A large genome-wide association study (GWAS) of U.S. veterans with rheumatoid arthritis (RA) has identified 5 novel single nucleotide polymorphisms (SNPs) associated with interstitial lung disease (ILD) in RA, building on the known risk conferred by the MUC5B promoter variant, according to an abstract represented at ACR Convergence. 

Using data from the Veterans Affairs Rheumatoid Arthritis (VARA) registry, the study included 3295 participants, of whom 345 had confirmed RA-ILD. Participants were genotyped using the Illumina Global Screening Array, and GWAS was performed with adjustment for ancestry and quality control thresholds.

As expected, MUC5B rs35705950 was the strongest risk variant for RA-ILD. However, 5 additional SNPs reached genome-wide suggestive significance and were mapped to PTPRT (chr20), GGT1 (chr22), NUP205 (chr7), PGBD1 (chr6), and a predicted enhancer near CDH5 (chr16).

“The strongest of these novel variants was rs191761566 on chromosome 20 in the PTPRT gene,” the authors reported. PTPRT is implicated in the STAT3 signaling pathway and is known to influence lung cancer response to immune checkpoint inhibitors.

The researchers also constructed a genetic risk score (GRS) incorporating all six SNPs. The GRS significantly improved discrimination of ILD risk compared to MUC5B alone, with an AUC of 0.67 (95% CI, 0.64–0.70) versus 0.57 (95% CI, 0.54–0.59) for MUC5B (p < 0.001).

“In addition to the well-established MUC5B promoter variant, this GWAS identified several other novel SNPs within genes and regions that have potential pathophysiologic connections to ILD,” the authors concluded.

For rheumatologists, these findings suggest that expanded genetic profiling could enhance ILD risk stratification in RA and inform future strategies for early detection and personalized management.

Reference
Wheeler A, Riley T, Takei R, et al. Genome-wide association study identifies novel genetic risk factors for rheumatoid arthritis-associated interstitial lung disease [abstract]. Arthritis Rheumatol. 2025; 77 (suppl 9). https://acrabstracts.org/abstract/genome-wide-association-study-identifies-novel-genetic-risk-factors-for-rheumatoid-arthritis-associated-interstitial-lung-disease/