Observational and genetic analyses clarify the relationship between type 2 diabetes mellitus and gallstone disease

Peijing Yan; Li Zhang; Chao Yang; Wenqiang Zhang; Yutong Wang; Min Zhang; Huijie Cui; Mingshuang Tang; Lin Chen; Xueyao Wu; Xunying Zhao; Yanqiu Zou; Jinyu Xiao; Yunjie Liu; Chenghan Xiao; Yanfang Yang; Ling Zhang; Yuqin Yao; Jiayuan Li; Zhenmi Liu; Chunxia Yang; Xia Jiang; Ben Zhang

doi:10.3389/fendo.2023.1337071

Observational and genetic analyses clarify the relationship between type 2 diabetes mellitus and gallstone disease

Front Endocrinol (Lausanne). 2024 Jan 31:14:1337071. doi: 10.3389/fendo.2023.1337071. eCollection 2023.

Authors

Peijing Yan¹, Li Zhang¹, Chao Yang^{1

2}, Wenqiang Zhang¹, Yutong Wang¹, Min Zhang³, Huijie Cui¹, Mingshuang Tang¹, Lin Chen¹, Xueyao Wu¹, Xunying Zhao¹, Yanqiu Zou¹, Jinyu Xiao¹, Yunjie Liu¹, Chenghan Xiao⁴, Yanfang Yang¹, Ling Zhang⁵, Yuqin Yao⁶, Jiayuan Li¹, Zhenmi Liu⁴, Chunxia Yang¹, Xia Jiang^{1

7

8}, Ben Zhang^{1

6}

Affiliations

¹ Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China.
² School of Public Health, Southwest Medical University, Luzhou, Sichuan, China.
³ Clinical Research Center, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
⁴ Department of Maternal, Child and Adolescent Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
⁵ Department of Iatrical Polymer Material and Artificial Apparatus, School of Polymer Science and Engineering, Sichuan University, Chengdu, China.
⁶ Department of Occupational and Environmental Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
⁷ Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
⁸ Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

Abstract

Background: The relationship between type 2 diabetes mellitus (T2DM) and gallstone disease (GSD) have been incompletely understood. We aimed to investigate their phenotypic and genetic associations and evaluate the biological mechanisms underlying these associations.

Methods: We first evaluated the phenotypic association between T2DM and GSD using data from the UK Biobank (n>450,000) using a prospective observational design. We then conducted genetic analyses using summary statistics from a meta-analysis of genome-wide association studies of T2DM, with and without adjusting for body mass index (BMI) (N_case=74,124, N_control=824,006; T2DM_adjBMI: N_case=50,409, N_control=523,897) and GSD (N_case=43,639, N_control=506,798).

Results: A unidirectional phenotypic association was observed, where individuals with T2DM exhibited a higher GSD risk (hazard ratio (HR)=1.39, P<0.001), but not in the reverse direction (GSD→T2DM: HR=1.00, P=0.912). The positive T2DM-GSD genetic correlation (r_g=0.35, P=7.71×10^-23) remained even after adjusting for BMI (T2DM_adjBMI: r_g=0.22, P=4.48×10^-10). Mendelian randomization analyses provided evidence of a unidirectional causal relationship (T2DM→GSD: odds ratio (OR)=1.08, P=4.6×10^-8; GSD→T2DM: OR=1.02, P=0.48), even after adjusting for important metabolic confounders (OR=1.02, P=0.02). This association was further corroborated through a comprehensive functional analysis reflected by 23 pleiotropic single nucleotide polymorphisms, as well as multiple neural and motor-enriched tissues.

Conclusion: Through comprehensive observational and genetic analyses, our study clarified the causal relationship between T2DM and GSD, but not in the reverse direction. These findings might provide new insights into prevention and treatment strategies for T2DM and GSD.

Keywords: Mendelian randomization; bidirectional; causal relationship; cohort; gallstone disease; genetic association; type 2 diabetes mellitus.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Body Mass Index
Diabetes Mellitus, Type 2* / complications
Diabetes Mellitus, Type 2* / epidemiology
Diabetes Mellitus, Type 2* / genetics
Gallstones* / epidemiology
Gallstones* / genetics
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Key R&D Program of China (2022YFC3600600, 2022YFC3600604), the National Natural Science Foundation of China (U22A20359, 81874283, 81673255), the Recruitment Program for Young Professionals of China, the Promotion Plan for Basic Medical Sciences and the Development Plan for Cutting-Edge Disciplines, Sichuan University, and other Projects from West China School of Public Health and West China Fourth Hospital, Sichuan University. The funder had no role in study design, data collection, analysis, interpretation, writing of the report, or the decision for submission.