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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