Uncovering specific genetic-respiratory disease endotypes for rheumatoid arthritis risk.

OBJECTIVE

We aimed to identify specific genetic-respiratory disease endotypes for rheumatoid arthritis (RA) risk.

METHODS

This case-control study used the Mass General Brigham (MGB) and Mayo Clinic (MC) Biobanks for discovery and replication, respectively. We matched criteria-confirmed incident RA cases to four non-RA controls on age, sex and health record history. Genetic exposures included the top 11 RA risk alleles, and a validated human leucocyte antigen (HLA) genetic risk score (GRS). We identified seven respiratory diseases by codes. Using logistic regression models adjusting for potential confounders, we estimated Rs with 95% CIs for the interactions between genetic and respiratory exposures for RA risk.

RESULTS

We identified 653 RA cases and 2607 controls in MGB, and 428 incident RA cases and 1712 non-RA controls in MC (mean age 64, 69% female). Respiratory diseases were associated with an increased risk of RA (OR 1.34, 95% CI 1.05, 1.71). Six out of 11 non-HLA RA risk alleles interacted strongly with specific respiratory diseases for RA risk, including NFKBIE and sinusitis (OR 5.49, 95% CI 1.56, 19.4 MGB; 5.26, 95% CI 2.00, 13.86 MC) and FAM167A and acute sinusitis for seronegative RA (OR 6.00, 95% CI 2.09, 17.24 MGB; 4.90, 95% CI 1.71, 14.1 MC). The RA HLA GRS interacted synergistically with interstitial lung disease for RA risk (OR 5.41, 95% CI 2.71, 10.8 in MC), with DPB1*02:01, DRB1*16:01 and DRB1*04:04 best predicting RA (positive predictive value 61%).

CONCLUSION

Several genetic-respiratory disease interactions strongly drive RA onset. If confirmed, these novel associations may reflect RA endotypes that can facilitate individualised prevention, diagnosis and treatment.