Abstract
Background: Rheumatoid arthritis (RA) is a complex autoimmune disease involving gene-environment interactions. Different subtypes of RA, based on the presence of specific antibodies, differ in each etiology. Interacting effects have been found in HLA-DRB1 shared epitope alleles with smoking, in relation to the increased risk of one subgroup of RA.
Aims: To identify interactions involving imputed amino acids in HLA proteins and smoking regarding risk of developing serologically defined subgroups of rheumatoid arthritis.
Methods: Two materials respectively including 3000 and 4337 individuals aged 18-70 recruited during 1996-2009 from the EIRA study, a population-based case-control study were used for this investigation. Serum antibodies against cyclic citrullinated peptide (CCP) were examined to decide subtypes of RA. We used 8961 genetic markers in HLA that were imputed from a reference panel based on individuals of European decent. Lifestyle variables including smoking were obtained from questionnaires. We used logistic regression to estimate odds ratios regarding risk of developing different subgroups of RA. We used attributable proportion to estimate interaction between genetic markers and smoking with consideration taken to genetic models.
Results: 48 amino acid positions in HLA-DRB1, DQA1, DQB1 regions were associated with interacting effects with smoking in ACPA-positive RA. Results are similar in two materials, and 22 remained after controlling for shared epitope
alleles in DRB1. No SNPs or interacting effect were found significant in ACPA-negative RA after correction for multiple testing.
Conclusion: The study found interacting effects in HLA proteins independent of shared epitope alleles with smoking, in relation to the risk of development of ACPA-positive RA.
