与HLA、IL12A和IL12RB2基因变异相关的原发性胆汁性肝硬化
Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.
作者信息
Hirschfield Gideon M, Liu Xiangdong, Xu Chun, Lu Yue, Xie Gang, Lu Yan, Gu Xiangjun, Walker Erin J, Jing Kaiyan, Juran Brian D, Mason Andrew L, Myers Robert P, Peltekian Kevork M, Ghent Cameron N, Coltescu Catalina, Atkinson Elizabeth J, Heathcote E Jenny, Lazaridis Konstantinos N, Amos Christopher I, Siminovitch Katherine A
机构信息
University of Toronto and Liver Center, Toronto Western Hospital, Toronto, ON, Canada.
出版信息
N Engl J Med. 2009 Jun 11;360(24):2544-55. doi: 10.1056/NEJMoa0810440. Epub 2009 May 20.
BACKGROUND
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.
METHODS
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.
RESULTS
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 beta chain 1) had the strongest association (P=1.78x10(-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-12alpha), rs6441286 (P=2.42x10(-14); odds ratio, 1.54) and rs574808 (P=1.88x10(-13); odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor beta2), rs3790567 (P=2.76x10(-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=1.15x10(-34)). We found a modest genomewide association (P<5.0x10(-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.
CONCLUSIONS
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.)
背景
原发性胆汁性肝硬化是一种慢性肉芽肿性胆管炎，其特征为与抗线粒体抗体相关。双胞胎和家族聚集数据表明，原发性胆汁性肝硬化存在显著的遗传易感性，但易感基因座尚不清楚。
方法
为了确定赋予原发性胆汁性肝硬化风险的基因座，我们进行了一项全基因组关联分析，对来自2072名加拿大和美国受试者（536例原发性胆汁性肝硬化患者和1536例对照）的DNA样本进行了超过30万个单核苷酸多态性（SNP）的基因分型。在两个独立的重复样本中对与原发性胆汁性肝硬化最强烈相关的16个SNP进行了基因分型。我们对与原发性胆汁性肝硬化相关的三个基因座进行了精细定位研究。
结果
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关联；HLA - DQB1基因座（编码主要组织相容性复合体II类，DQβ链1）的关联最强（P = 1.78×10^(-19)；患者与对照的优势比，1.75）。原发性胆汁性肝硬化还与IL12A基因座（编码白细胞介素-12α）的两个SNP，rs6441286（P = 2.42×10^(-14)；优势比，1.54）和rs574808（P = 1.88×10^(-13)；优势比，1.54），以及IL12RB2基因座（编码白细胞介素-12受体β2）的一个SNP，rs3790567（P = 2.76×10^(-11)；优势比，1.51）有显著且可重复的关联。精细定位分析表明，IL12A 3'侧翼的一个五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STAT4基因座（编码信号转导和转录激活因子4）、CTLA4基因座（编码细胞毒性T淋巴细胞相关蛋白4）和其他10个基因座的SNP与疾病风险存在适度的全基因组关联（P < 5.0×10^(-5)）。
结论
我们的数据显示原发性胆汁性肝硬化与HLA II类、IL12A和IL12RB2基因座的常见遗传变异之间存在显著关联，并表明白细胞介素-12免疫调节信号轴与原发性胆汁性肝硬化的病理生理学相关。（ClinicalTrials.gov编号，NCT00242125。）
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