Li He, Reksten Tove Ragna, Ice John A, Kelly Jennifer A, Adrianto Indra, Rasmussen Astrid, Wang Shaofeng, He Bo, Grundahl Kiely M, Glenn Stuart B, Miceli-Richard Corinne, Bowman Simon, Lester Sue, Eriksson Per, Eloranta Maija-Leena, Brun Johan G, Gøransson Lasse G, Harboe Erna, Guthridge Joel M, Kaufman Kenneth M, Kvarnström Marika, Cunninghame Graham Deborah S, Patel Ketan, Adler Adam J, Farris A Darise, Brennan Michael T, Chodosh James, Gopalakrishnan Rajaram, Weisman Michael H, Venuturupalli Swamy, Wallace Daniel J, Hefner Kimberly S, Houston Glen D, Huang Andrew J W, Hughes Pamela J, Lewis David M, Radfar Lida, Vista Evan S, Edgar Contessa E, Rohrer Michael D, Stone Donald U, Vyse Timothy J, Harley John B, Gaffney Patrick M, James Judith A, Turner Sean, Alevizos Ilias, Anaya Juan-Manuel, Rhodus Nelson L, Segal Barbara M, Montgomery Courtney G, Scofield R Hal, Kovats Susan, Mariette Xavier, Rönnblom Lars, Witte Torsten, Rischmueller Maureen, Wahren-Herlenius Marie, Omdal Roald, Jonsson Roland, Ng Wan-Fai, Nordmark Gunnel, Lessard Christopher J, Sivils Kathy L
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
PLoS Genet. 2017 Jun 22;13(6):e1006820. doi: 10.1371/journal.pgen.1006820. eCollection 2017 Jun.
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.
干燥综合征（SS）是一种常见的自身免疫性外分泌腺病，其特征为角结膜干燥症和口干症。患者常出现严重并发症，包括淋巴瘤、肺功能障碍、神经病变、血管炎和使人衰弱的疲劳。I型干扰素（IFN）通路失调是SS的一个显著特征，且与自身抗体滴度升高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定量性状基因座（eQTL）分析，重点关注通过转录组谱研究鉴定出的差异表达的I型IFN诱导转录本。多个顺式eQTL与2'-5'-寡腺苷酸合成酶1（OAS1）的转录水平相关，在rs10774671处达到峰值（PeQTL = 6.05 × 10-14）。通过对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；优势比 = 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亚型的产生转变为多种可变转录本，包括p42、p48和p44。我们发现，在有或没有自身抗体的对照和患者中，各基因型内这些亚型的表达存在差异。此外，我们的结果表明，这三种可变剪接亚型对I型IFN刺激缺乏翻译反应。p48和p44亚型的蛋白质表达也受转录本3'端的影响而受损。其他人已表明，rs10774671的SS风险等位基因与OAS1酶活性降低、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确立为SS的一个风险基因座，并支持因IFN反应改变导致病毒清除缺陷作为这种复杂自身免疫性疾病的遗传病理生理基础的潜在作用。
