Variants in ZNF365 isoform D are associated with Crohn's disease.
Variants in ZNF365 isoform D are associated with Crohn's disease.
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DOI：
10.1136/gut.2010.227256
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发表时间：
2011-08
期刊：
影响因子：
24.5
通讯作者：
Taylor KD
中科院分区：
文献类型：
--
作者：
Haritunians T;Jones MR;McGovern DP;Shih DQ;Barrett RJ;Derkowski C;Dubinsky MC;Dutridge D;Fleshner PR;Ippoliti A;King L;Leshinsky-Silver E;Levine A;Melmed GY;Mengesha E;Vasilauskas EA;Ziaee S;Rotter JI;Targan SR;Taylor KD
全基因组关联研究（GWAS）已经确定了多个克罗恩病（CD）易感基因座，包括与10 q21非编码基因间单核苷酸多态性（SNP）的关联。为了精细定位10 q21位点，我们对1632例CD患者和961例对照进行了86个SNP的基因分型，并使用Logistic回归进行了单标记和条件分析。我们观察到11个SNP与CD风险的相关性（p< 0.001）。在ZNF 365中观察到的最显著的关联是在非同义SNP rs7076156（Ala 62 Thr）处。丙氨酸等位基因在CD中的代表性过高（p= 5.23×10−7; OR= 1.39 [1.22-1.58]）;等位基因频率76% CD，69.7%对照）。对rs7076156的条件分析使所有其他显著关联无效，表明这是该位点的致病变异。此前已鉴定出ZNF 365的四种亚型，rs7076156位于ZNF 365亚型D特有的外显子中。我们证明，使用RT-PCR，表达ZNF 365 D在肠切除CD主题和控制。我们发现，在CD受试者中，风险等位基因（Ala）纯合子的EBV转化的淋巴母细胞样细胞系（ELCL）中，ZNF 365 D的平均表达水平显著降低。全基因组芯片表达研究进一步表明，ZNF 365亚型D中Ala 62 Thr的变化与CD中ARL 4A、MKKS、RRAGD、SUMF 2、TDR 1和ZNF 148基因的差异表达有关。总的来说，我们的数据支持这一假设，即非同义的Ala 62 Thr SNP rs7076156是10 q21和CD风险之间关联的基础，并表明该SNP通过改变ZNF 365亚型D控制下的基因表达而起作用。
Genome-wide association studies (GWAS) have identified multiple Crohn’s disease (CD) susceptibility loci, including association with non-coding intergenic single nucleotide polymorphisms (SNPs) at 10q21. To fine-map the 10q21 locus, we genotyped 86 SNPs in 1632 CD cases and 961 controls and performed single marker and conditional analyses using logistic regression. We observed association with CD risk spanning eleven SNPs (p< 0.001). The most significant association observed was at the nonsynonymous SNP rs7076156 (Ala62Thr) in ZNF365. The alanine allele was over-represented in CD (p= 5.23×10−7; OR= 1.39 [1.22–1.58]); allele frequency 76% CD, 69.7% controls). Conditional analysis on rs7076156 nullified all other significant associations, suggesting that this is the causative variant at this locus. Four isoforms of ZNF365 have previously been identified and rs7076156 is located in an exon unique to ZNF365 isoform D. We demonstrated, using RT-PCR, expression of ZNF365D in intestinal resections from both CD subjects and controls. We identified markedly reduced ZNF365D mean expression levels in EBV-transformed lymphoblastoid cell lines (ELCLs) from CD subjects homozygous for the risk allele (Ala). A whole-genome microarray expression study further suggested that the Ala62Thr change in ZNF365 isoform D is related to differential expression of the genes ARL4A, MKKS, RRAGD, SUMF2, TDR1 and ZNF148 in CD. Collectively our data support the hypothesis that the nonsynonymous Ala62Thr SNP rs7076156 underlies the association between 10q21 and CD risk and suggests that this SNP acts by altering expression of genes under the control of ZNF365 isoform D.
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影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
4.5
作者：
Libioulle C;Louis E;Hansoul S;Sandor C;Farnir F;Franchimont D;Vermeire S;Dewit O;de Vos M;Dixon A;Demarche B;Gut I;Heath S;Foglio M;Liang L;Laukens D;Mni M;Zelenika D;Van Gossum A;Rutgeerts P;Belaiche J;Lathrop M;Georges M
通讯作者：
Georges M
影响因子：
30.8
作者：
Hampe, Jochen;Franke, Andre;Schreiber, Stefan
通讯作者：
Schreiber, Stefan
影响因子：
3.5
作者：
McCarthy, Mark I.;Hirschhorn, Joel N.
通讯作者：
Hirschhorn, Joel N.
影响因子：
14.9
作者：
Law, DJ;Labut, EM;Merchant, JL
通讯作者：
Merchant, JL