MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.
MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.
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DOI：
10.1056/nejmoa1801562
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发表时间：
2018-12-06
期刊：
影响因子：
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通讯作者：
Dieudé P
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作者：
Juge PA;Lee JS;Ebstein E;Furukawa H;Dobrinskikh E;Gazal S;Kannengiesser C;Ottaviani S;Oka S;Tohma S;Tsuchiya N;Rojas-Serrano J;González-Pérez MI;Mejía M;Buendía-Roldán I;Falfán-Valencia R;Ambrocio-Ortiz E;Manali E;Papiris SA;Karageorgas T;Boumpas D;Antoniou K;van Moorsel CHM;van der Vis J;de Man YA;Grutters JC;Wang Y;Borie R;Wemeau-Stervinou L;Wallaert B;Flipo RM;Nunes H;Valeyre D;Saidenberg-Kermanac'h N;Boissier MC;Marchand-Adam S;Frazier A;Richette P;Allanore Y;Sibilia J;Dromer C;Richez C;Schaeverbeke T;Lioté H;Thabut G;Nathan N;Amselem S;Soubrier M;Cottin V;Clément A;Deane K;Walts AD;Fingerlin T;Fischer A;Ryu JH;Matteson EL;Niewold TB;Assayag D;Gross A;Wolters P;Schwarz MI;Holers M;Solomon JJ;Doyle T;Rosas IO;Blauwendraat C;Nalls MA;Debray MP;Boileau C;Crestani B;Schwartz DA;Dieudé P
鉴于类风湿性关节炎(RA)相关性间质性肺疾病(以下简称RA-ILD)和特发性肺纤维化在表型上的相似性，我们假设特发性肺纤维化发生的最大危险因素，即功能获得的MUC5B启动子变异rs35705950，也会导致RA患者发生ILD的风险。使用发现人群和多个验证人群，我们测试了620名RA-ILD患者、614名无ILD的RA患者和5448名未受影响的对照组中MUC5B启动子变异体rs35705950的关联性。对发现人群的分析显示，当RA-ILD患者与未受影响的对照组比较时，MUC5B启动子变异的微小等位基因与RA-ILD相关(调整后的优势比为3.8；95%可信区间[CI]为2.8~5.2；P=9.7×10−17)。在多民族病例系列分析(调整后的优势比，5.5；95%CI，4.2~7.3；P=4.7×10−35)以及发现人群和多民族病例系列的联合分析(调整后的优势比，4.7；95%CI，3.9~5.8；P=1.3×10−49)中，MUC5B启动子变异在RA-ILD患者中的表达也显著高于未受影响的对照组。此外，在RA患者中，MUC5B启动子变异与ILD的风险增加相关(合并分析中调整的优势比为3.1；95%可信区间为1.8~5.4；P=7.4×10−5)，特别是在高分辨率CT有常见间质性肺炎的患者中(合并分析中调整的优势比为6.1；95%可信区间为2.9~13.1；P=2.5×10−6)。然而，没有观察到MUC5B启动子变异与单独诊断类风湿关节炎的显著关联。我们发现MUC5B启动子变异与RA-ILD相关，更具体地说，与影像上常见的间质性肺炎相关。(由法国兴业银行和其他机构资助。)
Given the phenotypic similarities between rheumatoid arthritis (RA)–associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P = 9.7×10−17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multi-ethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P = 4.7×10−35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P = 1.3×10−49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P = 7.4×10−5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P = 2.5×10−6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.)