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)
