Background/Purpose: Rheumatoid arthritis (RA) is a systematic autoimmune disease caused by the interplay between environmental and genetic risk factors. The major genetic determinants of RA susceptibility comprise a group of alleles of the HLA DRB1 gene, which encode a similar amino-acid (aa) motif in the peptide binding groove of the beta chain and are collectively referred to as the shared epitope (SE). Several studies investigated different classifications of HLA-DRB1 alleles and their association with disease susceptibility. Recently, we reported a new classification system based on 3 HLA-DRB1 aa independently associated with RA susceptibility. We demonstrated that HLA-DRB1 haplotypes defined solely by aa at positions 11, 71 and 74 can be hierarchically classified regarding their effect size on RA susceptibility, ranging from risk to protective haplotypes. The impact of this classification on the prediction of radiological outcome in RA has not been studied so far.

Aims: To test whether the RA risk hierarchy within HLA-DRB1 haplotypes also associates with radiological outcome.

Methods: The Norfolk Arthritis Register (NOAR) is a primary care based inception cohort of patients with inflammatory polyarthritis (IP). Radiographs of the hands and feet were performed at baseline, year 1 and year 2 for some patients, and systematically at year 5 for all patients and scored using the Larsen technique. The HLA region of a subset of NOAR patients was densely genotyped using a custom Illumina® Infinium® array (ImmunoChip), imputed and HLA-DRB1 aa at positions 11, 71 and 74 were derived. In order to incorporate multiple records per patient over time and to fit the non-normal distribution of Larsen scores, Generalized Linear Latent and Mixed Modelling (GLLAMM) with discrete random effects and three latent classes was used to assess the association between Larsen score and HLA-DRB1 haplotypes longitudinally.

Results: 1685 NOAR patients had at least one x-ray available and 4-digit HLA-DRB1 typing with a total of 2796 x-rays. Of these, 482 were genotyped on the ImmunoChip platform. HLA-DRB1 haplotypes based on positions 11, 71 and 74 were grouped in 3 haplotype categories, based on their known effect on disease susceptibility (risk, neutral or protective). Preliminary multivariate haplotype group analysis showed a correlation between known effect sizes for susceptibility and effect sizes for severity. The protective group of HLA-DRB1 haplotypes on RA susceptibility (Ser-Lys-Arg or Ser-Glu-Ala at 11, 71, 74, corresponding to HLA-DRB1*03:01, *11:02, *11:03, *13:01, *13:02) is protective for the development of radiological damage as well, independently of the SE.

Conclusion: Susceptibility HLA-DRB1 haplotypes define severity haplotypes as well. Protective HLA-DRB1 haplotypes on radiological severity were also identified. Since the effect size of HLA-haplotypes is likely to outweigh the effect of non-HLA single nucleotide polymorphisms in the prediction of disease outcome, our findings may be relevant in stratifying patients into different risk categories prior to the initiation of treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hla-drb1-rheumatoid-arthritis-susceptibility-amino-acids-define-haplotypes-associated-with-radiological-outcome/