Characteristics of autoantibody-positive individuals without high-risk HLA-DR4-DQ8 or HLA-DR3-DQ2 haplotypes
Year: 2024
Type: article
Study design: Observational Study
Abstract: AIMS/HYPOTHESIS: Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking HLA-DRB1*04-DQA1*03-DQB1*0302 (HLA-DR4-DQ8) and/or HLA-DRB1*0301-DQA1*0501-DQB1*0201 (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes. METHODS: We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4; n=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3; n=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4; n=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX; n=1294). Group comparisons included demographics, metabolic markers and the prevalence of autoantibodies against GAD65 (GADA%), IA-2 (IA-2A%) or insulin (IAA%) at enrolment. A p value <0.01 was considered statistically significant. RESULTS: IA-2A% was lower in the DRX/DRX group (20.9%) than in the DR4/non-DR3 (38.5%, p<0.001) and DR3/DR4 (44.8%, p<0.001) groups, but similar to the DR3/non-DR4 group (20.0%). Conversely, IAA% was similar in the DRX/DRX (43.4%), DR4/non-DR3 (41.1%) and DR3/DR4 (41.0%) groups, but lower in the DR3/non-DR4 group (30.1%, p<0.001). Participants in the DRX/DRX group were older, with a lower prevalence of White participants and a higher prevalence of overweight/obesity, and higher preserved C-peptide (as measured by a lower Index60) than those in the DR3/DR4 group (all comparisons, p<0.005), a lower prevalence of White or non-Hispanic participants and a lower Index60 than those in the DR4/non-DR3 group, and younger age, a higher prevalence of Hispanic participants and a lower Index60 than those in the DR3/non-DR4 group (all comparisons, p<0.005). Among the 1292 participants who progressed to clinical type 1 diabetes, those in the DR3/non-DR4 group had higher GADA%, lower IA-2A% and lower IAA% than the other groups (all comparisons, p<0.01), and those in the DR3/DR4 group had the youngest age at diagnosis (all comparisons, p<0.001). CONCLUSIONS/INTERPRETATION: Autoantibody-positive individuals who lack both high-risk HLA haplotypes (DRX/DRX) or have HLA-DR3-DQ2 but lack HLA-DR4-DQ8 (DR3/non-DR4) have phenotypic differences compared with DR3/DR4 and DR4/non-DR3 individuals, suggesting that there is aetiological heterogeneity in type 1 diabetes.
Source: Diabetologia
Authors: Maria J. Redondo, David Cuthbertson, Andrea K. Steck, Kevan C. Herold, Richard Oram, Mark Atkinson, Todd M. Brusko, Hemang M. Parikh, Jeffrey P. Krischer, Suna Onengut-Gumuscu, Stephen S. Rich, Jay M. Sosenko, the Type 1 Diabetes TrialNet Study Group
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,290
Funders: National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, JDRF
Awards: G1044130170, G1058663374, G1236451951, G1335891746, G1567340913, G1667355478, G1778119441, G1874622916, G1979237160, Type 1 Diabetes-A Proposal for Prevention & Intervention, CLINICAL AFFILIATE OF THE TYPE 1 DIABETES TRIALNET, G2078056140, G215324815, Chicagoland Diabetes TrialNet Clinical Center, G2290638663, G2325591987, G2564331524, G2579296307, G263499696, G266093542, G28051265, G3345811275, G3631080139, Type 1 Diabetes Genetic Risk Score in TrialNet, G3998258134, G4055536045, G447712914, G457535738, G47144712, G4914271708, G491993124, Type 1 Diabetes TrialNet: Toronto Clinical Center, G5473625662, G5964144280, G6107671091, G6173851391, G6362470415, G6646637029, G6699656948, G6862536402, G6947964095, G695377212, G701880105, G7319114294, G7617495748, G8114795067, G881227773, G9000050447, G9000053785, G9000070396, G9000074482, G9000103942, G9000108131, G9000115250, G9000121273, G9000137445, G9000153846, G9000159741, G9000180806, G9000182208, G9000183277, G9000207758, G9000254921, G9000308555, G9000351679, Immune Function and the Progression to Type 1 Diabetes, Yale Clinical and Translational Science Award
OpenAlex ID: W4405384560