Type 1 Diabetes Genetic Risk in 109,954 Veterans With Adult-Onset Diabetes: The Million Veteran Program (MVP)
Authors: Yang Peter K. , Jackson Sandra L. , Charest Brian R. , Cheng Yiling J. , Sun Yan V. , Raghavan Sridharan , Litkowski Elizabeth M. , Legvold Brian T. , Rhee Mary K. , Oram Richard A. , Kuklina Elena V. , Vujkovic Marijana , Reaven Peter D. , Cho Kelly , Leong Aaron , Wilson Peter W.F. , Zhou Jin , Miller Donald R. , Sharp Seth A. , Staimez Lisa R. , North Kari E. , Highland Heather M. , Phillips Lawrence S. ,   Million Veteran Program, Muralidhar Sumitra , Moser Jennifer , Deen Jennifer E. , Gaziano J. Michael , Beckham Jean , Chang Kyong-Mi , Tsao Philip S. , Luoh Shiuh-Wen , Casas Juan P. , Churby Lori , Whitbourne Stacey B. , Brewer Jessica V. , Brophy Mary T. , Selva Luis E. , Shayan Shahpoor (Alex) , Cho Kelly , Pyarajan Saiju , DuVall Scott L. , Connor Todd , Argyres Dean P. , Stephens Brady , Wilson Peter , McArdle Rachel , Dellitalia Louis , Mattocks Kristin , Harley John , Whittle Jeffrey , Jacono Frank , Beckham Jean , Wells John , Gutierrez Salvador , Alexander Kathrina , Hammer Kimberly , Norton James , Villareal Gerardo , Kinlay Scott , Xu Junzhe , Hamner Mark , Mathew Roy , Bhushan Sujata , Iruvanti Pran , Godschalk Michael , Ballas Zuhair , Smith River , Mastorides Stephen , Moorman Jonathan , Gappy Saib , Klein Jon , Ratcliffe Nora , Palacio Ana , Okusaga Olaoluwa , Murdoch Maureen , Sriram Peruvemba , Yeh Shing Shing , Tandon Neeraj , Jhala Darshana , Aguayo Samuel , Cohen David , Sharma Satish , Liangpunsakul Suthat , Oursler Kris Ann , Whooley Mary , Ahuja Sunil , Constans Joseph , Meyer Paul , Greco Jennifer , Rauchman Michael , Servatius Richard , Gaddy Melinda , Wallbom Agnes , Morgan Timothy , Stapley Todd , Liang Peter , Fujii Daryl , Strollo Patrick , Boyko Edward , Walsh Jessica , Gupta Samir , Huq Mostaqul , Fayad Joseph , Hung Adriana , Lichy Jack , Hurley Robin , Robey Brooks , Balasubramanian Prakash 
Published: April 2024

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 participants with adult-onset diabetes, 2011–2021, who had T1D genetic risk scores (GRS) defined as low (0 to &lt;45%), medium (45 to &lt;90%), high (90 to &lt;95%), or highest (≥95%).

RESULTS
T1D characteristics increased progressively with higher genetic risk (P &lt; 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 their characteristics resembled those of individuals with T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared with the low-risk group, the highest-risk group was more likely to have diabetic ketoacidosis (low GRS 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose &lt;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 antibodies (6.9% vs. 45.2%), all P &lt; 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 those of people with 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.