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Objective Electrochemiluminescence (ECL) assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk human leukocyte antigen (HLA) haplotypes and genotypes with ECL positivity and levels in relatives of individuals with type 1 diabetes. Methods We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least 1 RBA diabetes-related Ab [glutamic acid decarboxylase autoantibodies (GADA) or insulin autoantibodies (IAA)] and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (z-scores) for analyses. Results Mean age at initial visit was 19.4 ± 13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA-DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all Ps < 0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both Ps < 0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (P < 0.05). Conclusions ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes.

Pancreas size, as measured by MRI, is smaller at the onset of T1D and in individuals at risk for T1D. To determine whether pancreas MRI predicts T1D progression, we measured pancreas size and shape longitudinally in Type 1 Diabetes TrialNet Pathway to Prevention study participants. To increase enrollment and expand this study across multiple TrialNet sites, we established the Multicenter Assessment of the Pancreas in T1D (MAP-T1D) group to develop harmonized MRI acquisition and image processing protocols and ensure the consistency of imaging results across sites. Using this standardized protocol (PMID: 34428220) , we performed longitudinal pancreas MRI in 41 multiple autoantibody-positive individuals (mean age y.o., range 8 - 45 y.o., 49% female) at three TrialNet Clinical Centers. Average time between study entry and diabetes diagnosis for individuals who progressed to Stage 3 was 54 months while non-progressors were followed for a median time of 63 months. Five study participants who developed Stage 3 T1D during follow up had a smaller pancreas (29.5 ± 9.0 ml vs. 54.8 ± 22.5 ml, p = 0.02) and smaller pancreas volume normalized by body weight (0.61 ± 0.18 ml/kg vs. 0.85 ± 0.23 ml, p = 0.03) at study entry compared with those who did not progress to Stage 3. We found that pancreas volume was stable over time, with no significant increase or decrease up to four years after the initial MRI (total of 123 MRIs) . There was no significant change in pancreas size in the five individuals who progressed to Stage 3 T1D. The shape of the pancreas at study onset was also different in the five individuals who progressed to Stage 3 T1D compared with non-progressors, with larger surface area to volume ratio (p = 0.02) , and shorter principal axes (p = 0.05, shortest axis; p = 0.02, second shortest axis) . These data suggest that small pancreas size and altered shape predicts progression from Stage 2 to Stage 3 T1D. Disclosure J.Virostko: None. L.H.Philipson: Advisory Panel; Nevro Corp., Research Support; Dompé, Novo Nordisk, provention BIo. T.Kay: None. H.E.Thomas: Research Support; Captix Biomedical, CSL Limited, Pandion Therapeutics, Procyon Technologies. S.W.Greeley: None. A.Steck: None. A.C.Powers: None. D.J.Moore: None. J.J.Wright: None. J.M.Williams: None. M.A.Hilmes: None. T.M.Triolo: None. H.C.Broncucia: None. L.Du: None. H.Kang: None. W.E.Russell: None. Funding NIDDK (R03DK129979, U24DK097771, UC4 DK106993, DK020593) ; JDRF International (3-SRA-2015-102-M-B, 3-SRA-2019-759-M-B) ; Thomas J. Beatson, Jr. Foundation (2021-003)

Development of islet autoimmunity (IA) and type 1 diabetes (T1D) are associated with high-risk HLA class II loci as well as non-HLA genes. Monozygotic (MZ) twins have a high rate of concordance to T1D progression after the first twin develops T1D, especially for those diagnosed at a young age. We analyzed 52 T1D-associated non-HLA SNPs from ImmunoChip data in 159 MZ twins from the Twin Family Study: 79 twin probands with T1D and their 80 unaffected cotwins/triplets (including one set of triplets). Subjects are enrolled into the Twin Study when the proband is diagnosed with T1D and cotwins are followed longitudinally for the development of IA and/or T1D. In the cotwins, we analyzed the association between each of the non-HLA SNPs and IA after adjusting for HLA DR3/4*0302. In the twin probands with T1D, we used a linear regression model to evaluate the association of non-HLA SNPs with diabetes age at onset after adjusting for HLA DR3/4*0302. Median (IQR) age of diagnosis of the twin probands was 9.9 (5.4-13.9) years and age of last visit for the cotwins was 17.5 (11.2-26.7) years. Of the 80 cotwins, 41 (51.3%) developed IA and 15 (18.8%) were diagnosed with T1D. After adjusting for HLA DR3/4*0302, SNPs in CTLA4 (rs3087243), IL2 (rs4505848), IKZF1 (rs62447205), and INS (rs7111341) were found to be associated with the development of IA in cotwin subjects (all p Disclosure T. M. Triolo: None. F. Dong: None. H. C. Broncucia: None. S. Onengut-gumuscu: None. A. Steck: None. S. S. Rich: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (K12DK094712)