Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.
Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.
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DOI：
10.1002/hep.24307
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发表时间：
2011-06
期刊：
影响因子：
13.5
通讯作者：
Weersma, Rinse K.
中科院分区：
文献类型：
--
作者：
Janse, Marcel;Lamberts, Laetitia E.;Franke, Lude;Raychaudhuri, Soumya;Ellinghaus, Eva;Boberg, Kirsten Muri;Melum, Espen;Folseraas, Trine;Schrumpf, Erik;Bergquist, Annika;Bjornsson, Einar;Fu, Jingyuan;Westra, Harm Jan;Groen, Harry J. M.;Fehrmann, Rudolf S. N.;Smolonska, Joanna;van den Berg, Leonard H.;Ophoff, Roel A.;Porte, Robert J.;Weismueller, Tobias J.;Wedemeyer, Jochen;Schramm, Christoph;Sterneck, Martina;Guenther, Rainer;Braun, Felix;Vermeire, Severine;Henckaerts, Liesbet;Wijmenga, Cisca;Ponsioen, Cyriel Y.;Schreiber, Stefan;Karlsen, Tom H.;Franke, Andre;Weersma, Rinse K.
原发性硬化性胆管炎（PSC）是一种慢性胆汁淤积性肝病，其特征是胆管炎症和纤维化。环境因素和遗传因素共同参与了其发病机制。为了进一步阐明其遗传背景，我们研究了最近在1186例PSC患者和1748例对照组中发现的溃疡性结肠炎（UC）易感基因。对来自比荷卢（331例，735例对照）、德国（265例，368例对照）和斯堪的纳维亚（258例，388例对照）的854例PSC患者和1491例对照进行了标记13个UC易感基因位点的单核苷酸多态性（SNP）的初步基因分型。随后，与独立的第二个斯堪的纳维亚队列（332例，257例对照）进行联合分析。在多重检验校正后的联合分析中，染色体2p16（p值4.12×10−4）、4q27（p值4.10×10−5）和9q34（p值8.41×10−4）的SNP与PSC相关。在没有炎症性肠病（IBD）的PSC患者中，4q27和9q34的SNPs名义上相关（p<0.05）。我们应用了额外的计算机模拟分析来鉴定PSC易感基因座的可能候选基因。为了确定非随机的、基于证据的联系，我们使用GRAIL分析，显示了总共9个PSC相关区域中6个基因之间的相互连接。从1469荷兰和英国的个人表达的数量性状分析表明，五个9个SNPs顺式基因表达的影响。这些分析优先考虑IL2、CARD9和REL作为新的候选物。我们已经确定了与PSC相关的三个UC易感基因座，其具有推定的候选基因REL、IL 2和CARD 9。这些结果增加了对PSC遗传背景的稀缺知识，并暗示了先天性和适应性免疫因素的重要作用。
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1186PSC patients and 1748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1491 controls from the Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls) and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes2p16 (p value 4.12×10−4), 4q27 (p value 4.10×10−5) and 9q34 (p value 8.41×10−4) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease(IBD), SNPs at 4q27and9q34 were nominally associated (p<0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify non-random, evidence-based links we used GRAIL analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9 and REL as novel candidates. We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2 and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors.
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影响因子：
30.8
作者：
Fisher, Sheila A.;Tremelling, Mark;Anderson, Carl A.;Gwilliam, Rhian;Bumpstead, Suzannah;Prescott, Natalie J.;Nimmo, Elaine R.;Massey, Dunecan;Berzuini, Carlo;Johnson, Christopher;Barrett, Jeffrey C.;Cummings, Fraser R.;Drummond, Hazel;Lees, Charlie W.;Onnie, Clive M.;Hanson, Catherine E.;Blaszczyk, Katarzyna;Inouye, Mike;Ewels, Philip;Ravindrarajah, Radhi;Keniry, Andrew;Hunt, Sarah;Carter, Martyn;Watkins, Nick;Ouwehand, Willem;Lewis, Cathryn M.;Cardon, Lon;Lobo, Alan;Forbes, Alastair;Sanderson, Jeremy;Jewell, Derek P.;Mansfield, John C.;Deloukas, Panos;Mathew, Christopher G.;Parkes, Miles;Satsangi, Jack
通讯作者：
Satsangi, Jack
影响因子：
25.7
作者：
Card, Tim R.;Solaymani-Dodaran, Masoud;West, Joe
通讯作者：
West, Joe
影响因子：
24.5
作者：
Broome, U;Olsson, R;Lindberg, G
通讯作者：
Lindberg, G
影响因子：
56.9
作者：
Duerr, Richard H.;Taylor, Kent D.;Cho, Judy H.
通讯作者：
Cho, Judy H.
影响因子：
2.1
作者：
Li, Yun;Willer, Cristen J.;Ding, Jun;Scheet, Paul;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.