Therapeutic targets for inflammatory bowel disease: proteome-wide Mendelian randomization and colocalization analyses

Jie Chen; Fengzhe Xu; Xixian Ruan; Jing Sun; Yao Zhang; Han Zhang; Jianhui Zhao; Jie Zheng; Susanna C Larsson; Xiaoyan Wang; Xue Li; Shuai Yuan

doi:10.1016/j.ebiom.2023.104494

Therapeutic targets for inflammatory bowel disease: proteome-wide Mendelian randomization and colocalization analyses

EBioMedicine. 2023 Mar:89:104494. doi: 10.1016/j.ebiom.2023.104494. Epub 2023 Feb 27.

Authors

Jie Chen¹, Fengzhe Xu², Xixian Ruan³, Jing Sun¹, Yao Zhang⁴, Han Zhang¹, Jianhui Zhao¹, Jie Zheng⁵, Susanna C Larsson⁶, Xiaoyan Wang⁷, Xue Li⁸, Shuai Yuan⁹

Affiliations

¹ Department of Big Data in Health Science, School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
² Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
³ Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁷ Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China. Electronic address: wangxiaoyan@csu.edu.cn.
⁸ Department of Big Data in Health Science, School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address: xueli157@zju.edu.cn.
⁹ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: shuai.yuan@ki.se.

Abstract

Background: Identifying new drug targets for inflammatory bowel disease (IBD) is urgently needed. The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) and colocalization analyses to identify possible targets for IBD.

Methods: Summary-level data of 4907 circulating protein levels were extracted from a large-scale protein quantitative trait loci study including 35,559 individuals. Genetic associations with IBD and its subtypes were obtained from the Inflammatory Bowel Disease Genetics Consortium (25,024 cases and 34,915 controls), the FinnGen study (7206 cases and 253,199 controls), and the UK Biobank study (7045 cases and 449,282 controls). MR analysis was conducted to estimate the associations between protein and IBD risk. The colocalization analysis was used to examine whether the identified proteins and IBD shared casual variants.

Findings: Genetically predicted levels of 3, and 5 circulating proteins were associated with IBD and ulcerative colitis (UC), respectively. With high supporting evidence of colocalization, genetically predicted MST1 (macrophage stimulating 1) and HGFAC (hepatocyte growth factor activator) levels were inversely associated with IBD risks. The associations of STAT3 (signal transducer and activator of transcription 3), MST1, CXCL5 (C-X-C motif chemokine ligand 5), and ITPKA (inositol-trisphosphate 3-kinase A) with the risk of UC were supported by colocalization analysis.

Interpretation: The proteome-wide MR investigation identified many proteins associated with the risk of IBD. MST1, HGFAC, STAT3, ITPKA, and CXCL5 deserve further investigation as potential therapeutic targets for IBD.

Funding: SCL is supported by research grants from the Swedish Research Council for Health, Working Life and Welfare (Forte; grant no. 2018-00123) and the Swedish Research Council (Vetenskapsrådet; grant no. 2019-00977). XYW is supported by research grants from the National Natural Science Foundation of China (81970494) and Key Project of Research and Development Plan of Hunan Province (2019SK2041). XL is supported by research grants from the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001).

Keywords: Inflammatory bowel disease; Mendelian randomization; Protein; Therapeutic target.

MeSH terms

Colitis, Ulcerative*
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Inflammatory Bowel Diseases* / genetics
Mendelian Randomization Analysis
Proteome / genetics

Substances

Proteome