title: Different patterns of associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in the extended major histocompatibility complex region.
abstract: OBJECTIVE
  To identify additional variants in the major histocompatibility complex (MHC) region that independently contribute to risk in 2 disease subsets of rheumatoid arthritis (RA) defined according to the presence or absence of antibodies to citrullinated protein antigens (ACPAs).
  
  
  METHODS
  In a multistep analytical strategy using unmatched as well as matched analyses to adjust for HLA-DRB1 genotype, we analyzed 2,221 single-nucleotide polymorphisms (SNPs) spanning 10.7 Mb, from 6p22.2 to 6p21.31, across the MHC. For ACPA-positive RA, we analyzed samples from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) and the North American Rheumatoid Arthritis Consortium (NARAC) studies (totaling 1,255 cases and 1,719 controls). For ACPA-negative RA, we used samples from the EIRA study (640 cases and 670 controls). Plink and SAS statistical packages were used to conduct all statistical analyses.
  
  
  RESULTS
  A total of 299 SNPs reached locus-wide significance (P<2.3x10(-5)) for ACPA-positive RA, whereas surprisingly, no SNPs reached this significance for ACPA-negative RA. For ACPA-positive RA, we adjusted for known DRB1 risk alleles and identified additional independent associations with SNPs near HLA-DPB1 (rs3117213; odds ratio 1.42 [95% confidence interval 1.17-1.73], Pcombined=0.0003 for the strongest association).
  
  
  CONCLUSIONS
  There are distinct genetic patterns of MHC associations in the 2 disease subsets of RA defined according to ACPA status. HLA-DPB1 is an independent risk locus for ACPA-positive RA. We did not identify any associations with SNPs within the MHC for ACPA-negative RA.
authors.affiliation: Karolinska Institutet, Stockholm, Sweden. Bo.Ding@ki.se
authors.forename: Bo
authors.initials: B
authors.lastname: Ding
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Emeli
authors.initials: E
authors.lastname: Lundström
authors.forename: Mark
authors.initials: M
authors.lastname: Seielstad
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
mesh_terms: D000918:Antibody Specificity; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D002956:Citrulline; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D015810:Linkage Disequilibrium; D010456:Peptides, Cyclic / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D001323:Autoantibodies; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D002956:Citrulline