Type 1 Diabetes Genetic Risk in 109,954 Veterans With Adult-Onset Diabetes

The Million Veteran Program (MVP)

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.
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

¹Division for Heart Disease and Stroke Prevention, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA
²Atlanta Veterans Administration Medical Center, Atlanta, GA
³Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC
⁴Massachusetts Veterans Epidemiology Research and Information Center, Boston, MA
⁵Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA
⁶Rollins School of Public Health, Emory University, Atlanta, GA
⁷Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO
⁸University of Colorado School of Medicine, Denver, CO
⁹Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, Atlanta, GA
¹⁰College of Medicine and Health, University of Exeter Medical School, Devon, U.K
¹¹Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
¹²Phoenix Veterans Affairs Health Care System, Phoenix, AZ
¹³Brigham and Women’s Hospital, Boston, MA
¹⁴Harvard Medical School, Boston, MA
¹⁵Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA
¹⁶Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA
¹⁷UCLA Department of Medicine, University of California, Los Angeles, CA
¹⁸Bedford Veterans Affairs Medical Center, Bedford, MA
¹⁹Division of Endocrinology and Diabetes, Stanford University, Palo Alto, CA

Corresponding author: Lawrence S. Phillips, [email protected]

Received October 13, 2023

Accepted March 11, 2024

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/journals/pages/license.

Diabetes Care 47(6):p 1032-1041, June 2024. | DOI: 10.2337/dc23-1927

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 <45%), medium (45 to <90%), high (90 to <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 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 <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 < 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.