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

doi:10.2337/dc18-0431

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)

Population Health and Genomics

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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 language	English
Pages (from-to)	208-214
Number of pages	7
Journal	Diabetes Care
Volume	42
Issue number	2
Early online date	23 Oct 2018
DOIs	https://doi.org/10.2337/dc18-0431
Publication status	Published - 1 Feb 2019

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Advanced and Specialised Nursing

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/dc18-0431

Author Accepted Manuscript
This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes Care. The American Diabetes Association (ADA), publisher of Diabetes Care, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes Care in print and online at http://care.diabetesjournals.org.
Accepted author manuscript, 185 KB
Author Accepted Manuscript: Supplementary Materials
This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes Care. The American Diabetes Association (ADA), publisher of Diabetes Care, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes Care in print and online at http://care.diabetesjournals.org.
Accepted author manuscript, 296 KB
Author Accepted Manuscript: Figure 1
This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes Care. The American Diabetes Association (ADA), publisher of Diabetes Care, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes Care in print and online at http://care.diabetesjournals.org.
Accepted author manuscript, 66.1 KB

1 Finished
1 Active

DIRECT: Diabetes Research on Patient Stratification (joint with 25 other partners)
Colhoun, H. (Investigator), Houston, G. (Investigator), Morris, A. (Investigator), Palmer, C. (Investigator) & Pearson, E. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/02/12 → 28/02/27
Project: Research
Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)
Pearson, E. (Investigator)
16/02/15 → 15/08/21
Project: Research

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

@article{d0ef9c056d854104af8fb2bc4a0018bb,

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

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.",

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

note = "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.",

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doi = "10.2337/dc18-0431",

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volume = "42",

pages = "208--214",

journal = "Diabetes Care",

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Grubb, AL, McDonald, TJ, Rutters, F, Donnelly, L, Hattersley, AT, Oram, RA, Palmer, C, van der Heijden, AA, Carr, F, Elders, PJM, Weedon, M, Slieker, RC, 't Hart, LM, Pearson, E, Shields, BM & Jones, AG 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, vol. 42, no. 2, pp. 208-214. https://doi.org/10.2337/dc18-0431

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 -

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

Abstract

ASJC Scopus subject areas

UN SDGs

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Projects

DIRECT: Diabetes Research on Patient Stratification (joint with 25 other partners)

Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)

Cite this