Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China.
Nat Commun. 2023 Mar 28;14(1):1732. doi: 10.1038/s41467-023-37213-5.
Genome-wide association studies have identified 19p13.3 locus associated with primary biliary cholangitis (PBC). Here we aim to identify causative variant(s) and initiate efforts to define the mechanism by which the 19p13.3 locus variant(s) contributes to the pathogenesis of PBC. A genome-wide meta-analysis of 1931 PBC subjects and 7852 controls in two Han Chinese cohorts confirms the strong association between 19p13.3 locus and PBC. By integrating functional annotations, luciferase reporter assay and allele-specific chromatin immunoprecipitation, we prioritize rs2238574, an AT-Rich Interaction Domain 3A (ARID3A) intronic variant, as a potential causal variant at 19p13.3 locus. The risk allele of rs2238574 shows higher binding affinity of transcription factors, leading to an increased enhancer activity in myeloid cells. Genome-editing demonstrates the regulatory effect of rs2238574 on ARID3A expression through allele-specific enhancer activity. Furthermore, knock-down of ARID3A inhibits myeloid differentiation and activation pathway, and overexpression of the gene has the opposite effect. Finally, we find ARID3A expression and rs2238574 genotypes linked to disease severity in PBC. Our work provides several lines of evidence that a non-coding variant regulates ARID3A expression, presenting a mechanistic basis for association of 19p13.3 locus with the susceptibility to PBC.
全基因组关联研究已经确定了与原发性胆汁性胆管炎（PBC）相关的 19p13.3 基因座。在此，我们旨在确定致病变异（多个）并努力定义 19p13.3 基因座变异（多个）在 PBC 发病机制中的作用机制。对两个汉族人群中的 1931 名 PBC 患者和 7852 名对照进行的全基因组荟萃分析证实了 19p13.3 基因座与 PBC 之间的强烈关联。通过整合功能注释、荧光素酶报告基因检测和等位基因特异性染色质免疫沉淀，我们将 rs2238574（ARID3A 内含子中的一个 AT 富含相互作用域 3A 变体）确定为 19p13.3 基因座的潜在致病变体。rs2238574 的风险等位基因显示出转录因子更高的结合亲和力，导致髓样细胞中增强子活性增加。基因组编辑证明了 rs2238574 通过等位基因特异性增强子活性对 ARID3A 表达的调节作用。此外，敲低 ARID3A 抑制髓样细胞分化和激活途径，而过表达该基因则具有相反的效果。最后，我们发现 ARID3A 的表达和 rs2238574 基因型与 PBC 的疾病严重程度相关。我们的工作提供了几条证据表明，非编码变体调节 ARID3A 的表达，为 19p13.3 基因座与 PBC 的易感性相关提供了机制基础。
