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

TY - JOUR

T1 - A Type 1 Diabetes Genetic Risk Score Can Identify Patients With GAD65 Autoantibody-Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy

AU - Grubb, Anita L.

AU - McDonald, Timothy J.

AU - Rutters, Femke

AU - Donnelly, Louise

AU - Hattersley, Andrew T.

AU - Oram, Richard A.

AU - Palmer, Colin

AU - van der Heijden, Amber A.

AU - Carr, Fiona

AU - Elders, Petra J. M.

AU - Weedon, Mike

AU - Slieker, Roderick C.

AU - 't Hart, Leen M

AU - Pearson, Ewan

AU - Shields, Beverley M.

AU - Jones, Angus G.

N1 - The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (GoDARTS) was funded by The Wellcome Trust (084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT program. GADA assessment in GoDARTS and DCS was funded by EU Innovative Medicines Initiative 115317 (DIRECT), resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013), and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies in kind contribution. The DCS cohort was partially funded by the Netherlands Organization for Health Research and Development (Priority Medicines Elderly Programme 113102006). The Diabetes Alliance for Research in England (DARE) study was funded by the Wellcome Trust and supported by the Exeter NIHR Clinical Research Facility. The MASTERMIND study was funded by the UK Medical Research Council (MR/N00633X/) and supported by the NIHR Exeter Clinical Research Facility. The PRIBA study was funded by the National Institute for Health Research (U.K.) (DRF-2010-03-72) and supported by the NIHR Exeter Clinical Research Facility.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

U2 - 10.2337/dc18-0431

DO - 10.2337/dc18-0431

M3 - Article

C2 - 30352895

SN - 0149-5992

VL - 42

SP - 208

EP - 214

JO - Diabetes Care

JF - Diabetes Care

IS - 2

ER -