title: Contribution of a haplotype in the HLA region to anti-cyclic citrullinated peptide antibody positivity in rheumatoid arthritis, independently of HLA-DRB1.
abstract: OBJECTIVE
  To examine the risk of anti-cyclic citrullinated peptide (anti-CCP) antibody positivity in rheumatoid arthritis (RA) patients carrying certain haplotypes in the HLA region.
  
  
  METHODS
  A total of 1,389 Japanese patients with RA were genotyped for 30 single-nucleotide polymorphisms (SNPs) in the HLA region using commercial oligonucleotide arrays (from Perlegen or Affymetrix) as well as for HLA-DRB1 alleles using a sequence-specific polymerase chain reaction method. Stepwise logistic regression was used to select from among the 30 SNPs the ones that represented a risk of anti-CCP antibody positivity. Haplotypes of the selected SNPs were inferred using an expectation-maximization algorithm. Associations of individual SNPs were evaluated with the Cochran-Armitage test for trend. DRB1 alleles and haplotypes were evaluated with the chi-square test. Heterogeneities of risks among the shared epitope (SE) and non-SE HLA-DRB1 alleles were examined using the exact test. Haplotype associations that were independent of individual HLA-DRB1 alleles were evaluated using the likelihood ratio test.
  
  
  RESULTS
  Significant associations were found for 9 SNPs (smallest P value being 2.4x10(-8)) and in 4 HLA-DRB1 alleles (smallest P value being 2.0x10(-10) in DRB1*0405). Stepwise logistic regression selected 4 SNPs (rs9262638, rs7775228, rs4713580, and rs9277359). Among the 16 inferred haplotypes of these 4 SNPs, 6 indicated significant associations (smallest P value being 1.9x10(-11)). Risks among SE and non-SE alleles were significantly heterogeneous (P=0.0095 and P=9.8x10(-9), respectively), indicating the importance of stratification with individual DRB1 alleles rather than SE alleles. Conditional analysis of the risk associated with individual DRB1 alleles identified a risk haplotype that was independent of DRB1 (odds ratio 2.00 [95% confidence interval 1.44-2.79], P=2.6x10(-5)).
  
  
  CONCLUSIONS
  Heterogeneous risks of anti-CCP antibody positivity were confirmed among SE and non-SE alleles in our patient population. A risk haplotype in the HLA region that is independent of HLA-DRB1 was confirmed.
authors: Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors: Yukinori
authors: Y
authors: Okada
authors: Ryo
authors: R
authors: Yamada
authors: Akari
authors: A
authors: Suzuki
authors: Yuta
authors: Y
authors: Kochi
authors: Kenichi
authors: K
authors: Shimane
authors: Keiko
authors: K
authors: Myouzen
authors: Michiaki
authors: M
authors: Kubo
authors: Yusuke
authors: Y
authors: Nakamura
authors: Kazuhiko
authors: K
authors: Yamamoto
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D000939:Epitopes / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide