HLA-DRB1-associated rheumatoid arthritis risk at multiple levels in African Americans: hierarchical classification systems, amino acid positions, and residues.

Academic Article

Abstract

  • OBJECTIVE: To evaluate HLA-DRB1 genetic risk of rheumatoid arthritis (RA) in African Americans by 3 validated allele classification systems and by amino acid position and residue, and to compare genetic risk between African American and European ancestries. METHODS: Four-digit HLA-DRB1 genotyping was performed on 561 autoantibody-positive African American cases and 776 African American controls. Association analysis was performed on Tezenas du Montcel (TdM), de Vries (DV), and Mattey classification system alleles and separately by amino acid position and individual residues. RESULTS: TdM S2 and S3P alleles were associated with RA (odds ratio [95% confidence interval] 2.8 [2.0-3.9] and 2.1 [1.7-2.7], respectively). The DV (P = 3.2 × 10(-12)) and Mattey (P = 6.5 × 10(-13)) system alleles were both protective in African Americans. Amino acid position 11 (permutation P < 0.00001) accounted for nearly all variability explained by HLA-DRB1, although conditional analysis demonstrated that position 57 was also significant (0.01 ≤ permutation P ≤ 0.05). The valine and aspartic acid residues at position 11 conferred the highest risk of RA in African Americans. CONCLUSION: With some exceptions, the genetic risk conferred by HLA-DRB1 in African Americans is similar to that in individuals of European ancestry at multiple levels: classification system (e.g., TdM), amino acid position (e.g., 11), and residue (Val11). Unlike that reported for individuals of European ancestry, amino acid position 57 was associated with RA in African Americans, but positions 71 and 74 were not. Asp11 (odds ratio 1 in European ancestry) corresponds to the 4-digit classical allele *09:01, which is also a risk allele for RA in Koreans.
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    Keywords

  • Adult, African Americans, Alleles, Amino Acid Motifs, Amino Acids, Arthritis, Rheumatoid, Case-Control Studies, Epitopes, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, HLA-DRB1 Chains, Humans, Male, Middle Aged, Odds Ratio
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    Author List

  • Reynolds RJ; Ahmed AF; Danila MI; Hughes LB; Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis Investigators; Gregersen PK; Raychaudhuri S; Plenge RM; Bridges SL
  • Start Page

  • 3274
  • End Page

  • 3282
  • Volume

  • 66
  • Issue

  • 12