Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Medical Informatics Division, Shinshu University Hospital, Matsumoto, Japan.
J Hum Genet. 2017 Nov;62(11):963-967. doi: 10.1038/jhg.2017.74. Epub 2017 Jul 13.
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an autoimmune reaction to hepatocytes. The Src homology 2 adaptor protein 3 (SH2B3) gene is a member of the SH2B family of adaptor proteins that has been implicated in the integration and regulation of multiple signaling events. SH2B3 is involved in cytokine signaling pathways and serves as a negative mediator of T-cell receptor signaling. Genome-wide association analyses in Caucasians have linked a missense mutation at rs3184504 in SH2B3 with AIH. Accordingly, four selected single-nucleotide polymorphisms (SNPs) in the SH2B3 gene were genotyped in 158 patients with AIH, 327 patients with primary biliary cholangitis, 160 patients with autoimmune pancreatitis, and 325 healthy subjects of Japanese descent. Although the functional rs3184504 was non-polymorphic in 952 subjects, the frequency of the minor rs11065904 T allele was significantly decreased in AIH patients compared with healthy controls (odds ratio (OR)=0.68; corrected P=0.025). Haplotype 2 (rs2238154 A, rs11065904 T and rs739496 G) was associated with resistance to AIH (OR 0.67, P=0.021) as well as to autoimmune pancreatitis (OR=0.70, P=0.035). Our findings suggest that an SNP and haplotype in SH2B3 are associated with AIH.
自身免疫性肝炎（AIH）是一种慢性炎症性肝病，其特征是针对肝细胞的自身免疫反应。Src 同源 2 衔接蛋白 3（SH2B3）基因是衔接蛋白 SH2B 家族的成员，其参与多种信号事件的整合和调节。SH2B3 参与细胞因子信号通路，并作为 T 细胞受体信号的负调节剂。高加索人群的全基因组关联分析将 SH2B3 中 rs3184504 处的错义突变与 AIH 相关联。因此，在 158 例 AIH 患者、327 例原发性胆汁性胆管炎患者、160 例自身免疫性胰腺炎患者和 325 例日本裔健康对照者中，对 SH2B3 基因中的 4 个选定单核苷酸多态性（SNP）进行了基因分型。虽然在 952 例受试者中功能性 rs3184504 是非多态性的，但与健康对照者相比，AIH 患者中 minor rs11065904 T 等位基因的频率显著降低（比值比（OR）=0.68；校正 P=0.025）。单体型 2（rs2238154 A、rs11065904 T 和 rs739496 G）与 AIH 的抗性相关（OR 0.67，P=0.021）以及与自身免疫性胰腺炎相关（OR=0.70，P=0.035）。我们的研究结果表明，SH2B3 中的 SNP 和单体型与 AIH 相关。
