{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T17:23:21Z","timestamp":1772040201500,"version":"3.50.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T00:00:00Z","timestamp":1685404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Crohn\u2019s 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.<\/jats:p><jats:p><jats:bold>Materials and methods:<\/jats:bold> 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 <jats:italic>in silico<\/jats:italic> variant effect prediction algorithms. Replication analyses were performed in an independent cohort including 381 patients with CD and 381 control subjects.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> 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 <jats:italic>SIRPB1<\/jats:italic> had significantly higher risk to develop CD (<jats:italic>p<\/jats:italic> = 0.03, OR 4.59, 95% CI 0.98\u201321.36, 81.82% vs. 49.53%). The frameshift variation induced tyrosine phosphorylation of Syk, Akt, and Jak2, elevated the expression of <jats:italic>SIRPB1<\/jats:italic> at the mRNA and protein levels, activated DAP12, and controlled the activation of NF-\u03baB in macrophages. Additionally, it promoted the synthesis of the pro-inflammatory cytokines IL-1, TNF-, and IL-6.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Our results suggest that the rare gain-of-function frameshift variant in <jats:italic>SIRPB1<\/jats:italic> is associated in Han Chinese patients with CD. The functional mechanism of <jats:italic>SIRPB1<\/jats:italic> and its downstream inflammatory pathways was preliminarily explored in CD.<\/jats:p>","DOI":"10.3389\/fgene.2023.1130529","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T08:41:53Z","timestamp":1685608913000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn\u2019s disease in a Chinese population"],"prefix":"10.3389","volume":"14","author":[{"given":"Jian","family":"Tang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingyang","family":"Wan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JunXiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na","family":"Diao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caibin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donglin","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.4049\/jimmunol.161.4.1853","article-title":"Signal-regulatory protein is selectively expressed by myeloid and neuronal cells","volume":"161","author":"Adams","year":"1998","journal-title":"J. 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