title: Influence of human leukocyte antigen-DRB1 on the susceptibility and severity of rheumatoid arthritis.
abstract: OBJECTIVE
  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.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gonzalez-Gay
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Porrua
authors.forename: Ali H
authors.initials: AH
authors.lastname: Hajeer
mesh_terms: D001172:Arthritis, Rheumatoid / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D000939:Epitopes / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D012720:Severity of Illness Index
chemical_list: D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen