TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits.
TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits.
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DOI：
10.1371/journal.pone.0122271
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Plenge RM
中科院分区：
文献类型：
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作者：
Diogo D;Bastarache L;Liao KP;Graham RR;Fulton RS;Greenberg JD;Eyre S;Bowes J;Cui J;Lee A;Pappas DA;Kremer JM;Barton A;Coenen MJ;Franke B;Kiemeney LA;Mariette X;Richard-Miceli C;Canhão H;Fonseca JE;de Vries N;Tak PP;Crusius JB;Nurmohamed MT;Kurreeman F;Mikuls TR;Okada Y;Stahl EA;Larson DE;Deluca TL;O'Laughlin M;Fronick CC;Fulton LL;Kosoy R;Ransom M;Bhangale TR;Ortmann W;Cagan A;Gainer V;Karlson EW;Kohane I;Murphy SN;Martin J;Zhernakova A;Klareskog L;Padyukov L;Worthington J;Mardis ER;Seldin MF;Gregersen PK;Behrens T;Raychaudhuri S;Denny JC;Plenge RM
尽管全基因组关联研究（GWAS）在检测复杂表型（如类风湿关节炎（RA）易感性）的大量基因座方面取得了成功，但在疾病生物学背景下，因果基因信息的缺乏给解释GWAS结果带来了重大挑战。本研究中，我们对类风湿关节炎风险位点19p13进行了遗传精细定位，以确定因果变异，并探索这些变异在其他复杂性状中的多效性效应。首先，我们结合免疫芯片致密基因分型（n = 23,092例/对照样本），Exomechip基因分型（n = 18,409例/对照样本）和靶向外显子测序（n = 2,236例/对照样本），证明TYK2（酪氨酸激酶2）的三个蛋白质编码变体：P1104A (rs34536443, OR = 0.66, P = 2.3 × 10-21), A928V （rs35018800, OR = 0.53, P = 1.2 × 10-9）和I684S （rs12720356, OR = 0.86, P = 4.6 × 10-7）独立保护RA。其次，我们发现同样的三种TYK2变体可以预防系统性红斑狼疮（SLE, Pomnibus = 6 × 10-18），并提供了两种TYK2变体（P1104A和A928V）也可以预防炎症性肠病（IBD; Pomnibus = 0.005）的暗示性证据。最后，在一项使用电子医疗记录（EMR）评估>29,000名受试者的>500种表型的全现象关联研究（PheWAS）中，我们没有发现令人信服的证据表明P1104A和A928V与RA、SLE和IBD等自身免疫性疾病以外的复杂表型相关。总之，我们的研究结果证明了TYK2在RA、SLE和IBD发病机制中的作用，并为TYK2作为治疗自身免疫性疾病的有希望的药物靶点提供了支持证据。
Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3x10-21), A928V (rs35018800, OR = 0.53, P = 1.2x10-9), and I684S (rs12720356, OR = 0.86, P = 4.6x10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6x10-18), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.
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影响因子：
120.1
作者：
Cook, David;Brown, Dearg;Pangalos, Menelas N.
通讯作者：
Pangalos, Menelas N.
影响因子：
46.9
作者：
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影响因子：
27.4
作者：
Curtis, Jeffrey R.;Xie, Fenglong;Delzell, Elizabeth
通讯作者：
Delzell, Elizabeth
影响因子：
4.5
作者：
Cunninghame Graham DS;Morris DL;Bhangale TR;Criswell LA;Syvänen AC;Rönnblom L;Behrens TW;Graham RR;Vyse TJ
通讯作者：
Vyse TJ
影响因子：
30.8
作者：
通讯作者：
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