Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.
Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.
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DOI：
10.1056/nejmoa0810440
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发表时间：
2009-06-11
期刊：
影响因子：
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通讯作者：
Siminovitch KA
中科院分区：
文献类型：
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作者：
Hirschfield GM;Liu X;Xu C;Lu Y;Xie G;Lu Y;Gu X;Walker EJ;Jing K;Juran BD;Mason AL;Myers RP;Peltekian KM;Ghent CN;Coltescu C;Atkinson EJ;Heathcote EJ;Lazaridis KN;Amos CI;Siminovitch KA
原发性胆汁性肝硬化是一种慢性肉芽肿性胆管炎，其特征是与抗线粒体抗体相关。双胞胎和家庭聚集数据表明，有一个显着的遗传易感性原发性胆汁性肝硬化，但易感基因座是未知的。为了确定原发性胆汁性肝硬化风险的遗传位点，我们进行了全基因组关联分析，其中来自2072名加拿大和美国受试者（536名原发性胆汁性肝硬化患者和1536名对照）的DNA样本进行了超过300，000个单核苷酸多态性（SNP）的基因分型。在两个独立的复制集中对与原发性胆汁性肝硬化最密切相关的16个SNP进行了基因分型。我们在与原发性胆汁性肝硬化相关的三个位点进行了精细定位研究。我们发现原发性胆汁性肝硬化与HLA II类区域的13个基因座之间存在显著相关性; HLA-DQB1基因座（编码主要组织相容性复合体II类，DQ β链1）的相关性最强（P = 1.78 × 10 − 19;患者与对照组的比值比为1.75）。原发性胆汁性肝硬化也与IL 12 A位点的两个SNP显著相关，且可重复（编码白细胞介素-12 α），rs6441286（P = 2.42 × 10 − 14;比值比，1.54）和rs574808（P = 1.88 × 10 − 13;比值比，1.54），以及IL 12 RB2位点（编码白细胞介素-12受体β 2）的一个SNP，rs3790567（P = 2.76 × 10 − 11;比值比，1.51）。精细作图分析显示，IL 12A 3 ′侧翼的5个等位基因单倍型与原发性胆汁性肝硬化显著相关（P = 1.15 × 10 − 34）。我们发现在STAT4位点（编码信号转导和转录激活因子4）和CTLA4位点（编码细胞毒性T淋巴细胞相关蛋白4）以及其他10个位点的SNP与疾病风险存在适度的全基因组关联（P <5.0 × 10 − 5）。我们的数据显示原发性胆汁性肝硬化与HLA II类、IL12A和IL12RB2位点的常见遗传变异之间存在显著相关性，并提示白细胞介素-12免疫调节信号传导轴与原发性胆汁性肝硬化的病理生理学相关。（ClinicalTrials.gov编号，NCT 00242125。）
Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown. To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis. We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ β chain 1) had the strongest association (P = 1.78×10−19; odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12α), rs6441286 (P = 2.42×10−14; odds ratio, 1.54) and rs574808 (P = 1.88×10−13; odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor β2), rs3790567 (P = 2.76×10−11; odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3′ flank of IL12A was significantly associated with primary biliary cirrhosis (P = 1.15×10−34). We found a modest genomewide association (P<5.0×10−5) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte–associated protein 4) and 10 other loci. Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. (ClinicalTrials.gov number, NCT00242125.)