Richard A Oram1, Seth A Sharp1, Catherine Pihoker2, Lauric Ferrat1, Giuseppina Imperatore3, Adrienne Williams4, Maria J Redondo5, Lynne Wagenknecht4, Lawrence M Dolan6, Jean M Lawrence7, Michael N Weedon1, Ralph D'Agostino4, William A Hagopian8, Jasmin Divers9, Dana Dabelea10. 1. Institute of Biomedical and Clinical Science, University of Exeter Medical School, and The Academic Kidney Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. 2. Department of Pediatrics, University of Washington, Seattle, WA. 3. Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, GA. 4. Biostatistics Shared Resource, Wake Forest School of Medicine, Winston-Salem, NC. 5. Section of Diabetes and Endocrinology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX. 6. Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. 7. Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA. 8. Pacific Northwest Diabetes Research Institute, Seattle, WA. 9. Division of Health Services Research, Foundation of Medicine, NYU Long Island School of Medicine, Mineola, NY. 10. Departments of Pediatrics and Epidemiology, University of Colorado School of Medicine, Aurora, CO.
Abstract
OBJECTIVE: Genetic risk scores (GRS) aid classification of diabetes type in White European adult populations. We aimed to assess the utility of GRS in the classification of diabetes type among racially/ethnically diverse youth in the U.S. RESEARCH DESIGN AND METHODS: We generated type 1 diabetes (T1D)- and type 2 diabetes (T2D)-specific GRS in 2,045 individuals from the SEARCH for Diabetes in Youth study. We assessed the distribution of genetic risk stratified by diabetes autoantibody positive or negative (DAA+/-) and insulin sensitivity (IS) or insulin resistance (IR) and self-reported race/ethnicity (White, Black, Hispanic, and other). RESULTS: T1D and T2D GRS were strong independent predictors of etiologic type. The T1D GRS was highest in the DAA+/IS group and lowest in the DAA-/IR group, with the inverse relationship observed with the T2D GRS. Discrimination was similar across all racial/ethnic groups but showed differences in score distribution. Clustering by combined genetic risk showed DAA+/IR and DAA-/IS individuals had a greater probability of T1D than T2D. In DAA- individuals, genetic probability of T1D identified individuals most likely to progress to absolute insulin deficiency. CONCLUSIONS: Diabetes type-specific GRS are consistent predictors of diabetes type across racial/ethnic groups in a U.S. youth cohort, but future work needs to account for differences in GRS distribution by ancestry. T1D and T2D GRS may have particular utility for classification of DAA- children.
OBJECTIVE: Genetic risk scores (GRS) aid classification of diabetes type in White European adult populations. We aimed to assess the utility of GRS in the classification of diabetes type among racially/ethnically diverse youth in the U.S. RESEARCH DESIGN AND METHODS: We generated type 1 diabetes (T1D)- and type 2 diabetes (T2D)-specific GRS in 2,045 individuals from the SEARCH for Diabetes in Youth study. We assessed the distribution of genetic risk stratified by diabetes autoantibody positive or negative (DAA+/-) and insulin sensitivity (IS) or insulin resistance (IR) and self-reported race/ethnicity (White, Black, Hispanic, and other). RESULTS: T1D and T2D GRS were strong independent predictors of etiologic type. The T1D GRS was highest in the DAA+/IS group and lowest in the DAA-/IR group, with the inverse relationship observed with the T2D GRS. Discrimination was similar across all racial/ethnic groups but showed differences in score distribution. Clustering by combined genetic risk showed DAA+/IR and DAA-/IS individuals had a greater probability of T1D than T2D. In DAA- individuals, genetic probability of T1D identified individuals most likely to progress to absolute insulin deficiency. CONCLUSIONS: Diabetes type-specific GRS are consistent predictors of diabetes type across racial/ethnic groups in a U.S. youth cohort, but future work needs to account for differences in GRS distribution by ancestry. T1D and T2D GRS may have particular utility for classification of DAA- children.
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