Influence of human leukocyte antigen-DRB1 on the susceptibility and severity of rheumatoid arthritis

Background and Objectives: All human leukocyte antigen (HLA)-DRB1 alleles associated with rheumatoid arthritis (RA) encode a conserved amino acid sequence (QKRAA, QRRAA, or RRRAA) at position 70-74 in the third hypervariable region (HVR3) of the DRbeta(1) chain, which is commonly called the shared epitope (SE). Several studies, however, have associated the HLA-DRB1 gene in RA severity and progression rather than with susceptibility. Moreover, the association with disease severity and presence of the SE varies among different ethnic populations. HLA-DRB1 alleles also influence the disease onset. In this manuscript, the role of the HLA genes in RA was examined. Methods: A retrospective review of the literature was conducted to analyze the influence of the HLA-class II genes on the susceptibility, severity and protection against RA. Results:The HLA-DRB1*0401/*0404 genotype was associated with a higher risk for early disease onset in more severe forms in patients from the United Kingdom (UK). In northwest Spain, RA onset under 40 years is strongly associated with HLA-DRB1*0401 and *0404. In contrast, RA onset above 60 years is associated with HLA-DRB1*01. The protection against RA linked to some HLA-DRB1 alleles encoding a DERAA sequence of amino acids at position 70-74 in the HVR3 of the DRbeta1 chain, and specifically aspartic acid (D) at position 70 of this chain, recently was confirmed in both UK and northwest Spanish populations. Besides HLA-class II, other genes may be implicated in RA. Polymorphism in the tumor necrosis factor (TNF) region seems to be associated with RA, even in patients without the HLA-DRB1 SE. However, other genes such as interleukin-1 (IL-1) and corticotropin-releasing hormone may play a role in susceptibility to RA. Conclusions: The additive effect of various genes may account for the development of RA and its clinical severity.