Shared molecular amino acid signature in the HLA-DR peptide binding pocket predisposes to both autoimmune diabetes and thyroiditis
Year: 2010
Type: article
Study design: Observational Study
Abstract: There is strong genetic association between type 1A diabetes (T1D) and autoimmune thyroid disease (AITD). T1D and AITD frequently occur together in the same individual, a condition classified as a variant of the autoimmune polyglandular syndrome type 3 (APS3). Because T1D and AITD are individually strongly associated with different HLA class II sequences, we asked which HLA class II pocket sequence and structure confer joint susceptibility to both T1D and AITD in the same individual (APS3v). We sequenced the HLA-DR gene in 105 APS3v patients and 153 controls, and identified a pocket amino acid signature, DRβ-Tyr-26, DRβ-Leu-67, DRβ-Lys-71, and DRβ-Arg-74, that was strongly associated with APS3v (P = 5.4 × 10(-14), odds ratio = 8.38). Logistic regression analysis demonstrated that DRβ-Leu-67 (P = 9.4 × 10(-13)) and DRβ-Arg-74 (P = 1.21 × 10(-13)) gave strong independent effects on disease susceptibility. Structural modeling studies demonstrated that pocket 4 was critical for the development of T1D+AITD; all disease-associated amino acids were linked to areas of the pocket that interact directly with the peptide and, therefore, influence peptide binding. The disease-susceptible HLA-DR pocket was more positively charged (Lys-71, Arg-74) compared with the protective pocket (Ala-71, Gln-74). We conclude that a specific pocket amino acid signature confers joint susceptibility to T1D+AITD in the same individual by causing significant structural changes in the MHC II peptide binding pocket and influencing peptide binding and presentation. Moreover, Arg-74 is a major amino acid position for the development of several autoimmune diseases. These findings suggest that blocking the critical Arg-74 pocket might offer a method for treating certain autoimmune conditions.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: G3087501273, G4283347220, Identifying and Analyzing Genes Linked to Autoimmune Thyroid Diseases, A MULTICENTER STUDY OF IDIOPATHIC GENERALIZED EPILEPSY, Psychiatric Genetics and Family Studies: Robust Methods, G709123266, G744565816, Thyroid Derived Peptide Presentation by HLA-DR in Thyroiditis, Analyzing Genes for Autoimmune Thyroiditis and Diabetes: Translation to Therapy, G976693344
OpenAlex ID: W2139164352