Cited 35 times since 2018 (5.1 per year) source: EuropePMC Diabetes care, Volume 42, Issue 2, 23 4 2018, Pages 208-214 A Type 1 Diabetes Genetic Risk Score Can Identify Patients With GAD65 Autoantibody-Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy. Grubb AL, McDonald TJ, Rutters F, Donnelly LA, Hattersley AT, Oram RA, Palmer CNA, van der Heijden AA, Carr F, Elders PJM, Weedon MN, Slieker RC, 't Hart LM, Pearson ER, Shields BM, Jones AG
Objective
Progression to insulin therapy in clinically diagnosed type 2 diabetes is highly variable. GAD65 autoantibodies (GADA) are associated with faster progression, but their predictive value is limited. We aimed to determine if a type 1 diabetes genetic risk score (T1D GRS) could predict rapid progression to insulin treatment over and above GADA testing.
Research design and methods
We examined the relationship between T1D GRS, GADA (negative or positive), and rapid insulin requirement (within 5 years) using Kaplan-Meier survival analysis and Cox regression in 8,608 participants with clinical type 2 diabetes (onset >35 years and treated without insulin for ≥6 months). T1D GRS was both analyzed continuously (as standardized scores) and categorized based on previously reported centiles of a population with type 1 diabetes (<5th [low], 5th-50th [medium], and >50th [high]).
Results
In GADA-positive participants (3.3%), those with higher T1D GRS progressed to insulin more quickly: probability of insulin requirement at 5 years (95% CI): 47.9% (35.0%, 62.78%) (high T1D GRS) vs. 27.6% (20.5%, 36.5%) (medium T1D GRS) vs. 17.6% (11.2%, 27.2%) (low T1D GRS); P = 0.001. In contrast, T1D GRS did not predict rapid insulin requirement in GADA-negative participants (P = 0.4). In Cox regression analysis with adjustment for age of diagnosis, BMI, and cohort, T1D GRS was independently associated with time to insulin only in the presence of GADA: hazard ratio per SD increase was 1.48 (1.15, 1.90); P = 0.002.
Conclusions
A T1D GRS alters the clinical implications of a positive GADA test in patients with clinical type 2 diabetes and is independent of and additive to clinical features.
