Primary Biliary Cholangitis in British Columbia First Nations: Clinical features and discovery of novel genetic susceptibility loci
Primary Biliary Cholangitis in British Columbia First Nations: Clinical features and discovery of novel genetic susceptibility loci
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DOI：
10.1111/liv.13686
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发表时间：
2018-05-01
影响因子：
6.7
通讯作者：
Arbour, Laura
中科院分区：
文献类型：
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作者：
Asuri, Sirisha;McIntosh, Sarah;Arbour, Laura
背景和目标：原发性胆汁性胆管炎（PBC）是一种慢性自身免疫性肝病，以肝内胆管破坏、门静脉炎症和肝硬化为特征。虽然在大多数人群中很少见，但在不列颠哥伦比亚省第一民族中很普遍，而且往往是家族性的。我们假设，主要的遗传因素增加的风险，在第一Nations.Methods：在所有的，44个人与原发性胆汁性胆管炎和61个未受影响的亲属从32个第一民族家庭参加。记录家族史和合并症。我们的团队病理学家审查了医疗记录，并重新审查了可用的活检。使用Affyscore Human Mapping 500 K Array Set对36名受影响人员和27名未受影响亲属的DNA进行基因分型。采用MERLIN软件进行多点参数和非参数连锁分析。候选基因进行了鉴定，并输入到InnateDB和KEGG软件，以确定潜在的途径影响pathogenicity.Results：在所有的，34%的家庭是多重的。50%的病例和33%未受影响的亲属报告了其他自身免疫性疾病。三个基因组区域（9 q21，17 p13和19 p13）产生的LOD分数为2.3或更高，提示连锁，但没有一个连锁峰达到统计学显著性。在这三个区域中鉴定的候选基因表明参与IL 17、NF κ B B、IL 6、JAK-STAT、IFN γ和TGF β免疫信号传导途径。具体而言，四个基因-ACT 1，PIN 1，DNMT 1和NTN 1-出现在这些途径中的作用，可能会影响原发性胆汁性胆管炎pathogenicity.Conclusions：我们的全基因组连锁研究结果反映了原发性胆汁性胆管炎的多因素的性质，支持以前的研究表明信号通路参与，并确定新的候选基因考虑。
Background & Aims: Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by destruction of intrahepatic bile ducts, portal inflammation and cirrhosis. Although rare in most populations, it is prevalent and often familial in British Columbia First Nations. We hypothesized that major genetic factors increased the risk in First Nations.Methods: In all, 44 individuals with Primary Biliary Cholangitis and 61 unaffected relatives from 32 First Nations families participated. Family history and co-morbidities were documented. Medical records were reviewed and available biopsies were re-reviewed by our team pathologist. Genotyping was performed on DNA from 36 affected persons and 27 unaffected relatives using the Affymetrix Human Mapping 500K Array Set. MERLIN software was used to carry out multipoint parametric and nonparametric linkage analysis. Candidate genes were identified and entered into InnateDB and KEGG software to identify potential pathways affecting pathogenesis.Results: In all, 34% of families were multiplex. Fifty per cent of cases and 33% of unaffected relatives reported other autoimmune disease. Three genomic regions (9q21, 17p13 and 19p13) produced LOD scores of 2.3 or greater suggestive of linkage, but no single linkage peak reached statistical significance. Candidate genes identified in the three regions suggested involvement of IL17, NF kappa B, IL6, JAK-STAT, IFN gamma and TGF beta immune signalling pathways. Specifically, four genes-ACT1, PIN1, DNMT1 and NTN1-emerged as having roles in these pathways that may influence Primary Biliary Cholangitis pathogenesis.Conclusions: Our whole genome linkage study results reflect the multifactorial nature of Primary Biliary Cholangitis, support previous studies suggesting signalling pathway involvement and identify new candidate genes for consideration.