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 A. Donnelly, Andrew T. Hattersley, Richard A. Oram, Colin N. A. Palmer, Amber A. van der Heijden, Fiona Carr, Petra J. M. Elders, Mike N. Weedon, Roderick C. Slieker, Leen M. 't Hart, Ewan R. Pearson, Beverley M. Shields, Angus G. Jones

Research output: Contribution to journalArticleAcademicpeer-review

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 (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.
LanguageEnglish
Pages208-214
JournalDiabetes Care
Volume42
Issue number2
DOIs
StatePublished - 2019

Cite this

Grubb, A. L., McDonald, T. J., Rutters, F., Donnelly, L. A., Hattersley, A. T., Oram, R. A., ... 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. DOI: 10.2337/dc18-0431
Grubb, Anita L. ; McDonald, Timothy J. ; Rutters, Femke ; Donnelly, Louise A. ; Hattersley, Andrew T. ; Oram, Richard A. ; Palmer, Colin N. A. ; van der Heijden, Amber A. ; Carr, Fiona ; Elders, Petra J. M. ; Weedon, Mike N. ; Slieker, Roderick C. ; 't Hart, Leen M. ; Pearson, Ewan R. ; Shields, Beverley M. ; Jones, Angus G./ A Type 1 Diabetes Genetic Risk Score Can Identify Patients With GAD65 Autoantibody-Positive Type 2 Diabetes Who Rapidly Progress to Insulin Therapy. In: Diabetes Care. 2019 ; Vol. 42, No. 2. pp. 208-214
@article{d969c5d2caab4aa0bda5f5509ecd1cd6,
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 (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.",
author = "Grubb, {Anita L.} and McDonald, {Timothy J.} and Femke Rutters and Donnelly, {Louise A.} and Hattersley, {Andrew T.} and Oram, {Richard A.} and Palmer, {Colin N. A.} and {van der Heijden}, {Amber A.} and Fiona Carr and Elders, {Petra J. M.} and Weedon, {Mike N.} and Slieker, {Roderick C.} and {'t Hart}, {Leen M.} and Pearson, {Ewan R.} and Shields, {Beverley M.} and Jones, {Angus G.}",
year = "2019",
doi = "10.2337/dc18-0431",
language = "English",
volume = "42",
pages = "208--214",
journal = "Diabetes Care",
issn = "0149-5992",
publisher = "American Diabetes Association Inc.",
number = "2",

}

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

In: Diabetes Care, Vol. 42, No. 2, 2019, p. 208-214.

Research output: Contribution to journalArticleAcademicpeer-review

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 A.

AU - Hattersley,Andrew T.

AU - Oram,Richard A.

AU - Palmer,Colin N. A.

AU - van der Heijden,Amber A.

AU - Carr,Fiona

AU - Elders,Petra J. M.

AU - Weedon,Mike N.

AU - Slieker,Roderick C.

AU - 't Hart,Leen M.

AU - Pearson,Ewan R.

AU - Shields,Beverley M.

AU - Jones,Angus G.

PY - 2019

Y1 - 2019

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 (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.

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 (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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30352895

U2 - 10.2337/dc18-0431

DO - 10.2337/dc18-0431

M3 - Article

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SP - 208

EP - 214

JO - Diabetes Care

T2 - Diabetes Care

JF - Diabetes Care

SN - 0149-5992

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ER -