A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn’s disease in a Chinese population
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 fun...
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2023.1130529/full |
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| author | Jian Tang Xingyang Wan JunXiao Zhang Na Diao Caibin Zhang Xiang Gao Donglin Ren |
| author_facet | Jian Tang Xingyang Wan JunXiao Zhang Na Diao Caibin Zhang Xiang Gao Donglin Ren |
| author_sort | Jian Tang |
| collection | DOAJ |
| description | 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. |
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| last_indexed | 2024-03-13T08:04:27Z |
| publishDate | 2023-05-01 |
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| series | Frontiers in Genetics |
| spelling | doaj.art-9ab03f55b2474d95aaffe65b6547bdb62023-06-01T08:41:37ZengFrontiers Media S.A.Frontiers in Genetics1664-80212023-05-011410.3389/fgene.2023.11305291130529A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn’s disease in a Chinese populationJian Tang0Xingyang Wan1JunXiao Zhang2Na Diao3Caibin Zhang4Xiang Gao5Donglin Ren6Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Colorectal and Anal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaInstitute of Biomedical Sciences, SequMed Biotech Inc., Guangzhou, ChinaDepartment of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaInstitute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, ChinaDepartment of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Colorectal and Anal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaBackground: 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.https://www.frontiersin.org/articles/10.3389/fgene.2023.1130529/fullCrohn ‘s diseasehan Chinese patientsgene susceptibilitywhole gene sequencingSIRPB1 |
| spellingShingle | Jian Tang Xingyang Wan JunXiao Zhang Na Diao Caibin Zhang Xiang Gao Donglin Ren A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn’s disease in a Chinese population Frontiers in Genetics Crohn ‘s disease han Chinese patients gene susceptibility whole gene sequencing SIRPB1 |
| title | A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn’s disease in a Chinese population |
| title_full | A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn’s disease in a Chinese population |
| title_fullStr | A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn’s disease in a Chinese population |
| title_full_unstemmed | A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn’s disease in a Chinese population |
| title_short | A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn’s disease in a Chinese population |
| title_sort | frameshift variant in the sirpb1 gene confers susceptibility to crohn s disease in a chinese population |
| topic | Crohn ‘s disease han Chinese patients gene susceptibility whole gene sequencing SIRPB1 |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2023.1130529/full |
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