Introduction and Objective: In presymptomatic type 1 diabetes (T1D) the initial islet autoantibody (IAb) has been characterized as GADA-first with DR3 or IAA-first with DR4 in Caucasian population. Recently the PREP-T1D study, screening first-degree relatives in Japan for presymptomatic T1D, found ZnT8A-positivity was the most prevalent among IAb-positive cases. We aim to characterize the initial IAb patterns and their association with HLA haplotypes in the Japanese population. Methods: A cross-sectional analysis was conducted on 96 IAb-positive cases from PREP-T1D. Participants with single IAb positivity (SP) were extracted and HLA DRB1-DQB1 haplotypes were classified as disease-susceptible (*0405-*0401, *0802-*0302 and *0901- *0303) or protective (*1501-*0602, *1502-*0601 and *08:03-*06:01). Associations between IAb type and HLA haplotypes were analyzed. Results: The cohort comprised 26 GADA-only, 18 IA-2A-only, and 35 ZnT8A-only positive cases, with no significant age (P=0.893) or sex (P=0.631) differences. GADA-only group was strongly associated with the presence of two susceptible HLA haplotypes (13/20, P0.01 vs. other SPs), while few cases carried protective HLA haplotypes (2/16, P=0.05 vs. other SPs). In contrast, the IA-2A-only and ZnT8A-only groups included a substantial proportion of protective HLA haplotypes (27.8% and 27.3%, respectively). ZnT8A-only group was significantly enriched in DRB1*08:03-DQB1*06:01 (7/8, P=0.01 vs other SPs), while IA-2A-only group was in DRB1*15:01-DQB1*06:02 (4/7, P=0.03 vs other SPs). Conclusion: GADA-only positivity with strong association of susceptible HLA may reflect the typical GADA-first progression of T1D pathogenesis. In contrast, ZnT8A/IA-2A-only positivity exhibits a “dual-layer structure” based on HLA background, where those with protective HLA may represent a “non-progressor” population. This unique immunogenetic architecture may partly explain the distinct Japanese T1D disease structure and its lower prevalence versus Caucasians. Disclosure Y. Oikawa: Other - Honoraria; Ended; Novo Nordisk, Eli Lilly and Company, Sanofi, Daiichi Sankyo, Kowa Company, Ltd., Astellas Pharma Inc., Medtronic, Bayer AG, AstraZeneca, Taiho Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Dexcom, Inc., Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Sanwa Kagaku Kenkyusho. D. Chujo: Speaker's Bureau; Current; Sanofi K.K. A. Imagawa: Consultant; Current; Sanofi. T. Kawamura: Speaker's Bureau; Ended; Abbott Japan Co., Ltd., Sanofi, Novo Nordisk, Eli Lilly and Company, Medtronic, Terumo Corporation. T. Kikuchi: Advisory Panel; Current; Sanofi K.K. Other - Lecture fee; Current; Novo Nordisk A/S. Y. Shiraki: Employee; Current; Sanofi K.K. R. Koshiba: Employee; Current; Sanofi K.K. A. Shimada: Speaker's Bureau; Current; Sanofi. Funding Sanofi
Oikawa et al. (Fri,) studied this question.