Arginine at position 74 of the HLA-DR beta1 chain is associated with Graves' disease

Genes Immun. 2004 May;5(3):203-8. doi: 10.1038/sj.gene.6364059.

Abstract

Graves' disease (GD) is associated with HLA-DR3 (DRB1*03) in Caucasians, but the exact amino-acid sequence in the DR beta1 chain conferring susceptibility to GD is unknown. Therefore, the aim of our study was to identify the critical sequence among the HLA-DRB1 amino-acid residues occupying the peptide-binding pocket, which conferred susceptibility to GD. We sequenced the HLA-DRB1 locus in 208 Caucasian GD patients and 149 Caucasian controls. Sequence analysis showed an increased frequency of DR beta-Arg-74 in GD patients compared to controls (41.8 and 13.4%, respectively; P=2.3 x 10(-8), OR=4.6). Moreover, subset analyses showed that DR beta-Arg-74 was also significantly more frequent in the HLA-DR3 negative GD patients than in controls (7.6 vs 0.8%, P=0.02, OR=10.5), suggesting that the association with DR beta-Arg-74 is independent of the association with HLA-DR3. Structural modeling studies demonstrated that the change at position 74 from the neutral amino acids Ala or Gln to the positively charged amino-acid Arg significantly modifies the three-dimensional structure of the DR peptide-binding pocket. Our results suggested that structural heterogeneity of the DR beta-chain peptide-binding pocket P4 at residue 74 predispose some at risk individuals to GD.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles*
  • Arginine / chemistry
  • Arginine / genetics*
  • Case-Control Studies
  • European Continental Ancestry Group
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Graves Disease / epidemiology
  • Graves Disease / genetics*
  • HLA-DR Antigens / genetics*
  • HLA-DRB1 Chains
  • Humans
  • Male
  • Middle Aged
  • Polymerase Chain Reaction

Substances

  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • Arginine