HLA-C alleles confer risk for anti-citrullinated peptide antibody-positive rheumatoid arthritis independent of HLA-DRB1 alleles

Rheumatology (Oxford). 2013 Nov;52(11):1973-82. doi: 10.1093/rheumatology/ket252. Epub 2013 Jul 30.


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).

Conclusion: 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.

Keywords: HLA-C; HLA-DRB1; MHC; RA; genetic risk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology
  • Autoantibodies / blood*
  • Biomarkers / blood
  • Case-Control Studies
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • HLA-C Antigens / genetics*
  • HLA-DRB1 Chains / genetics*
  • Histocompatibility Testing / methods
  • Humans
  • Peptides, Cyclic / immunology*
  • Polymorphism, Single Nucleotide


  • Autoantibodies
  • Biomarkers
  • HLA-C Antigens
  • HLA-DRB1 Chains
  • Peptides, Cyclic
  • cyclic citrullinated peptide