Multiple Loci within the major histocompatibility complex confer risk of psoriasis.
Multiple Loci within the major histocompatibility complex confer risk of psoriasis.
复制标题
主要组织相容性复合体内的多个基因座会带来患牛皮癣的风险。
DOI：
10.1371/journal.pgen.1000606
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发表时间：
2009-08
期刊：
影响因子：
4.5
通讯作者：
Goldgar DE
中科院分区：
文献类型：
--
作者：
Feng BJ;Sun LD;Soltani-Arabshahi R;Bowcock AM;Nair RP;Stuart P;Elder JT;Schrodi SJ;Begovich AB;Abecasis GR;Zhang XJ;Callis-Duffin KP;Krueger GG;Goldgar DE
牛皮癣是一种常见的炎症性皮肤病，其特征是鳞状红色斑块增厚。此前，我们对牛皮癣进行了一项全基因组关联研究（GWAS），其中1359例和1400例对照，对447,249个snp进行了基因分型。最显著的发现是SNP rs12191877，它与牛皮癣的公认风险等位基因HLA-Cw*0602存在紧密的连锁不平衡。然而，目前尚不清楚MHC中除HLA-C外是否还有其他银屑病位点。在本研究中，我们通过对GWAS数据的深入分析，在人类白细胞抗原（HLA）区域寻找其他易感位点；然后，我们对1139名独立汉族牛皮癣患者和1132名对照者进行了随访。以分阶段的CEPH数据集为参考，我们在所有样本中以较高的精度输入HLA-Cw*0602。输入HLA-Cw*0602剂量与疾病的相关性远强于最显著相关SNP rs12191877。对HLA-Cw*0602进行调整后，剩下两个关联信号：一个是rs2073048 (p = 2×10−6,OR = 0.66)，位于tnf - α的潜在下游效应体c6orf10内；另一个是rs13437088 (p = 9×10−6,OR = 1.3)，位于HLA-B的30 kb中心体和MICA的16 kb端粒。当HLA-Cw*0602、rs2073048和rs13437088均纳入logistic回归模型时，它们与疾病均有显著相关性（p分别= 3×10−47、6×10−8和3×10−7）。在控制输入HLA-Cw*0602后，这两个假定的基因座在汉族样本中也显著相关。两种人群的HLA-B详细分析显示，HLA-B*57与银屑病风险增加相关，HLA-B*40与风险降低相关，独立于HLA-Cw*0602和C6orf10位点，提示HLA-B可能参与致病。这些结果表明，在MHC中至少有两个额外的位点赋予牛皮癣的风险。牛皮癣（Ps）是一种慢性皮肤炎症性疾病，影响了大约2%的欧洲人。HLA-C基因位于6号染色体上的主要组织相容性复合体（MHC）区域，是银屑病的主要遗传决定因素。然而，MHC中的多个易感基因也被假设。最近，我们对1359例牛皮癣患者和1400名健康对照者进行了全基因组关联扫描（GWAS），鉴定出人类基因组中的7个牛皮癣位点，并证实了HLA-C的作用。该数据集包含密集分布的遗传变异，单核苷酸多态性（snp），然后进一步分析以寻找MHC区域内的其他易感基因。利用SNP数据，我们在所有样本中以高精度估算出HLA-C风险等位基因。调整HLA-C，另外两个位点，一个靠近C6orf10，一个靠近HLA-B/MICA，与牛皮癣有显著关联，这也在一个独立的汉族数据集中观察到，表明MHC中至少有三个基因调节牛皮癣的易感性。
Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; then, we followed up our findings in an independent Han Chinese 1,139 psoriasis cases and 1,132 controls. Using the phased CEPH dataset as a reference, we imputed the HLA-Cw*0602 in all samples with high accuracy. The association of the imputed HLA-Cw*0602 dosage with disease was much stronger than that of the most significantly associated SNP, rs12191877. Adjusting for HLA-Cw*0602, there were two remaining association signals: one demonstrated by rs2073048 (p = 2×10−6, OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9×10−6, OR = 1.3), located 30 kb centromeric of HLA-B and 16 kb telomeric of MICA. When HLA-Cw*0602, rs2073048, and rs13437088 were all included in a logistic regression model, each of them was significantly associated with disease (p = 3×10−47, 6×10−8, and 3×10−7, respectively). Both putative loci were also significantly associated in the Han Chinese samples after controlling for the imputed HLA-Cw*0602. A detailed analysis of HLA-B in both populations demonstrated that HLA-B*57 was associated with an increased risk of psoriasis and HLA-B*40 a decreased risk, independently of HLA-Cw*0602 and the C6orf10 locus, suggesting the potential pathogenic involvement of HLA-B. These results demonstrate that there are at least two additional loci within the MHC conferring risk of psoriasis. Psoriasis (Ps) is a chronic inflammatory disease of the skin, affecting approximately 2% of Europeans. The HLA-C gene, located within the major histocompatibility complex (MHC) region on chromosome 6, is the major genetic determinant of psoriasis. However, multiple susceptibility genes within MHC are also hypothesized. Recently, we carried out a genome-wide association scan (GWAS) on psoriasis with 1,359 patients and 1,400 healthy controls, which identified seven psoriasis loci in the human genome and confirmed the effect of HLA-C. This dataset contains densely distributed genetic variations, single nucleotide polymorphisms (SNPs), which were then further analyzed in search for additional susceptibility genes within the MHC region. Using the SNP data, we imputed in all samples the HLA-C risk allele with high accuracy. Adjusting for the HLA-C, two additional loci, one near C6orf10 and one near HLA-B/MICA, have significant associations with psoriasis, which were also observed in an independent Han Chinese dataset, suggesting that within the MHC there are at least three genes moderating susceptibility to psoriasis.
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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：
6.5
作者：
Balendran, N;Clough, RL;Trembath, RC
通讯作者：
Trembath, RC
影响因子：
10.3
作者：
Gudjonsson, JE;Karason, A;Valdimarsson, H
通讯作者：
Valdimarsson, H
影响因子：
9.8
作者：
Cargill, Michele;Schrodi, Steven J.;Begovich, Ann B.
通讯作者：
Begovich, Ann B.
影响因子：
4.6
作者：
Johnston, A;Gudjonsson, JE;Valdimarsson, H
通讯作者：
Valdimarsson, H