Arginine at position 74 of the HLA-DR β1 chain is associated with Graves' disease

Y. Ban, T. F. Davies, D. A. Greenberg, E. S. Concepcion, R. Osman, T. Oashi, Yaron Tomer

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

Graves' disease (GD) is associated with HLA-DR3 (DRB1*03) in Caucasians, but the exact amino-acid sequence in the DR β 1 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 β-Arg-74 in GD patients compared to controls (41.8 and 13.4%, respectively; P = 2.3 × 10-8, OR = 4.6). Moreover, subset analyses showed that DR β-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 β-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 β-chain peptide-binding pocket P4 at residue 74 predispose some at risk individuals to GD.

Original languageEnglish (US)
Pages (from-to)203-208
Number of pages6
JournalGenes and Immunity
Volume5
Issue number3
DOIs
StatePublished - May 1 2004
Externally publishedYes

Keywords

  • Association
  • Autoimmunity
  • Gene
  • Graves' disease
  • HLA

ASJC Scopus subject areas

  • Immunology
  • Genetics
  • Genetics(clinical)

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    Ban, Y., Davies, T. F., Greenberg, D. A., Concepcion, E. S., Osman, R., Oashi, T., & Tomer, Y. (2004). Arginine at position 74 of the HLA-DR β1 chain is associated with Graves' disease. Genes and Immunity, 5(3), 203-208. https://doi.org/10.1038/sj.gene.6364059