title: HLA-DRB1-associated rheumatoid arthritis risk at multiple levels in African Americans: hierarchical classification systems, amino acid positions, and residues.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Alabama at, Birmingham.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Reynolds
authors.forename: Altan F
authors.initials: AF
authors.lastname: Ahmed
authors.forename: Maria I
authors.initials: MI
authors.lastname: Danila
authors.forename: Laura B
authors.initials: LB
authors.lastname: Hughes
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: S Louis
authors.initials: SL
authors.lastname: Bridges
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D020816:Amino Acid Motifs / Q000235:genetics; D000596:Amino Acids; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D000939:Epitopes / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D044465:White People / Q000235:genetics*
chemical_list: D000596:Amino Acids; D000939:Epitopes; D059811:HLA-DRB1 Chains