Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.
Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.
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OAS1处Sjögren综合征易感性基因座的鉴定，该基因座影响了同工型切换，蛋白质表达和对I型干扰素的反应性。
DOI：
10.1371/journal.pgen.1006820
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发表时间：
2017-06
期刊：
影响因子：
4.5
通讯作者：
Sivils KL
中科院分区：
文献类型：
--
作者：
Li H;Reksten TR;Ice JA;Kelly JA;Adrianto I;Rasmussen A;Wang S;He B;Grundahl KM;Glenn SB;Miceli-Richard C;Bowman S;Lester S;Eriksson P;Eloranta ML;Brun JG;Gøransson LG;Harboe E;Guthridge JM;Kaufman KM;Kvarnström M;Cunninghame Graham DS;Patel K;Adler AJ;Farris AD;Brennan MT;Chodosh J;Gopalakrishnan R;Weisman MH;Venuturupalli S;Wallace DJ;Hefner KS;Houston GD;Huang AJW;Hughes PJ;Lewis DM;Radfar L;Vista ES;Edgar CE;Rohrer MD;Stone DU;Vyse TJ;Harley JB;Gaffney PM;James JA;Turner S;Alevizos I;Anaya JM;Rhodus NL;Segal BM;Montgomery CG;Scofield RH;Kovats S;Mariette X;Rönnblom L;Witte T;Rischmueller M;Wahren-Herlenius M;Omdal R;Jonsson R;Ng WF;for UK Primary Sjögren's Syndrome Registry;Nordmark G;Lessard CJ;Sivils KL
干燥综合征 (SS) 是一种常见的自身免疫性外分泌病，以干燥性角结膜炎和口干症为特征。患者经常出现严重的并发症，包括淋巴瘤、肺功能障碍、神经病变、血管炎和虚弱性疲劳。 I 型干扰素 (IFN) 通路失调是 SS 的一个显着特征，与自身抗体滴度增加和疾病严重程度相关。为了确定 SS 中 IFN 通路失调的遗传决定因素，我们进行了顺式表达数量性状位点 (eQTL) 分析，重点关注通过转录组分析研究确定的差异表达的 I 型 IFN 诱导转录本。多个 cis-eQTL 与 2'-5'-寡腺苷酸合成酶 1 (OAS1) 的转录水平相关，峰值位于 rs10774671 (PeQTL = 6.05 × 10−14)。通过两个独立队列的荟萃分析，确定并证实了 rs10774671 与 SS 易感性的关联（Pmeta = 2.59 × 10−9；比值比 = 0.75；95% 置信区间 = 0.66–0.86）。 rs10774671 的风险等位基因将 OAS1 的剪接从 p46 同种型的产生转变为多种替代转录本，包括 p42、p48 和 p44。我们发现，在对照以及有或没有自身抗体的患者中，每种基因型的亚型表达存在差异。此外，我们的结果表明，三种选择性剪接异构体缺乏对 I 型 IFN 刺激的翻译反应。 p48 和 p44 亚型的转录本 3' 端控制的蛋白质表达也受损。其他人已证明 rs10774671 的 SS 风险等位基因与 OAS1 酶活性和清除病毒感染的能力降低以及对 IFN 治疗的反应性降低有关。我们的结果将 OAS1 确定为 SS 的风险位点，并支持由于 IFN 反应改变而导致病毒清除缺陷的潜在作用，作为这种复杂自身免疫性疾病的遗传病理生理学基础。干燥综合征 (SS) 是一种常见的自身免疫性疾病，免疫细胞会渗入产生水分的腺体，导致眼睛和口腔干燥。 SS 患者还表现出衰弱性疲劳以及肝、肺、肾和皮肤的其他疾病。这种复杂疾病的病因尚不完全清楚；然而，具有遗传风险因素的个体中的环境触发因素（例如病毒感染）被认为会导致 SS 的发生。 1 型干扰素 (IFN) 是病毒感染后的第一批防御者之一，可诱导各种病毒反应基因的表达。在 SS 患者中观察到 1 型 IFN 信号持续升高。在这里，我们首先复制了先前鉴定的导致 SS 患者异常 1 型 IFN 信号传导的 RNA 转录本。然后我们在 IFN 诱导基因 OAS1 中发现了一个与疾病相关的遗传变异。该变体控制 OAS1 的剪接，将转录物改变为缺乏蛋白质表达和对 IFN 反应的多种亚型。这项研究的结果可能有助于深入了解 SS 以及 1 型干扰素系统中具有类似失调的其他自身免疫性疾病的遗传基础。
Sjögren’s syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10−14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10−9; odds ratio = 0.75; 95% confidence interval = 0.66–0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease. Sjögren’s syndrome (SS) is a common autoimmune condition where immune cells infiltrate moisture-producing glands, leading to dryness typically in the eyes and mouth. SS patients also manifest debilitating fatigue as well as other diseases in liver, lung, kidney, and skin. The cause of this complex disease is still not fully understood; however, an environmental trigger, such as viral infections, in individuals with genetic risk factor(s) is thought to contribute to the development of SS. Type 1 interferons (IFNs) are one of the first defenders after viral infection and induce the expression of various virus-responding genes. Perpetual elevation of type 1 IFN signaling has been observed in SS patients. Here, we first replicated previously identified RNA transcripts contributing to the abnormal type 1 IFN signaling in SS patients. We then identified a disease-associated genetic variant in an IFN-inducible gene, OAS1. This variant governs splicing of OAS1, altering the transcript into multiple isoforms that lack protein expression and responsiveness to IFNs. The results of this study may provide insight into the genetic basis of SS, as well as other autoimmune disease with similar dysregulation in the type 1 IFN system.
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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
抗病毒 2′,5′-寡腺苷酸合成酶（2′5′AS）酶活性的变化受 OAS1 基因中剪接接受位点单核苷酸多态性的控制
影响因子：
9.8
作者：
Bonnevie-Nielsen, V;Field, LL;Pociot, F
通讯作者：
Pociot, F
影响因子：
3.7
作者：
Gupta, Rajat M.;Musunuru, Kiran
通讯作者：
Musunuru, Kiran
影响因子：
4.9
作者：
Crow MK
通讯作者：
Crow MK
DOI：
10.1126/science.1246949
发表时间：
2014-03-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fairfax BP;Humburg P;Makino S;Naranbhai V;Wong D;Lau E;Jostins L;Plant K;Andrews R;McGee C;Knight JC
通讯作者：
Knight JC