A new U.S.-based case-control study integrating genomic and environmental data, presented at ACR Convergence, has demonstrated that combining polygenic risk scores (PRS) with air pollutant exposure can more accurately predict the risk of developing rheumatoid arthritis (RA). Notably, lead and fine particulate matter (PM2.5) emerged as strong environmental risk factors, while higher education and income were protective.

“Given the rising pollution level, it is essential to integrate environmental and genetic factors to better identify individuals at risk for RA and to inform prevention strategies,” the authors wrote.

Using data from the NIH All of Us v8 database, the study included 283 incident RA cases and 2,830 matched controls. RA was defined based on a combination of ICD-9/10 diagnosis codes, prescription of RA-specific medications, and exclusion of overlapping autoimmune conditions, with all cases requiring at least one year of prior EHR data.

Participants with short-read whole genome sequencing (srWGS) data were analyzed. Genetic risk was calculated using a PRS based on 92 known RA-associated variants. Environmental exposures were derived from long-term annual air pollution data from the EPA (1980–2024), assessed at the 3-digit ZIP code level.

Key findings included:

• Polygenic risk score (PRS): Associated with increased RA risk (HR = 1.25; 95% CI: 1.12–1.40)

• Lead exposure: Strongest environmental risk factor (HR = 6.76; 95% CI: 2.00–22.82)

• PM2.5 exposure: Also significantly associated (HR = 1.38; 95% CI: 1.30–1.46)

• SO₂ and ozone: Modest but significant associations

• NO₂: Unexpectedly linked to reduced RA risk (HR = 0.93; 95% CI: 0.90–0.96)

• Socioeconomic factors: Higher income and education levels were protective

• Smoking and ambient pressure: Not significantly associated

The combined model of PRS and air pollutant exposures yielded the best predictive performance, with an integrated area under the curve (iAUC) of 0.72 (95% CI: 0.70–0.76), outperforming PRS-only models (iAUC = 0.66).

“Integrating PRS with air pollutants enhances the prediction of RA incidence. Notably, lead and PM2.5 exhibited the strongest associations with increased risk for RA,” the authors concluded. “These findings underscore the importance of combined genetic and environmental assessments in identifying individuals at elevated risk for RA.”

Reference
Zhao X, Nepa P, Yu H, et al. Genetic and environmental risk factors and incident rheumatoid arthritis [abstract]. Arthritis Rheumatol. 2025; 77 (suppl 9). https://acrabstracts.org/abstract/genetic-and-environmental-risk-factors-and-incident-rheumatoid-arthritis/ Accessed October 15, 2025.