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.
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.
Authors: Kevan C Herold; Brian N Bundy; S Alice Long; Jeffrey A Bluestone; Linda A DiMeglio; Matthew J Dufort; Stephen E Gitelman; Peter A Gottlieb; Jeffrey P Krischer; Peter S Linsley; Jennifer B Marks; Wayne Moore; Antoinette Moran; Henry Rodriguez; William E Russell; Desmond Schatz; Jay S Skyler; Eva Tsalikian; Diane K Wherrett; Anette-Gabriele Ziegler; Carla J Greenbaum Journal: N Engl J Med Date: 2019-06-09 Impact factor: 91.245
Authors: Manuela Battaglia; Simi Ahmed; Mark S Anderson; Mark A Atkinson; Dorothy Becker; Polly J Bingley; Emanuele Bosi; Todd M Brusko; Linda A DiMeglio; Carmella Evans-Molina; Stephen E Gitelman; Carla J Greenbaum; Peter A Gottlieb; Kevan C Herold; Martin J Hessner; Mikael Knip; Laura Jacobsen; Jeffrey P Krischer; S Alice Long; Markus Lundgren; Eoin F McKinney; Noel G Morgan; Richard A Oram; Tomi Pastinen; Michael C Peters; Alessandra Petrelli; Xiaoning Qian; Maria J Redondo; Bart O Roep; Desmond Schatz; David Skibinski; Mark Peakman Journal: Diabetes Care Date: 2019-11-21 Impact factor: 19.112
Authors: L Yu; M Rewers; R Gianani; E Kawasaki; Y Zhang; C Verge; P Chase; G Klingensmith; H Erlich; J Norris; G S Eisenbarth Journal: J Clin Endocrinol Metab Date: 1996-12 Impact factor: 5.958
Authors: Amanda Rewers; Sunanda Babu; Tian Bao Wang; Teodorica L Bugawan; Kathy Barriga; George S Eisenbarth; Henry A Erlich Journal: Ann N Y Acad Sci Date: 2003-11 Impact factor: 5.691
Authors: Andrea K Steck; Kelly Johnson; Katherine J Barriga; Dongmei Miao; Liping Yu; John C Hutton; George S Eisenbarth; Marian J Rewers Journal: Diabetes Care Date: 2011-05-11 Impact factor: 19.112
Authors: Liping Yu; Fran Dong; Dongmei Miao; Alexandra R Fouts; Janet M Wenzlau; Andrea K Steck Journal: Diabetes Care Date: 2013-02-19 Impact factor: 19.112
Authors: Dongmei Miao; K Michelle Guyer; Fran Dong; Ling Jiang; Andrea K Steck; Marian Rewers; George S Eisenbarth; Liping Yu Journal: Diabetes Date: 2013-08-23 Impact factor: 9.461