A Type 1 Diabetes Genetic Risk Score Can Identify Patients With GAD65 Autoantibody-Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy

Anita L. Grubb, Timothy J. McDonald, Femke Rutters, Louise Donnelly, Andrew T. Hattersley, Richard A. Oram, Colin Palmer, Amber A. van der Heijden, Fiona Carr, Petra J. M. Elders, Mike Weedon, Roderick C. Slieker, Leen M 't Hart, Ewan Pearson, Beverley M. Shields, Angus G. Jones (Lead / Corresponding author)

Research output: Contribution to journalArticle

12 Citations (Scopus)
396 Downloads (Pure)

Abstract

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 (T1DGRS) could predict rapid progression to insulin treatment over and above GADA testing.

Research Design and Methods: We examined the relationship between T1DGRS, 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, treated without insulin for ≥6 months). T1DGRS was analyzed both continuously (as standardized scores) and categorized based on previously reported centiles of a type 1 diabetes population (<5th (low), 5th-50th (medium), >50th (high)).

Results: In GADA positive participants (3.3%), those with higher T1DGRS progressed to insulin more quickly: Probability of insulin requirement at five years [95% CI]: 47.9%[35.0%,62.78%] (high T1DGRS) vs 27.6%[20.5%,36.5%] (medium T1DGRS) vs 17.6%[11.2%,27.2%] (low T1DGRS), p=0.001. In contrast T1DGRS 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, T1DGRS was independently associated with time to insulin only in the presence of GADA: hazard ratio per SD increase 1.48 (1.15,1.90), p=0.002.

Conclusions: A Type 1 Diabetes Genetic Risk Score 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.
Original languageEnglish
Pages (from-to)208-214
Number of pages7
JournalDiabetes Care
Volume42
Issue number2
Early online date23 Oct 2018
DOIs
Publication statusPublished - 1 Feb 2019

Fingerprint Dive into the research topics of 'A Type 1 Diabetes Genetic Risk Score Can Identify Patients With GAD65 Autoantibody-Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy'. Together they form a unique fingerprint.

  • Projects

    Cite this

    Grubb, A. L., McDonald, T. J., Rutters, F., Donnelly, L., Hattersley, A. T., Oram, R. A., Palmer, C., van der Heijden, A. A., Carr, F., Elders, P. J. M., Weedon, M., Slieker, R. C., 't Hart, L. M., Pearson, E., Shields, B. M., & Jones, A. G. (2019). A Type 1 Diabetes Genetic Risk Score Can Identify Patients With GAD65 Autoantibody-Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy. Diabetes Care, 42(2), 208-214. https://doi.org/10.2337/dc18-0431