A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn's disease in a Chinese population

Jian Tang; Xingyang Wan; JunXiao Zhang; Na Diao; Caibin Zhang; Xiang Gao; Donglin Ren

doi:10.3389/fgene.2023.1130529

A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn's disease in a Chinese population

Front Genet. 2023 May 30:14:1130529. doi: 10.3389/fgene.2023.1130529. eCollection 2023.

Authors

Jian Tang¹, Xingyang Wan², JunXiao Zhang³, Na Diao¹, Caibin Zhang⁴, Xiang Gao¹, Donglin Ren²

Affiliations

¹ Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
² Department of Colorectal and Anal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
³ Institute of Biomedical Sciences, SequMed Biotech Inc., Guangzhou, China.
⁴ Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.

Abstract

Background: Crohn's disease (CD), a chronic gastrointestinal inflammatory disease, is increasing in China. With a focus on Han Chinese families with CD, the aim of this study was to find genetic variations that increase CD susceptibility by genome sequencing, genetic association, expression, and functional research. Materials and methods: We performed family-based genome sequencing (WGS) analysis on 24 patients with CD from 12 families and then filtered shared potential causal variants by incorporating association results from meta-analyses of CD GWAS and immunology genes and in silico variant effect prediction algorithms. Replication analyses were performed in an independent cohort including 381 patients with CD and 381 control subjects. Results: There were 92 genetic variants significantly associated with CD in Chinese individuals. Among them, 61 candidate loci were validated in replication analyses. As a result, patients carrying a rare frameshift variant (c.1143_1144insG; p. Leu381_Leu382fs) in gene SIRPB1 had significantly higher risk to develop CD (p = 0.03, OR 4.59, 95% CI 0.98-21.36, 81.82% vs. 49.53%). The frameshift variation induced tyrosine phosphorylation of Syk, Akt, and Jak2, elevated the expression of SIRPB1 at the mRNA and protein levels, activated DAP12, and controlled the activation of NF-κB in macrophages. Additionally, it promoted the synthesis of the pro-inflammatory cytokines IL-1, TNF-, and IL-6. Conclusion: Our results suggest that the rare gain-of-function frameshift variant in SIRPB1 is associated in Han Chinese patients with CD. The functional mechanism of SIRPB1 and its downstream inflammatory pathways was preliminarily explored in CD.

Keywords: Crohn ‘s disease; SIRPB1; gene susceptibility; han Chinese patients; whole gene sequencing.

Grants and funding

This project was supported by the National Nature Science Foundation of China (81870382), the Major Scientific and Technological Project of Guangdong Province (A2020123), the Science and Technology Program of Guangzhou (201903010081), and the Youth Project for National Nature Science Foundation of China (82100547).