title: The HLA-DRB1 shared epitope alleles differ in the interaction with smoking and predisposition to antibodies to cyclic citrullinated peptide.
abstract: OBJECTIVE
  The HLA shared epitope (SE) alleles are primarily a risk factor for the presence of antibodies to cyclic citrullinated peptide (anti-CCP antibodies) rather than for the development of rheumatoid arthritis (RA). The SE alleles interact with the environmental risk factor tobacco exposure (TE) for predisposition to anti-CCP+ RA. The objectives of this study were to determine 1) whether different SE subtypes contribute differently to the presence of anti-CCP antibodies, 2) whether different SE subtypes all interact with TE for the development of anti-CCP antibodies, and 3) the effect of TE in relation to the SE alleles and anti-CCP antibodies on the risk of progression from undifferentiated arthritis (UA) to RA.
  
  
  METHODS
  We assessed the effect of SE subtypes and TE on the presence and level of anti-CCP antibodies and on the risk of progression from UA to RA in 977 patients with early arthritis who were included in the Leiden Early Arthritis Clinic.
  
  
  RESULTS
  The HLA-DRB1*0401, *0404, *0405, or *0408 SE alleles conferred the highest risk of developing anti-CCP antibodies (odds ratio [OR] 5.0, compared with an OR of 2.0 for the HLA-DRB1*0101 or *0102 SE alleles and an OR of 1.7 for the HLA-DRB1*1001 SE allele). Conversely, the TE-SE allele interaction was the strongest for the HLA-DRB1*0101 or *0102 SE alleles and the HLA-DRB1*1001 SE allele. TE in SE+, anti-CCP+ patients correlated with higher levels of anti-CCP antibodies and with progression from UA to RA. In logistic regression analysis, only the presence and level of anti-CCP antibodies were associated independently with RA development.
  
  
  CONCLUSIONS
  The HLA-DRB1 SE subtypes differ in their interaction with smoking and in their predisposition to anti-CCP antibodies. TE contributes to the development of RA in SE+, anti-CCP+ patients, which is explained by its effect on the level of anti-CCP antibodies.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Annette H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
authors.forename: Kirsten N
authors.initials: KN
authors.lastname: Verpoort
authors.forename: Saskia
authors.initials: S
authors.lastname: le Cessie
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: René R P
authors.initials: RR
authors.lastname: de Vries
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000906:Antibodies / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D015331:Cohort Studies; D018450:Disease Progression; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology* / Q000502:physiology; D011485:Protein Binding; D012307:Risk Factors; D012907:Smoking / Q000235:genetics* / Q000276:immunology; D014026:Nicotiana
chemical_list: D000906:Antibodies; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide