Molecular Medicine

, Volume 14, Issue 5–6, pp 293–300 | Cite as

Several Regions in the Major Histocompatibility Complex Confer Risk for Anti-CCP-Antibody Positive Rheumatoid Arthritis, Independent of the DRB1 Locus

  • Hye-Soon Lee
  • Annette T. Lee
  • Lindsey A. Criswell
  • Michael F. Seldin
  • Christopher I. Amos
  • John P. Carulli
  • Cristina Navarrete
  • Elaine F. Remmers
  • Daniel L. Kastner
  • Robert M. Plenge
  • Wentian Li
  • Peter K. Gregersen
Research Article


Recent evidence suggests that additional risk loci for RA are present in the major histocompatibility complex (MHC), independent of the class II HLA-DRB1 locus. We have now tested a total of 1,769 SNPs across 7.5Mb of the MHC located from 6p22.2 (26.03 Mb) to 6p21.32 (33.59 Mb) derived from the Illumina 550K Beadchip (Illumina, San Diego, CA, USA). For an initial analysis in the whole dataset (869 RA CCP + cases, 1,193 controls), the strongest association signal was observed in markers near the HLA-DRB1 locus, with additional evidence for association extending out into the Class I HLA region. To avoid confounding that may arise due to linkage disequilibrium with DRB1 alleles, we analyzed a subset of the data by matching cases and controls by DRB1 genotype (both alleles matched 1:1), yielding a set of 372 cases with 372 controls. This analysis revealed the presence of at least two regions of association with RA in the Class I region, independent of DRB1 genotype. SNP alleles found on the conserved A1-B8-DR3 (8.1) haplotype show the strongest evidence of positive association (P ~ 0.00005) clustered in the region around the HLA-C locus. In addition, we identified risk alleles that are not present on the 8.1 haplotype, with maximal association signals (P ~ 0.001–0.0027) located near the ZNF311 locus. This latter association is enriched in DRB1*0404 individuals. Finally, several additional association signals were found in the extreme centromeric portion of the MHC, in regions containing the DOB1, TAP2, DPB1, and COL11A2 genes. These data emphasize that further analysis of the MHC is likely to reveal genetic risk factors for rheumatoid arthritis that are independent of the DRB1 shared epitope alleles.



Support was provided by the National Institutes of Health, RO1-AR44222 and U19 IMAGEN. The research also was supported in part by the intramural program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, as well as the Eileen Ludwig Greenland Center for Rheumatoid Arthritis at the Feinstein Institute. LAC is supported by R01 AI065841.

Supplementary material

10020_2008_1405293_MOESM1_ESM.pdf (412 kb)
Several Regions in the Major Histocompatibility Complex Confer Risk for Anti-CCP-Antibody Positive Rheumatoid Arthritis, Independent of the DRB1 Locus


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Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Hye-Soon Lee
    • 1
    • 2
    • 10
  • Annette T. Lee
    • 1
    • 10
  • Lindsey A. Criswell
    • 3
    • 10
  • Michael F. Seldin
    • 4
    • 10
  • Christopher I. Amos
    • 5
    • 10
  • John P. Carulli
    • 6
    • 10
  • Cristina Navarrete
    • 7
    • 10
  • Elaine F. Remmers
    • 8
    • 10
  • Daniel L. Kastner
    • 8
    • 10
  • Robert M. Plenge
    • 9
    • 10
  • Wentian Li
    • 1
    • 10
  • Peter K. Gregersen
    • 1
    • 10
  1. 1.Feinstein Institute for Medical Research, North Shore LIJ Health SystemRobert S. Boas Center for Genomics and Human GeneticsManhassetUSA
  2. 2.Hanyang University College of MedicineSeoulSouth Korea
  3. 3.The University of California San FranciscoSan FranciscoUSA
  4. 4.the University of California DavisDavisUSA
  5. 5.M.D. Anderson Cancer CenterThe University of TexasHoustonUSA
  6. 6.Biogen Idec Inc.CambridgeUSA
  7. 7.National Blood ServiceLondonUK
  8. 8.The National Institute of Arthritis and Musculoskeletal and Skin DiseasesBethesdaUSA
  9. 9.The Broad Institute of Harvard and the Massachusetts Institute of TechnologyCambridgeUSA
  10. 10.Division of Rheumatology, Immunology and Allergy, Department of MedicineBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA

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