Faculty Collaboration Database

A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk. Diabetes Care 2018 Sep;41(9):1887-1894

Date

07/14/2018

Pubmed ID

30002199

Pubmed Central ID

PMC6105323

DOI

10.2337/dc18-0087

Scopus ID

2-s2.0-85052711351 (requires institutional sign-in at Scopus site)   97 Citations

Abstract

OBJECTIVE: We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.

RESEARCH DESIGN AND METHODS: We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.

RESULTS: Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06-1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51; P = 0.0002).

CONCLUSIONS: The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.

Author List

Redondo MJ, Geyer S, Steck AK, Sharp S, Wentworth JM, Weedon MN, Antinozzi P, Sosenko J, Atkinson M, Pugliese A, Oram RA, Type 1 Diabetes TrialNet Study Group

Author

Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Autoantibodies
Autoimmunity
Child
Child, Preschool
Diabetes Complications
Diabetes Mellitus, Type 1
Disease Progression
Female
Genetic Predisposition to Disease
Genotype
HLA-DQ Antigens
Humans
Infant
Islets of Langerhans
Male
Middle Aged
Polymorphism, Single Nucleotide
Prognosis
Risk Factors
Young Adult