Genomic and Serological Rheumatoid Arthritis Biomarkers, MUC5B Promoter Variant, and Interstitial Lung Abnormalities

Abstract

Rationale: Rheumatoid arthritis (RA) has been implicated in interstitial lung disease (ILD) as majority of studies have been comprised of patients with known RA. However, it remains unclear whether an underlying risk for RA in combination with genetic risk for pulmonary fibrosis is associated with radiological markers of early lung injury and fibrosis in broader population samples.

Objective: Determine whether genetic and serological biomarkers of RA risk in combination with the MUC5B (rs35705950) risk allele (T) are associated with interstitial lung abnormalities (ILA) on computed tomography (CT) scans.

Methods: Associations of RA-risk HLA-DRB1 alleles (*04:01, *04:08, *04:05, *04:04, *10:01) and serum RA autoantibodies with ILA in the Multi-Ethnic Study of Atherosclerosis (MESA, n=4,018) and COPDGene (n=5,963) cohorts were modeled using logistic regression and adjusted for age, sex, self-reported race and ethnicity, smoking history, body mass index, and principal components of genetic ancestry.

Results: The prevalence of an RA risk HLA-DRB1 allele was 16.5% and 21.9% in MESA and COPDGene, respectively. ILA was present in 3.9% and 11% in MESA and COPDGene, respectively. An RA risk HLA-DRB1 allele was not significantly associated with ILA in MESA and COPDGene. In MESA, higher serum levels of IgA rheumatoid factor (RF) and anti-cyclic citrullinated peptide were associated with an odds ratio (OR) for ILA of 1.20 (95% CI 1.07-1.35) and 1.19 (95% CI 1.04-1.37), respectively. Among smokers without baseline ILA, per doubling of IgM RF was associated with an OR for ILA 10 years later of 1.25 (95% CI 1.08-1.43). Associations were not significantly different by MUC5B risk allele status.

Conclusions: RA-related HLA-DRB1 alleles were not associated with ILA, whereas higher serum levels of IgM RF among smokers without baseline ILA were associated with subsequent ILA.