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.

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.

Figure 1

TdM classified HLA DRB1 genotypic and allelic odds ratios of RA risk compared between Europeans and African Americans. Confidence limits (Cl) along y-axis correspond to African Americans from the CLEAR registry and CI limits along x-axis correspond to European SE OR reported by Morgan et al. The black (white) filled circles are allelic (genotypic) odds ratios. The 1:1 dotted line indicates equivalent odds ratios between ethnicities. All genotypic odds ratios are significantly different from the referent genotype, L/L, except for African American S2/S2. The inserted graph in the upper right hand quadrant of the figure zooms in on the region defined by OR less than four.

Figure 2

Permutation test distribution of deviance statistics under the null hypothesis (top) that there is no correlation between any tested amino acid position and RA and (bottom) that there is no correlation between any tested position after accounting for the effect due to position 11.

Figure 3

Univariate odds ratios (95% CI) for amino acid positions 11 and 57 associated significantly with RA in African African Americans. Bar plots show frequency of reference alleles between cases and controls.