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 3.75 [95%CI 2.02-6.84]), RA-ILD before or within 2 years of RA diagnosis (OR 6.25 [95%CI 2.24-18.20]), and RA onset after age 55 years (OR 1.53, [95%CI 1.06-2.20]).

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.