title: HLA-C alleles confer risk for anti-citrullinated peptide antibody-positive rheumatoid arthritis independent of HLA-DRB1 alleles.
abstract: OBJECTIVE
  The MHC exerts the greatest contribution to RA susceptibility, where certain HLA-DRB1 alleles confer the greatest risk. Interestingly, there is evidence for more risk factors in the MHC with regions surrounding the HLA class I loci, but whether these antigen-presenting loci could be causal risk variants has not been directly investigated. In this study we investigate the HLA association by direct genotyping of the HLA loci.
  
  
  METHODS
  Nine hundred and fifty RA patients and 933 healthy controls were genotyped for HLA-A, -B and -C. Eleven single-nucleotide polymorphisms (SNPs) and one insertion/deletion in the MHC were also included. Conditional logistic regression analyses were performed separately in ACPA-positive and -negative RA to identify the strongest susceptibility locus and additional risk loci.
  
  
  RESULTS
  In ACPA-positive RA, the most significantly associated locus was HLA-DRB1 (P = 1.58 × 10(-54)), with SE alleles being predisposing. After controlling for HLA-DRB1, the HLA-C locus was found to confer susceptibility (P = 2.32 × 10(-9)), particularly, the HLA-C*03 allele. Also, in ACPA-negative RA, HLA-DRB1 was the most significant locus (P = 7.22 × 10(-9)), but with other risk alleles (particularly DRB1*03). A possible independent involvement of HLA-C was also observed for ACPA-negative RA (P = 0.02).
  
  
  CONCLUSIONS
  HLA-DRB1 was the major MHC risk locus in both ACPA-positive and ACPA-negative RA, but with allelic risk heterogeneity. Joint analyses of the HLA class I loci together with previously proposed SNP associations pointed at HLA-C as a second susceptibility locus in ACPA-positive RA.
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Postboks 4956 Nydalen, 0424 Oslo, Norway. b.a.lie@medisin.uio.no.
authors.forename: Gry B N
authors.initials: GB
authors.lastname: Nordang
authors.forename: Siri T
authors.initials: ST
authors.lastname: Flåm
authors.forename: Marthe T
authors.initials: MT
authors.lastname: Maehlen
authors.forename: Tore K
authors.initials: TK
authors.lastname: Kvien
authors.forename: Marthe K
authors.initials: MK
authors.lastname: Viken
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D015236:HLA-C Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006650:Histocompatibility Testing / Q000379:methods; D006801:Humans; D010456:Peptides, Cyclic / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D015236:HLA-C Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide
keywords: HLA-C; HLA-DRB1; MHC; RA; genetic risk