Genetic variation of the alpha-1-antitrypsin gene is associated with increased autoantibody production in rheumatoid arthritis

Objective. To examine the prevalence of alpha(1)-antitrypsin deficiency (AATD) in rheumatoid arthritis (RA), and to determine whether AATD is associated with higher levels of rheumatoid factor (RF), antinuclear antibodies (ANAs), and anti-citrullinated peptide autoantibodies (ACPAs). Methods. RF, ANAs, and ACPAs were measured by standard immunoturbidimetry, immunofluorescence assay, and enzyme-linked immunosorbent assay, respectively. Characterization of AAT phenotypes was performed by isoelectric focusing and immunofixation. The chi-square test with Yates' correction and the Mann-Whitney U test were used to assess the prevalence of alleles associated with AATD in RA and to compare mean antibody titers, respectively. Results. Of 246 patients with RA, 24 who were heterozygous for AATD were identified, with no statistically significant difference in the prevalence of AATD between RA patients and the general population (P=0.39). A positive association between heterozygosity for AATD and the production of ACPAs was observed (P<0.0001), with increased ACPA titers recorded in the AATD RA cohort compared with the general population (P=0.01). Conclusion. AAT heterozygous status in RA is strongly associated with positive ACPAs and may define a distinct subset of patients with increased disease severity.