Associations of the MUC5B promoter variant with timing of interstitial lung disease and rheumatoid arthritis onset.

To investigate the associations of the common MUC5B promoter variant with timing of RA-associated interstitial lung disease (RA-ILD) and RA onset. We identified patients with RA meeting 2010 ACR/EULAR criteria and available genotype information in the Mass General Brigham Biobank, a multihospital biospecimen and clinical data collection research study. We determined RA-ILD presence by reviewing all RA patients who had CT imaging, lung biopsy or autopsy results. We determined the dates of RA and RA-ILD diagnoses by manual records review. We examined the associations of the MUC5B promoter variant (G>T at rs35705950) with RA-ILD, RA-ILD occurring before or within 2 years of RA diagnosis and RA diagnosis at age >55 years. We used multivariable logistic regression to estimate odds ratios (ORs) for each outcome by MUC5B promoter variant status, adjusting for potential confounders including genetic ancestry and smoking. We identified 1005 RA patients with available genotype data for rs35705950 (mean age 45 years, 79% female, 81% European ancestry). The MUC5B promoter variant was present in 155 (15.4%) and was associated with RA-ILD [multivariable OR 3.34 (95% CI 1.97, 5.60)], RA-ILD before or within 2 years of RA diagnosis [OR 4.01 (95% CI 1.78, 8.80)] and RA onset after age 55 years [OR 1.52 (95% CI 1.08, 2.12)]. The common MUC5B promoter variant was associated with RA-ILD onset earlier in the RA disease course and older age of RA onset. These findings suggest that the MUC5B promoter variant may impact RA-ILD risk early in the RA disease course, particularly in patients with older-onset RA.

McDermott G ，Gill R ，Gagne S ，Byrne S ，Huang W ，Cui J ，Prisco L ，Zaccardelli A ，Martin L ，Kronzer VL ，Moll M ，Cho MH ，Shadick N ，Dellaripa PF ，Doyle T ，Sparks JA ... -  《-》

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 ... -  《-》

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 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 ... -  《-》

Lifetime risk of rheumatoid arthritis-associated interstitial lung disease in MUC5B mutation carriers.

To estimate lifetime risk of developing rheumatoid arthritis-associated interstitial lung disease (RA-ILD) with respect to the strongest known risk factor for pulmonary fibrosis, a MUC5B promoter variant. FinnGen is a collection of epidemiological cohorts and hospital biobank samples, integrating genetic data with up to 50 years of follow-up within nationwide registries in Finland. Patients with RA and ILD were identified from the Finnish national hospital discharge, medication reimbursement and cause-of-death registries. We estimated lifetime risks of ILD by age 80 with respect to the common variant rs35705950, a MUC5B promoter variant. Out of 293 972 individuals, 1965 (0.7%) developed ILD by age 80. Among all individuals in the dataset, MUC5B increased the risk of ILD with a HR of 2.44 (95% CI: 2.22 to 2.68). Out of 6869 patients diagnosed with RA, 247 (3.6%) developed ILD. In patients with RA, MUC5B was a strong risk factor of ILD with a HR similar to the full dataset (HR: 2.27, 95% CI: 1.75 to 2.95). In patients with RA, lifetime risks of ILD were 16.8% (95% CI: 13.1% to 20.2%) for MUC5B carriers and 6.1% (95% CI: 5.0% to 7.2%) for MUC5B non-carriers. The difference between risks started to emerge at age 65, with a higher risk among men. Our findings provide estimates of lifetime risk of RA-ILD based on MUC5B mutation carrier status, demonstrating the potential of genomics for risk stratification of RA-ILD.

Palomäki A ，FinnGen Rheumatology Clinical Expert Group ，Palotie A ，Koskela J ，Eklund KK ，Pirinen M ，FinnGen ，Ripatti S ，Laitinen T ，Mars N ... -  《-》