The KAG motif of HLA-DRB1 (ß71, ß74, ß86) predicts seroconversion and development of type 1 diabetes.
EBioMedicine
; 69: 103431, 2021 Jul.
Article
en En
| MEDLINE
| ID: mdl-34153873
BACKGROUND: HLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk of type 1 diabetes (T1D); however, some are risk neutral or resistant. The pathobiological mechanism of HLA-DR4 subtypes remains to be elucidated. METHODS: We used a population-based case-control study of T1D (962 patients and 636 controls) to decipher genetic associations of HLA-DR4 subtypes and specific residues with susceptibility to T1D. Using a birth cohort of 7865 children with periodically measured islet autoantibodies (GADA, IAA or IA-2A), we proposed to validate discovered genetic associations with a totally different study design and time-to-seroconversions prior to clinical onset of T1D. A novel analytic strategy hierarchically organized the HLA-DRB1 alleles by sequence similarity and identified critical amino acid residues by minimizing local genomic architecture and higher-order interactions. FINDINGS: Three amino acid residues of HLA-DRB1 (ß71, ß74, ß86) were found to be predictive of T1D risk in the population-based study. The "KAG" motif, corresponding to HLA-DRB1×04:01, was most strongly associated with T1D risk ([O]dds [R]atio=3.64, p = 3.19 × 10-64). Three less frequent motifs ("EAV", OR = 2.55, p = 0.025; "RAG", OR = 1.93, p = 0.043; and "RAV", OR = 1.56, p = 0.003) were associated with T1D risk, while two motifs ("REG" and "REV") were equally protective (OR = 0.11, p = 4.23 × 10-4). In an independent birth cohort of HLA-DR3 and HLA-DR4 subjects, those having the "KAG" motif had increased risk for time-to-seroconversion (Hazard Ratio = 1.74, p = 6.51 × 10-14) after adjusting potential confounders. INTERPRETATIONS: DNA sequence variation in HLA-DRB1 at positions ß71, ß74, and ß86 are non-conservative (ß74 AâE, ß71 E vs K vs R and ß86 G vs V). They result in substantial differences in peptide antigen anchor pocket preferences at p1, p4 and potentially neighboring regions such as pocket p7. Differential peptide antigen binding is likely to be affected. These sequence substitutions may account for most of the HLA-DR4 contribution to T1D risk as illustrated in two HLA-peptide model complexes of the T1D autoantigens preproinsulin and GAD65. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases and the Swedish Child Diabetes Foundation and the Swedish Research Council.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Diabetes Mellitus Tipo 1
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Cadenas HLA-DRB1
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Seroconversión
Tipo de estudio:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Child
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Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
EBioMedicine
Año:
2021
Tipo del documento:
Article