Associations of the MUC5B Promoter Variant with Timing of Interstitial Lung Disease and Rheumatoid Arthritis Onset

Objective To investigate the associations of the common MUC5B promoter variant with timing of RA-associated interstitial lung disease (RA-ILD) and RA onset. Methods We identified patients with RA meeting 2010 ACR/EULAR criteria and available genotype information in the Mass General Brigham Biobank, a multi-hospital biospecimen and clinical data collection research study. We determined RA-ILD presence by reviewing all RA patients who had computed tomography (CT) imaging, lung biopsy, or autopsy results. We determined the dates of RA and RA-ILD diagnoses by manual record 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 (OR) for each outcome by MUC5B promoter variant status, adjusting for potential confounders including genetic ancestry and smoking. Results We identified 1,005 RA patients with available genotype data for rs35705950 (mean age 45 years; 79% women; 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%1.78-8.80]), and RA onset after age 55 years (OR 1.52, [95%CI 1.08-2.12]). Conclusions 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 MUC5B may impact RA-ILD risk early in the RA disease course, particularly in patients with older-onset RA.