The genetically predicted causal relationship of inflammatory bowel disease with bone mineral density and osteoporosis: evidence from two-sample Mendelian randomization

Dengyong Xu; Yao Chen; Xing Gao; Weidong Xie; Ya Wang; Jiaying Shen; Guang Yang; Binbin Xie

doi:10.3389/fimmu.2023.1148107

The genetically predicted causal relationship of inflammatory bowel disease with bone mineral density and osteoporosis: evidence from two-sample Mendelian randomization

Front Immunol. 2023 May 18:14:1148107. doi: 10.3389/fimmu.2023.1148107. eCollection 2023.

Authors

Dengyong Xu¹, Yao Chen², Xing Gao³, Weidong Xie⁴, Ya Wang^{5

6

7}, Jiaying Shen², Guang Yang⁸, Binbin Xie²

Affiliations

¹ Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
² Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
³ Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
⁴ Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁵ Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China.
⁶ Department of Hospital Infection-Control, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China.
⁷ Department of Hospital Infection-Control, Zhejiang Cancer Hospital, Hangzhou, China.
⁸ Department of Orthopedic Surgery, The Second Affiliated Hospital of Zhejiang University, Hangzhou, China.

Abstract

Background: Many existing studies indicated that patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), tend to have the risk of low total body bone mineral density (BMD), and are more likely to have osteoporosis (OS). To determine the causal relationship between IBD and bone metabolic disorders, we herein performed a two-sample Mendelian randomization analysis (TSMR) using publicly available summary statistics.

Methods: Summary statistics of total body BMD, OS and IBD were downloaded from the Open Genome-Wide Association Study (GWAS), FinnGen consortium and International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). The European and East Asian populations have consisted in this Mendelian Randomization (MR) work. A range of quality control procedures were taken to select eligible instrument SNPs closely associated with total body BMD, OS and IBD. To make the conclusions more reliable, we applied five robust analytical methods, among which the inverse variance weighting (IVW) method acted as the major method. Besides, heterogeneity, pleiotropy and sensitivity were evaluated.

Results: In the European population, the genetic association of UC on total body BMD (OR=0.97, 95%CI=0.96,0.99, P<0.001) and overall IBD on total body BMD (OR=0.98, 95%CI=0.97,1.00, P=0.013) were significant, while the effect of CD on total body BMD was not significant enough (OR=0.99, 95%CI=0.98,1.00, P=0.085). All of UC, CD and overall IBD can be the genetic risk factor of having OS with pathological fracture (UC: OR=1.13, 95%CI=1.02,1.26, P=0.024, CD: OR=1.14, 95%CI=1.05,1.25, P=0.003, overall IBD: OR=1.13, 95%CI=1.02,1.24, P=0.015). In East Asian groups, only CD had a causal relationship with OS (OR=1.04, 95% CI=1.01,1.07, P=0.019).

Conclusion: Our study revealed genetically predicted associations between IBD on total body BMD and OS in European and East Asian populations. This work supplemented the results of previous retrospective studies and demonstrated the necessity of BMD monitoring in patients with IBD.

Keywords: Crohn’s disease; Mendelian randomization; bone mineral density; inflammatory bowel disease; osteoporosis; ulcerative colitis.

Publication types

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

MeSH terms

Bone Density / genetics
Bone Diseases, Metabolic*
Colitis, Ulcerative* / genetics
Crohn Disease* / complications
Crohn Disease* / genetics
Genome-Wide Association Study
Humans
Inflammatory Bowel Diseases* / complications
Inflammatory Bowel Diseases* / genetics
Mendelian Randomization Analysis
Osteoporosis* / genetics

Grants and funding

This work was supported by grants from National Natural Science Foundation of China (No. 82100542 to BX), Zhejiang Provincial Natural Science Foundation of China (No. LQ21H160027 to BX), the China Postdoctoral Science Foundation (No. 2020M681893 to BX), National Natural Science Foundation of China (No.81903160 to JS), Zhejiang Provincial Natural Science Foundation of China (No. LQ20H260002 to YW).