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

Abstract

Graves' disease (GD) is associated with HLA-DR3 (DRB1*03) in Caucasians, but the exact amino-acid sequence in the DR β1 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.

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Acknowledgements

This work was supported in part by DK61659 and DK58072 from NIDDKD (to YT), DK35764, DK45011, and DK52464 from NIDDKD (to TFD), DK31775, NS27941, and MH48858 (to DAG). Presented in part at the 84th Annual Meeting of the Endocrine Society, June 2002, San Francisco. We thank Dr Stephen Gough (University of Birmingham, UK) for sharing his data with us and for helpful discussions.

Competing interests statement: The authors declare that they have no competing financial interests.

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Correspondence to Y Tomer.

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Ban, Y., Davies, T., Greenberg, D. et al. Arginine at position 74 of the HLA-DR β1 chain is associated with Graves' disease. Genes Immun 5, 203–208 (2004). https://doi.org/10.1038/sj.gene.6364059

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