The KAG motif of HLA-DRB1 (β71, β74, β86) predicts seroconversion and development of type 1 diabetes

• DOI: 10.1016/j.ebiom.2021.103431
• Publication Date: 2021-06-19T06:11:50Z
• Authors: Lue Ping Zhao; George K Papadopo...; Terry P. Lybrand; Antonis K. Moustakas; George P. Bondinas; Annelie Carlsson; Helena Elding Lar...; Johnny Ludvigsson; Claude Marcus; Martina Persson; Ulf Samuelsson; Ruihan Wang; Chul-Woo Pyo; Wyatt C. Nelson; Daniel E. Geraghty; Stephen S. Rich; Åke Lernmark
• Keywords: HLA-DRB1

BackgroundHLA-DR4, a common antigen of HLA-DRB1, has multiple subtypes that are strongly associated with risk type 1 diabetes (T1D); however, some neutral or resistant. The pathobiological mechanism HLA-DR4 remains to be elucidated.MethodsWe used population-based case-control study T1D (962 patients and 636 controls) decipher genetic associations specific residues susceptibility T1D. Using birth cohort 7865 children periodically measured islet autoantibodies (GADA, IAA IA-2A), we proposed validate discovered totally different design time-to-seroconversions prior clinical onset A novel analytic strategy hierarchically organized the HLA-DRB1 alleles by sequence similarity identified critical amino acid minimizing local genomic architecture higher-order interactions.FindingsThree (β71, β74, β86) were found predictive in study. "KAG" motif, corresponding HLA-DRB1×04:01, was most ([O]dds [R]atio=3.64, p = 3.19 × 10−64). Three less frequent motifs ("EAV", OR 2.55, 0.025; "RAG", 1.93, 0.043; "RAV", 1.56, 0.003) risk, while two ("REG" "REV") equally protective (OR 0.11, 4.23 10−4). In an independent HLA-DR3 subjects, those having motif had increased for time-to-seroconversion (Hazard Ratio 1.74, 6.51 10−14) after adjusting potential confounders.InterpretationsDNA variation at positions β71, β86 non-conservative (β74 A→E, β71 E vs K R G V). They result substantial differences peptide anchor pocket preferences p1, p4 potentially neighboring regions such as p7. Differential binding is likely affected. These substitutions may account contribution illustrated HLA-peptide model complexes autoantigens preproinsulin GAD65.FundingNational Institute Diabetes Digestive Kidney Diseases Swedish Child Foundation Research Council.