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Type 1 Diabetes Genetic Risk in 109,954 Veterans with Adult-Onset Diabetes: The Million VeteranProgram (MVP)

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posted on 2024-04-12, 20:42 authored by Peter K Yang, Sandra L Jackson, Brian R Charest, Yiling J Cheng, Yan V Sun, Sridharan Raghavan, Elizabeth M Litkowski, Brian T Legvold, Mary K Rhee, Richard A Oram, Elena V Kuklina, Marijana Vujkovic, Peter D Reaven, Kelly Cho, Aaron Leong, Peter W F Wilson, Jin Zhou, Donald R Miller, Seth A Sharp, Lisa R Staimez, Kari E North, Heather M Highland, Lawrence S Phillips

Objective: To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates.

Research Design and Methods: Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program (MVP) participants with adult-onset diabetes 2011–2021, who had T1D genetic risk scores (GRS) defined as low (0-<45%), medium (45-<90%), high (90-<95%), or highest (≥95%).

Results: T1D characteristics increased progressively with higher genetic risk (p<0.001 for trend). A GRS ≥90% was more common with diabetes diagnoses before age 40 years, but 95% of those participants were diagnosed at age ≥40 years, and they resembled T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared to the low risk group, the highest risk group was more likely to have diabetic ketoacidosis (DKA) (low 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose <50 mg/dL (7.5% vs. 13.4%), a shorter median time to start insulin (3.5 vs. 1.4 years), use of a T1D diagnostic code (16.3% vs. 28.1%), low C peptide levels if tested (1.8% vs. 32.4%), and glutamic acid decarboxylase (GAD) antibodies (6.9% vs. 45.2%), all p<0.001.

Conclusions: Characteristics associated with T1D were increased with higher genetic risk, and especially with the top 10% of risk. However, the age and BMI of those participants resemble T2D, and a substantial proportion did not have diagnostic testing or use of T1D diagnostic codes. T1D genetic screening could be used to aid identification of adult-onset T1D in settings in which T2D predominates

Funding

This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award MVP009. P.K.Y. is supported by funding from the Oak Ridge Institute for Science and Education, IHRC, Inc., and a T32 National Heart Lung Blood training grant from the National Institutes of Health. L.S.P. is supported in part by VA awards I01-CX001025, I01-BX003340, CX001899, and I01CX001737, and NIH awards U01DK098245, P30DK111024, AI156161, and DK127083, and a Cystic Fibrosis Foundation award PHILLI12A0. LSP, BC, SR, MKR, MV, PDR, KC, PWFW, and JZ are also supported in part by the Veterans Health Administration (VA). S.R. is supported by US Department of Veterans Affairs Career Development Award IK2-CX001907, by funding from the US National Institutes of Health award P30DK116073, and by the Webb-Waring Biomedical Research Program of the Boettcher Foundation. R.A.O. is supported by a Diabetes UK Harry Keen Fellowship (16/0005529). A.L. is supported by grant 2020096 from the Doris Duke Foundation (https://www.ddcf.org)., the American Diabetes Association Grant 7-22-ICTSPM-23, and NHGRI U01HG011723. L.R.S. was supported in part by the National Center for Advancing Translational Sciences of the NIH under award number UL1 TR002378 and by NIH KL2TR002381.

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