Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations.
Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations.
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DOI：
10.1371/journal.pone.0029819
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Matesanz F
中科院分区：
文献类型：
--
作者：
Alcina A;Abad-Grau Mdel M;Fedetz M;Izquierdo G;Lucas M;Fernández O;Ndagire D;Catalá-Rabasa A;Ruiz A;Gayán J;Delgado C;Arnal C;Matesanz F
人类白细胞抗原（HLA）DRB 1 *1501一直与多发性硬化症（MS）在几乎所有的测试人群。这表明特异性抗原呈递是致病机制，尽管这并不能完全解释疾病相关性。HLA基因座中基因的表达数量性状基因座（eQTL）的鉴定提出了基因表达在MS易感性中的作用的问题。我们分析了eQTL在HLA区域相对于MS相关的HLA变体从全基因组关联研究（GWAS）。我们发现DRB 1 *1501的标签rs3135388 A等位基因与高加索人群中DRB 1、DRB 5和DQB 1基因的高表达相关。在定量方面，MS风险rs3135388 AA基因型携带者与DQB 1，DRB 5和DRB 1的表达分别比非风险GG携带者高15.7，5.2和8.3倍。西班牙MS队列中表达相关变体的单倍型分析显示，DRB 1和DQB 1单独高表达并不导致该疾病。然而，在高加索人、亚洲人和非洲裔美国人人群中，DRB 1 *1501等位基因总是高表达。在其他免疫相关疾病如1型糖尿病、炎症性肠病、溃疡性结肠炎、哮喘和伊加缺乏症中，最好的GWAS相关HLA SNPs也是不同HLA II类基因的eQTL。我们的数据表明，DR/DQ表达水平，连同等位基因的特定结构特性，似乎是在MS和其他免疫病理学，而不是单独的特异性抗原呈递的因果关系。
The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone.
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影响因子：
5
作者：
Handunnetthi, L.;Ramagopalan, S. V.;Ebers, G. C.;Knight, J. C.
通讯作者：
Knight, J. C.
影响因子：
30.8
作者：
Kugathasan, Subra;Baldassano, Robert N.;Bradfield, Jonathan P.;Sleiman, Patrick M. A.;Imielinski, Marcin;Guthery, Stephen L.;Cucchiara, Salvatore;Kim, Cecilia E.;Frackelton, Edward C.;Annaiah, Kiran;Glessner, Joseph T.;Santa, Erin;Willson, Tara;Eckert, Andrew W.;Bonkowski, Erin;Shaner, Julie L.;Smith, Ryan M.;Otieno, F. George;Peterson, Nicholas;Abrams, Debra J.;Chiavacci, Rosetta M.;Grundmeier, Robert;Mamula, Petar;Tomer, Gitit;Piccoli, David A.;Monos, Dimitri S.;Annese, Vito;Denson, Lee A.;Grant, Struan F. A.;Hakonarson, Hakon
通讯作者：
Hakonarson, Hakon
中国汉族人群的全基因组关联研究确定了系统性红斑狼疮的九个新易感位点
影响因子：
30.8
作者：
Han, Jian-Wen;Zheng, Hou-Feng;Zhang, Xue-Jun
通讯作者：
Zhang, Xue-Jun
影响因子：
30.8
作者：
Bahlo, Melanie;Booth, David R.;Willoughby, Ernest
通讯作者：
Willoughby, Ernest
影响因子：
30.8
作者：
Anderson, Carl A.;Boucher, Gabrielle;Lees, Charlie W.;Franke, Andre;D'Amato, Mauro;Taylor, Kent D.;Lee, James C.;Goyette, Philippe;Imielinski, Marcin;Latiano, Anna;Lagace, Caroline;Scott, Regan;Amininejad, Leila;Bumpstead, Suzannah;Baidoo, Leonard;Baldassano, Robert N.;Barclay, Murray;Bayless, Theodore M.;Brand, Stephan;Buening, Carsten;Colombel, Jean-Frederic;Denson, Lee A.;De Vos, Martine;Dubinsky, Marla;Edwards, Cathryn;Ellinghaus, David;Fehrmann, Rudolf S. N.;Floyd, James A. B.;Florin, Timothy;Franchimont, Denis;Franke, Lude;Georges, Michel;Glas, Juergen;Glazer, Nicole L.;Guthery, Stephen L.;Haritunians, Talin;Hayward, Nicholas K.;Hugot, Jean-Pierre;Jobin, Gilles;Laukens, Debby;Lawrance, Ian;Lemann, Marc;Levine, Arie;Libioulle, Cecile;Louis, Edouard;McGovern, Dermot P.;Milla, Monica;Montgomery, Grant W.;Morley, Katherine I.;Mowat, Craig;Ng, Aylwin;Newman, William;Ophoff, Roel A.;Papi, Laura;Palmieri, Orazio;Peyrin-Biroulet, Laurent;Panes, Julian;Phillips, Anne;Prescott, Natalie J.;Proctor, Deborah D.;Roberts, Rebecca;Russell, Richard;Rutgeerts, Paul;Sanderson, Jeremy;Sans, Miquel;Schumm, Philip;Seibold, Frank;Sharma, Yashoda;Simms, Lisa A.;Seielstad, Mark;Steinhart, A. Hillary;Targan, Stephan R.;van den Berg, Leonard H.;Vatn, Morten;Verspaget, Hein;Walters, Thomas;Wijmenga, Cisca;Wilson, David C.;Westra, Harm-Jan;Xavier, Ramnik J.;Zhao, Zhen Z.;Ponsioen, Cyriel Y.;Andersen, Vibeke;Torkvist, Leif;Gazouli, Maria;Anagnou, Nicholas P.;Karlsen, Tom H.;Kupcinskas, Limas;Sventoraityte, Jurgita;Mansfield, John C.;Kugathasan, Subra;Silverberg, Mark S.;Halfvarson, Jonas;Rotter, Jerome I.;Mathew, Christopher G.;Griffiths, Anne M.;Gearry, Richard;Ahmad, Tariq;Brant, Steven R.;Chamaillard, Mathias;Satsangi, Jack;Cho, Judy H.;Schreiber, Stefan;Daly, Mark J.;Barrett, Jeffrey C.;Parkes, Miles;Annese, Vito;Hakonarson, Hakon;Radford-Smith, Graham;Duerr, Richard H.;Vermeire, Severine;Weersma, Rinse K.;Rioux, John D.
通讯作者：
Rioux, John D.