Background/Purpose: The strongest genetic risk for rheumatoid arthritis (RA) is contributed from the HLA region. RA-risk associated HLA-DRB1 alleles including *04:01/4/5/8, *01:01, *10:01, and *14:02 code for the ‘Shared Epitope’ (SE) motif of the DRβ1 third hypervariable region. In an individual’s genotype, different combinations of SE and non-SE alleles contribute differently to RA-risk, as has been delineated in a table of Odds Ratios (OR) in a prior publication (1). Other studies have pointed to the importance in RA of specific DQA1‒DQB1 allele combinations in linkage disequilibrium (LD) with SE alleles that have been referred to as DQ5.1, DQ7.3, and DQ8 (2, 3). Interestingly, these particular DQ molecules, but not other DQs or DRs, bind certain peptides involved in autoantibody-positive RA (3). In the current study we investigated RA risk according to the DQ genotype and evaluated combinations of DQ molecules for hierarchy in RA risk.

Methods: 314 RA patients meeting 1988 ACR criteria and 316 controls from Washington State (USA) and the surrounding area were genotyped for DRB1‒DQA1‒DQB1 haplotypes. DQA1 and DQB1 combinations were classified into 10 groups based on functional relevance and most frequent LD with DRB1: DQ5.1 (LD: DRB1*01), DQ5.2/3 (LD: DRB1*14 and *16), DQ6.1/2 (LD: DRB1*15), DQ6.3/4/5/9 (LD: DRB1*13, RA protective), DQ2 (LD: DRB1*03 and *07, both RA protective), DQ7.3 (LD: DRB1*04), DQ7.5/6 (LD: DRB1*11 and *12), DQ8 (LD: DRB1*04), DQ9 (LD: DRB1*07 and *09), and DQ4 (LD: DRB1*08). ORs for RA-risk were calculated for 48 of 55 possible combinations accounting for 97% of subjects.

Results: The genotypic OR [and 95% confidence intervals] for developing RA based on DQ ranged from 24.9 [4.63‒259.0] to 0.16 [0.04‒0.64]. The risk was generally significant when an individual carried simultaneously 2 of the 3 DQs in linkage with the SE (DQ5.1, DQ7.3 and DQ8), and was alleviated when the second DQ was no longer of those 3. DQ2 provided significant protection when combined with itself, DQ6.3/4/5/9, or DQ7.5/6, which are in linkage with DRB1 alleles previously associated with protection against RA.

Conclusion: The risk of developing RA is influenced by both HLA-DQ alleles in the genotype. ORs varied according to particular combinations of DQ molecules. These observations considered along with recognition that HLA molecules present peptides derived from other (self) HLA molecules point to likely functional significance of HLA-DQ molecules in RA risk.

References:

1. N. Balandraud et al., PLOS ONE. 8, e64108 (2013).
2. E. Zanelli, C. J. Krco, J. M. Baisch, S. Cheng, C. S. David, PNAS. 93, 1814–1819 (1996).
3. J. van Heemst et al., Nature Communications. 6, 6681 (2015).

Funding: This work was supported by NIH grants HL117737 and AI 45659.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-risk-of-developing-rheumatoid-arthritis-based-on-hla-dq-genotypes/