Association of rare single nucleotide variant MUC5B rs35705950 with interstitial lung disease in Japanese rheumatoid arthritis.

Rheumatoid arthritis (RA) is sometimes complicated by interstitial lung disease (ILD) with a poor prognosis. A single nucleotide variant (SNV) in MUC5B was associated with ILD in European RA patients. However, associations of this SNV were not found in Japanese RA patients, because its frequency in Japanese populations is very low. We investigated the associations of candidate SNVs including the MUC5B variant with ILD in Japanese RA. Genotyping of MUC5B rs35705950, MUC2 rs7934606, MAD1L1 rs12699415, and PPFIBP2 rs6578890 in Japanese RA patients was conducted for association analyses. MUC5B rs35705950 was associated with usual interstitial pneumonia (UIP) (p = 0.0039, Pc = 0.0156, odds ratio [OR] 10.66, 95% confidence interval [CI] 2.05-55.37) or ILD (p = 0.0071, Pc = 0.0284, OR 7.33, 95%CI 1.52-35.44) in Japanese RA under the allele model. MUC2 rs7934606 was associated with UIP (p = 0.0072, Pc = 0.0288, OR 29.55, 95%CI 1.52-574.57) or ILD (p = 0.0037, Pc = 0.0148, OR 22.95, 95%CI 1.27-416.13) in RA. Haplotype analyses suggested the primary association of MUC5B rs35705950 with UIP in Japanese RA. No significant association of MAD1L1 rs12699415 or PPFIBP2 rs6578890 with UIP, nonspecific interstitial pneumonia, or ILD in RA was observed. MUC5B rs35705950 is associated with, and might be involved in the pathogenesis of ILD, especially UIP, in Japanese RA.

Higuchi T ，Oka S ，Shimada K ，Tsunoda S ，Ito S ，Okamoto A ，Fujimori M ，Nakamura T ，Katayama M ，Suzuki M ，Saisho K ，Shinohara S ，Matsui T ，Migita K ，Nagaoka S ，Tohma S ，Furukawa H ... -  《-》

MUC5B promoter variant rs35705950, rare but significant susceptibility locus in rheumatoid arthritis-interstitial lung disease with usual interstitial pneumonia in Asian populations.

MUC5B variant rs35705950 is the common and most significant risk variant for rheumatoid arthritis-interstitial lung disease (RA-ILD) in Western populations. However, little is known about its significant association with RA-ILD in Asian populations. We here investigate the association of rs35705950 with Korean patients with RA-ILD. In this cross-sectional study, we genotyped rs35705950 in 2444 patients with RA. Among them, 683 patients with RA who have chest CT were divided into RA-ILD and RA-noILD. RA-ILD was classified as usual interstitial pneumonia (UIP) and other than UIP. The associations of rs35705950 with RA-ILD and its subtype were analysed using multivariable regression adjusted for age at RA diagnosis. Meta-analysis of a previously reported Japanese dataset and Korean dataset obtained for this study was conducted. The minor allele (T) frequency of rs35705950 was 0.37%, 1.43% and 2.38% in 2444 patients with RA, 105 patients with RA-ILD and 63 patients with UIP, respectively. Genotypic association of rs35705950 with RA-ILD was insignificant (OR 2.49, 95% CI 0.64 to 9.69, p=0.187), but showed significant association with UIP (OR 4.90, 95% CI 1.23 to 19.59, p=0.024) compared with RA-noILD. In meta-analysis (123 UIP and 878 RA-noILD) combining our data with previously reported Japanese data, this variant was found to be significantly associated with UIP (OR 3.51, 95% CI 1.19 to 10.37, p=0.023). MUC5B variant rs35705950 is a rare but significant risk factor for Asian patients with RA-ILD with UIP, suggesting a sharing of the genetic background between Asian and Western populations.

Joo YB ，Ahn SM ，Bang SY ，Park Y ，Hong SJ ，Lee Y ，Cho SK ，Choi CB ，Sung YK ，Kim TH ，Jun JB ，Yoo DH ，Bae SC ，Lee HS ... -  《-》

Association of a FAM13A variant with interstitial lung disease in Japanese rheumatoid arthritis.

Interstitial lung disease (ILD) occasionally occurs in rheumatoid arthritis (RA) and confers a dismal prognosis. We previously reported that a single-nucleotide variant (SNV) of MUC5B was associated with ILD in RA. However, the pathogenesis of ILD in Japanese patients with RA could not be explained solely by this SNV because its frequency is extremely low in the Japanese population. Here, we examined whether a different idiopathic pulmonary fibrosis susceptibility SNV might be associated with ILD in Japanese patients with RA. Genotyping of rs2609255 (G/T) in FAM13A was conducted in 208 patients with RA with ILD and 420 without chronic lung disease using TaqMan assays. A significant association with usual interstitial pneumonia (UIP) in RA was detected for rs2609255 under the allele model (p=0.0092, Pc=0.0276, OR 1.53, 95% CI 1.12 to 2.11) and recessive model for the G allele (p=0.0003, Pc=0.0009, OR 2.63, 95% CI 1.59 to 4.32). FAM13A rs2609255 was significantly associated with UIP in male patients with RA (p=0.0043, OR 3.65, 95% CI 1.52 to 8.73) under the recessive model. This study is the first to document an association of rs2609255 with ILD in Japanese patients with RA, implicating it in the pathogenesis of UIP, though studies on the function of rs2609255 are warranted.

Higuchi T ，Oka S ，Furukawa H ，Shimada K ，Tsunoda S ，Ito S ，Okamoto A ，Katayama M ，Saisho K ，Shinohara S ，Matsui T ，Migita K ，Nagaoka S ，Tohma S ... -  《-》

MUC5B promoter variant rs35705950 and rheumatoid arthritis associated interstitial lung disease survival and progression.

The major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD. Through an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline. Out of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern. In this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.

Juge PA ，Solomon JJ ，van Moorsel CHM ，Garofoli R ，Lee JS ，Louis-Sydney F ，Rojas-Serrano J ，González-Pérez MI ，Mejia M ，Buendia-Roldán I ，Falfán-Valencia R ，Ambrocio-Ortiz E ，Manali E ，Papiris SA ，Karageorgas T ，Boumpas D ，Antoniou KM ，Sidiropoulos P ，Trachalaki A ，van der Vis JJ ，Jamnitski A ，Grutters JC ，Kannengiesser C ，Borie R ，Kawano-Dourado L ，Wemeau-Stervinou L ，Flipo RM ，Nunes H ，Uzunhan Y ，Valeyre D ，Saidenberg-Kermanac'h N ，Boissier MC ，Richez C ，Schaeverbeke T ，Doyle T ，Wolters PJ ，Debray MP ，Boileau C ，Porcher R ，Schwartz DA ，Crestani B ，Dieudé P ... -  《-》

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.

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 ... -  《-》