Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors

Results from the prospective TEDDY study

Andreas Beyerlein, Ezio Bonifacio, Kendra Vehik, Markus Hippich, Christiane Winkler, Brigitte I. Frohnert, Andrea K. Steck, William A. Hagopian, Jeffrey P. Krischer, Åke Lernmark, Marian J. Rewers, Jin-Xiong She, Jorma Toppari, Beena Akolkar, Stephen S. Rich, Anette G. Ziegler

Research output: Contribution to journalArticle

Abstract

Background Progression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown. Methods In 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression. Results Islet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93). Conclusions Genetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

Original languageEnglish (US)
Pages (from-to)602-605
Number of pages4
JournalJournal of medical genetics
Volume56
Issue number9
DOIs
StatePublished - Sep 1 2019

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Autoimmunity
Type 1 Diabetes Mellitus
Autoantibodies
HLA Antigens
Genotype
Disease Progression

Keywords

  • diabetes
  • diagnostics tests
  • epidemiology
  • immunology (including allergy)

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors : Results from the prospective TEDDY study. / Beyerlein, Andreas; Bonifacio, Ezio; Vehik, Kendra; Hippich, Markus; Winkler, Christiane; Frohnert, Brigitte I.; Steck, Andrea K.; Hagopian, William A.; Krischer, Jeffrey P.; Lernmark, Åke; Rewers, Marian J.; She, Jin-Xiong; Toppari, Jorma; Akolkar, Beena; Rich, Stephen S.; Ziegler, Anette G.

In: Journal of medical genetics, Vol. 56, No. 9, 01.09.2019, p. 602-605.

Research output: Contribution to journalArticle

Beyerlein, A, Bonifacio, E, Vehik, K, Hippich, M, Winkler, C, Frohnert, BI, Steck, AK, Hagopian, WA, Krischer, JP, Lernmark, Å, Rewers, MJ, She, J-X, Toppari, J, Akolkar, B, Rich, SS & Ziegler, AG 2019, 'Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: Results from the prospective TEDDY study', Journal of medical genetics, vol. 56, no. 9, pp. 602-605. https://doi.org/10.1136/jmedgenet-2018-105532
Beyerlein, Andreas ; Bonifacio, Ezio ; Vehik, Kendra ; Hippich, Markus ; Winkler, Christiane ; Frohnert, Brigitte I. ; Steck, Andrea K. ; Hagopian, William A. ; Krischer, Jeffrey P. ; Lernmark, Åke ; Rewers, Marian J. ; She, Jin-Xiong ; Toppari, Jorma ; Akolkar, Beena ; Rich, Stephen S. ; Ziegler, Anette G. / Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors : Results from the prospective TEDDY study. In: Journal of medical genetics. 2019 ; Vol. 56, No. 9. pp. 602-605.
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abstract = "Background Progression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown. Methods In 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression. Results Islet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95{\%} CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95{\%} CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95{\%} CI 1.28 to 2.93). Conclusions Genetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.",
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T1 - Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors

T2 - Results from the prospective TEDDY study

AU - Beyerlein, Andreas

AU - Bonifacio, Ezio

AU - Vehik, Kendra

AU - Hippich, Markus

AU - Winkler, Christiane

AU - Frohnert, Brigitte I.

AU - Steck, Andrea K.

AU - Hagopian, William A.

AU - Krischer, Jeffrey P.

AU - Lernmark, Åke

AU - Rewers, Marian J.

AU - She, Jin-Xiong

AU - Toppari, Jorma

AU - Akolkar, Beena

AU - Rich, Stephen S.

AU - Ziegler, Anette G.

PY - 2019/9/1

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N2 - Background Progression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown. Methods In 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression. Results Islet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93). Conclusions Genetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

AB - Background Progression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown. Methods In 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression. Results Islet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93). Conclusions Genetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

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KW - diagnostics tests

KW - epidemiology

KW - immunology (including allergy)

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DO - 10.1136/jmedgenet-2018-105532

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