Background/Purpose:

Val and Leu at HLA-DRB1 position 11 have been reported to be associated with radiographic progression in Caucasians with RA, independent of shared epitope status but not independent of ACPA status. In this study we examined the role of Val at position 11 in radiographic severity of RA in African Americans.

Methods:

DNA samples were directly sequenced for HLA-DRB1 and then aligned to call four digit resolution genotypes from seropositive (either RF or ACPA positive) RA patients from the Consortium for the Longitudinal Evaluation of African Americans with Rheumatoid Arthritis (CLEAR) Registry. Radiographic severity was defined as total Sharp/van der Heijde scores of hands/feet at study entry (mean (SD) disease duration 7.7 (9.4) years). Base models of van der Heijde modified total Sharp scores (N = 527) were fit using a negative binomial regression conditional on the covariates, sex, disease duration, BMI, local European ancestry at HLA-DRB1 (estimated using HAPMIX), and smoking. A second series of models were fit that included the covariates of the base model plus the presence of amino acid residues at 29 selected positions from 9 through 86. A third model was fit that included the base model’s covariates plus the presence of 21 four digit alleles with appreciable frequency in the patient sample. Significance tests were performed by log likelihood ratio tests of the full and base models.

Results:

From the base model, disease duration (P < 2.0E-16) was positively associated, and local ancestry was negatively associated (P = 0.032) with radiographic severity. Four digit alleles were significantly associated with radiographic severity (χ² = 41, DF = 21, P = 0.0056), but substitutions of residues at amino acid positions were not, after multiple testing correction. Val 11 was not associated with radiographic severity (P value = 0.55), but the study was well-powered (0.85) to detect the OR previously reported in Caucasians (1.75). HLA-DRB1 *04:01, *09:01, *13:03, and *16:02 were significantly associated with radiographic severity in this study. 

Conclusion:

In African Americans with seropositive RA, HLA-DRB1 alleles, but not Val 11, are associated with radiographic severity. Local European ancestry was negatively associated with radiographic damage, but did not modify the associations of the alleles with radiographic severity (χ² = 27, DF=21, P = 0.17). These findings have implications on the mechanisms of radiographic damage in RA.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-association-of-hla-drb1-alleles-and-amino-acid-residues-with-radiographic-severity-in-african-americans-with-seropositive-rheumatoid-arthritis/