiang, China, 3 Department of Gastroenterology Surgery, The Second Afﬁliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Background: Gastric cancer (GC) is the third leading cause of cancer death worldwide, and hypothyroidism has been identiﬁed as a potential inﬂuencing factor. Despite known associations between hypothyroidism and various cancers, the causal link between hypothyroidism and GC and potential mediators of this relationship remains unclear. This study aimed to clarify these relationships using Mendelian randomization (MR) . Methods: Utilizing genetic variant information from the FinnGen and MRC Integrative Epidemiology Unit open genome-wide association studies (GWAS) databases, we conducted univariable and multivariable MR analyses to explore the causal relationship between hypothyroidism and GC risk. The analysis was adjusted for confounders such as BMI, smoking status, and alcohol intake, and included mediator MR analysis to examine the role of high cholesterol. Results: We identiﬁed a signiﬁcant inverse association between hypothyroidism and GC risk (OR = 0.93, 95% CI= 0.89–0.98, P = 0.003), with no evidence of reverse causation or pleiotropy. Adjustments for Helicobacter pylori infection weakened this association. Mediator analysis highlighted high cholesterol levels, chronic hepatitis B infection, and diabetes/endocrine disease status as signiﬁcant mediators of the protective effect of hypothyroidism on GC risk. Conclusion: Our ﬁndings suggest that hypothyroidism may confer a protective effect against GC, mediated in part by high cholesterol and other factors. These results underscore the importance of thyroid function and metabolic health in GC risk, offering new insights for preventive strategies and highlighting the need for further research into these complex associations. KEYWORDS gastric cancer, hypothyroidism, Mendelian randomization, genetic variants, causal analysis Frontiers in Endocrinology 01 [frontiersin.org](frontiersin.org) 1 Introduction Gastric cancer ranks as the ﬁfth most common cancer and the third most common cause o

FAQs

What was the main aim of the study?

To determine whether hypothyroidism causally affects gastric cancer risk and to identify potential mediators involved in this relationship.

Which method was used to infer causality?

The study applied univariable and multivariable Mendelian randomization using genetic variant data, along with mediator MR analysis.

What did the results show about the relationship between hypothyroidism and gastric cancer risk?

Hypothyroidism showed a significant inverse association with gastric cancer risk (OR = 0.93, 95% CI 0.89–0.98, P = 0.003), and adjustments for Helicobacter pylori weakened this association.

Sep 22, 2026

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