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Utility of Diabetes Type–Specific Genetic Risk Scores for the Classification of Diabetes Type Among Multiethnic Youth

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posted on 21.03.2022, 21:52 by Richard A Oram, Seth A Sharp, Catherine Pihoker, Lauric Ferrat, Giuseppina Imperatore, Adrienne Williams, Maria J. Redondo, Lynne Wagenknecht, Lawrence M. Dolan, Jean M Lawrence, Michael N Weedon, Ralph D’Agostino Jr, William A Hagopian, Jasmin Divers, Dana Dabelea
Objective: Genetic risk scores (GRS) aid classification of diabetes type in white European adult populations. We aimed to assess the utility of GRS in classification of diabetes type among racially/ethnically diverse youth in the U.S.


Research Design and Methods: We generated type 1 (T1D) and type 2 diabetes (T2D) specific GRS in 2045 individuals from the SEARCH for Diabetes in Youth study. We assessed the distribution of genetic risk stratified by diabetes type defined by autoantibody positive or negative (DAA+/-) and insulin sensitive (IS) or insulin resistant (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 diabetes autoantibody positive insulin sensitive group and lowest in the diabetes autoantibody negative insulin resistant group, with the inverse relationship observed with the T2D GRS. Discrimination was similar across all racial/ethnic groups but showed between race/ethnicity differences in score distribution. Clustering by combined genetic risk showed diabetes autoantibody positive insulin resistant and diabetes autoantibody negative insulin sensitive individuals show a greater probability of T1D than T2D. In diabetes autoantibody negative individuals, genetic probability of T1D identified individuals most likely to progress to absolute insulin deficiency.

Conclusion: 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 diabetes autoantibody negative children.

Funding

SEARCH 4: The SEARCH for Diabetes in Youth Cohort Study (1R01DK127208-01, 1UC4DK108173) is funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases and supported by the Centers for Disease Control and Prevention. The Population Based Registry of Diabetes in Youth Study (1U18DP006131, U18DP006133, U18DP006134, U18DP006136, U18DP006138, U18DP006139) is funded by the Centers for Disease Control and Prevention (DP-15-002) and supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. SEARCH 1-3: SEARCH for Diabetes in Youth is funded by the Centers for Disease Control and Prevention (PA numbers 00097, DP-05-069, and DP-10-001) and supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Kaiser Permanente Southern California (U48/CCU919219, U01 DP000246, and U18DP002714), University of Colorado Denver (U48/CCU819241-3, U01 DP000247, and U18DP000247-06A1), Cincinnati's Children's Hospital Medical Center (U48/CCU519239, U01 DP000248, and 1U18DP002709), University of North Carolina at Chapel Hill (U48/CCU419249, U01 DP000254, and U18DP002708), Seattle Children's Hospital (U58/CCU019235-4, U01 DP000244, and U18DP002710-01] and Wake Forest University School of Medicine (U48/CCU919219, U01 DP000250, and 200-2010-35171). R.A.O is funded by a Diabetes UK Harry Keen Fellowship (16/0005529), S.A.S is funded by a Diabetes UK PhD studentship (16/0005529) and R.A.O, W.A.H and L.A.F are funded by a JDRF strategic research agreement (3-SRA-2019-827-S-B)

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