来自英国维尔康姆基金会桑格研究所的Carl Anderson及其同事使用免疫芯片数据,对2861例原发性胆汁性肝硬化(PBC)患者和8514例正常个体进行致密性基因型分型。他们新鉴定到3个与PBC相关的位点。对先前已知的易感位点进行精细定位,他们鉴定到5个具有多个独立常见、低频率和罕见关联变异的染色体区域。相关的研究论文于9月9日在线发表在《Nature Genetics》期刊上。

-2012年10月《自然-遗传》

中文翻译


【题目】致密性精细定位研究鉴定影响原发性胆汁性肝硬化的新易感位点 

【译文】我们对来自英国PBC项目的2861例原发性胆汁性肝硬化(PBC)患者和8514例正常个体的基因进行基因型分型,我们在186个已知的自生免疫性风险位点中鉴定到196524个变异。我们新鉴定到3个与PBC相关的位点(P < 5 × 10−8)。因此,与PBC相关的已知易感基因位点增加到25个。染色体19p12上最密切相关的变异是位于TYK2上的低频率非同义SNP,进一步暗示了在疾病的发病机理中,JAK-STAT与细胞因子信号互作。额外的包含有非同义变异的5个位点在高度连锁不平衡染色质区域中(LD;r2 > 0.8)与该位点最密切相关的变异。我们在这5个位点上发现多个独立常见的、低频率和罕见的变异关联信号。研究发现26个独立的、紧随免疫芯片的非人类白细胞抗原(HLA)信号,其中15个信号在B类淋巴母细胞的开放性染色质区域(高LD(r2>0.8),且具有最密切相关的变异)具有SNPs。这项研究表明来自致密精细定位芯片如何与功能基因组数据相结合,并用于鉴定候选的、解释随后功能的因果变异。

英文原稿


[Title]: Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis  

[Authors]: Jimmy Z Liu, Mohamed A Almarri, Daniel J Gaffney, George F Mells, Luke Jostins, Heather J Cordell, Samantha J Ducker, Darren B Day, Michael A Heneghan, James M Neuberger, Peter T Donaldson, Andrew J Bathgate, Andrew Burroughs, Mervyn H Davies, David E Jones, Graeme J Alexander, Jeffrey C Barrett, The UK Primary Biliary Cirrhosis (PBC) Consortium, The Wellcome Trust Case Control Consortium 3, Richard N Sandford & Carl A Anderson

[Abstract]: We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P < 5 × 10−8), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r2 > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non–human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2 > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

原文地址

http://www.nature.com/ng/journal/v44/n10/full/ng.2395.html

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