title: Interaction of HLA-DRB1*09:01 and *04:05 with smoking suggests distinctive mechanisms of rheumatoid arthritis susceptibility beyond the shared epitope.
abstract: OBJECTIVE
  Although HLA-DRB1 shared epitope (SE) alleles and HLA-DRB1*09:01 have repeatedly been shown to be associated with susceptibility to rheumatoid arthritis (RA), the effect of each allele on levels of anticyclic citrullinated peptide autoantibodies (anti-CCP) and interaction with cigarette smoking in RA remains to be fully defined. We investigated whether HLA-DRB1 risk alleles influence anti-CCP levels and whether each allele interacts with smoking in anti-CCP-positive or -negative RA.
  
  
  METHODS
  All patients with RA (n = 1924) and controls (n = 1119) were Korean. The HLA-DRB1 4-digit genotyping was performed by standard PCR-sequencing based typing method. OR and biologic interactions as departures from additivity or multiplicity were analyzed by logistic regression.
  
  
  RESULTS
  SE alleles were significantly associated with increased anti-CCP levels. Conversely, HLA-DRB1*09:01 was associated with reduced levels, in both SE-positive and SE-negative patients. Each of SE alleles interacted significantly with smoking, whereas HLA-DRB1*09:01 did not. Interactions between the 2 most significant risk alleles, HLA-DRB1*04:05 and HLA-DRB1*09:01, (attributable proportion = 0.68, 95% CI 0.46-0.89, multiplicity p = 0.012) significantly increased RA susceptibility regardless of anti-CCP and smoking status. Smoking increased the risk for RA by significant interaction with the heterozygote HLA-DRB1*04:05/*09:01.
  
  
  CONCLUSIONS
  HLA-DRB1*09:01 differs from SE alleles with regard to anti-CCP levels and interaction with smoking, suggesting a distinct mechanism of HLA-DRB1*09:01 in the pathogenesis of RA that may bypass anti-CCP formation. Also, a significant increase of the HLA-DRB1*04:05/ *09:01 heterozygote in RA susceptibility may be attributable to the synergistic contribution of 2 different pathways in which 2 alleles participate independently.
authors: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea.
authors: So-Young
authors: SY
authors: Bang
authors: Hye-Soon
authors: HS
authors: Lee
authors: Kyung Wha
authors: KW
authors: Lee
authors: Sang-Cheol
authors: SC
authors: Bae
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000235:genetics; D012217:Rheumatoid Factor / Q000235:genetics; D012907:Smoking / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D059811:HLA-DRB1 Chains; C493960:HLA-DRB1*04:05 antigen; C487381:HLA-DRB1*09:01 antigen; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor
keywords: ANTICITRULLINATED PROTEIN AUTOANTIBODIES; HLA-DRB1*09:01; RHEUMATOID ARTHRITIS; SHARED EPITOPE; SMOKING