Polygenic risk scores for rheumatoid arthritis and idiopathic pulmonary fibrosis and associations with RA, interstitial lung abnormalities, and quantitative interstitial abnormalities among smokers

Abstract

Objective

Genome-wide association studies (GWAS) facilitate construction of polygenic risk scores (PRSs) for rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). We investigated associations of RA and IPF PRSs with RA and high-resolution chest computed tomography (HRCT) parenchymal lung abnormalities.

Methods

Participants in COPDGene, a prospective multicenter cohort of current/former smokers, had chest HRCT at study enrollment. Using genome-wide genotyping, RA and IPF PRSs were constructed using GWAS summary statistics. HRCT imaging underwent visual inspection for interstitial lung abnormalities (ILA) and quantitative CT (QCT) analysis using a machine-learning algorithm that quantified percentage of normal lung, interstitial abnormalities, and emphysema. RA was identified through self-report and DMARD use. We investigated associations of RA and IPF PRSs with RA, ILA, and QCT features using multivariable logistic and linear regression.

Results

We analyzed 9,230 COPDGene participants (mean age 59.6 years, 46.4 % female, 67.2 % non-Hispanic White, 32.8 % Black/African American). In non-Hispanic White participants, RA PRS was associated with RA diagnosis (OR 1.32 per unit, 95 %CI 1.18–1.49) but not ILA or QCT features. Among non-Hispanic White participants, IPF PRS was associated with ILA (OR 1.88 per unit, 95 %CI 1.52–2.32) and quantitative interstitial abnormalities (adjusted β=+0.50 % per unit, p = 7.3 × 10⁻⁸) but not RA. There were no statistically significant associations among Black/African American participants.

Conclusions

RA and IPF PRSs were associated with their intended phenotypes among non-Hispanic White participants but performed poorly among Black/African American participants. PRS may have future application to risk stratify for RA diagnosis among patients with ILD or for ILD among patients with RA.