Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study

Maria Lonnrot; Kristian F. Lynch; Marian Rewers; Åke Lernmark; Kendra Vehik; Beena Akolkar; William Hagopian; Jeffrey Krischer; Rickhard A. McIndoe; Jorma Toppari; Anette G. Ziegler; Joseph F. Petrosino; Richard Lloyd; Heikki Hyoty; on behalf of the TEDDY Study Group

doi:10.2337/dc23-0518

Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study

Maria Lonnrot, Kristian F. Lynch, Marian Rewers, Åke Lernmark, Kendra Vehik, Beena Akolkar, William Hagopian, Jeffrey Krischer, Rickhard A. McIndoe, Jorma Toppari, Anette G. Ziegler, Joseph F. Petrosino, Richard Lloyd, Heikki Hyoty, on behalf of the TEDDY Study Group

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Abstract

OBJECTIVE To investigate gastrointestinal infection episodes (GIEs) in relation to the appear-ance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. RESEARCH DESIGN AND METHODS GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. RESULTS GIE reports (odds ratio [OR] 2.17 [95% CI 1.39–3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36–23.7]) at <1 year of age were associated with an increased IAA risk at 2–4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35–0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12–23 months prior [1.41–2.96]). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 [1.54–3.02]). CONCLUSIONS Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12–23 months prior to IAA. Nor-walk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.

Original language	English
Pages (from-to)	1908-1915
Number of pages	8
Journal	DIABETES CARE
Volume	46
Issue number	11
DOIs	https://doi.org/10.2337/dc23-0518
Publication status	Published - 2023
Publication type	A1 Journal article-refereed

Funding

Acknowledgments. The authors thank Sarah Austin-Gonzalez with the Health Informatics Institute at the University of South Florida for assistance with editing and preparing the graphical abstract. The authors especially acknowledge the TEDDY families for continued participation in this wonderful study. Funding. The TEDDY study is funded by National Institute of Diabetes and Digestive and Kidney Diseases grants U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, U01 DK124166, and U01 DK128847 and contract HHSN267200700014C and by the National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, Centers for Disease Control and Prevention, and JDRF. This work is also supported in part by the National Institutes of Health/National Center for Advancing Translation Science clinical and translational science awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR002535).

Funders	Funder number
National Institutes of Health
Centers for Disease Control and Prevention
National Institute of Allergy and Infectious Diseases
National Institute of Diabetes and Digestive and Kidney Diseases	U01 DK128847, UC4 DK117483, UC4 DK95300, U01 DK63790, UC4 DK100238, UC4 DK106955, U01 DK63821, UC4 DK63865, UC4 DK63836, U01 DK63829, HHSN267200700014C, UC4 DK112243, U01 DK124166, UC4 DK63861, UC4 DK63863
National Institute of Environmental Health Sciences
National Center for Advancing Translational Sciences	UL1 TR000064
Juvenile Diabetes Research Foundation United States of America
Eunice Kennedy Shriver National Institute of Child Health and Human Development
University of Colorado	UL1 TR002535

Keywords

Child
Humans
Infant
Child, Preschool
Autoantibodies
Diabetes Mellitus, Type 1
Case-Control Studies
Insulin
Insulin Antibodies
Glutamate Decarboxylase
Islets of Langerhans

Publication forum classification

Publication forum level 3

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/dc23-0518

Gastrointestinal Infections
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Cite this

Lonnrot, M., Lynch, K. F., Rewers, M., Lernmark, Å., Vehik, K., Akolkar, B., Hagopian, W., Krischer, J., McIndoe, R. A., Toppari, J., Ziegler, A. G., Petrosino, J. F., Lloyd, R., Hyoty, H., & on behalf of the TEDDY Study Group (2023). Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study. DIABETES CARE, 46(11), 1908-1915. https://doi.org/10.2337/dc23-0518

@article{4e9525e13c894e7facade0641898705d,

title = "Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study",

abstract = "OBJECTIVE To investigate gastrointestinal infection episodes (GIEs) in relation to the appear-ance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. RESEARCH DESIGN AND METHODS GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. RESULTS GIE reports (odds ratio [OR] 2.17 [95% CI 1.39–3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36–23.7]) at <1 year of age were associated with an increased IAA risk at 2–4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35–0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12–23 months prior [1.41–2.96]). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 [1.54–3.02]). CONCLUSIONS Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12–23 months prior to IAA. Nor-walk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.",

keywords = "Child, Humans, Infant, Child, Preschool, Autoantibodies, Diabetes Mellitus, Type 1, Case-Control Studies, Insulin, Insulin Antibodies, Glutamate Decarboxylase, Islets of Langerhans",

author = "Maria Lonnrot and Lynch, {Kristian F.} and Marian Rewers and {\AA}ke Lernmark and Kendra Vehik and Beena Akolkar and William Hagopian and Jeffrey Krischer and McIndoe, {Rickhard A.} and Jorma Toppari and Ziegler, {Anette G.} and Petrosino, {Joseph F.} and Richard Lloyd and Heikki Hyoty and {on behalf of the TEDDY Study Group}",

note = "Publisher Copyright: {\textcopyright} 2023 by the American Diabetes Association.",

year = "2023",

doi = "10.2337/dc23-0518",

language = "English",

volume = "46",

pages = "1908--1915",

journal = "DIABETES CARE",

issn = "0149-5992",

publisher = "American Diabetes Association",

number = "11",

}

Lonnrot, M, Lynch, KF, Rewers, M, Lernmark, Å, Vehik, K, Akolkar, B, Hagopian, W, Krischer, J, McIndoe, RA, Toppari, J, Ziegler, AG, Petrosino, JF, Lloyd, R, Hyoty, H & on behalf of the TEDDY Study Group 2023, 'Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study', DIABETES CARE, vol. 46, no. 11, pp. 1908-1915. https://doi.org/10.2337/dc23-0518

TY - JOUR

T1 - Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study

AU - Lonnrot, Maria

AU - Lynch, Kristian F.

AU - Rewers, Marian

AU - Lernmark, Åke

AU - Vehik, Kendra

AU - Akolkar, Beena

AU - Hagopian, William

AU - Krischer, Jeffrey

AU - McIndoe, Rickhard A.

AU - Toppari, Jorma

AU - Ziegler, Anette G.

AU - Petrosino, Joseph F.

AU - Lloyd, Richard

AU - Hyoty, Heikki

AU - on behalf of the TEDDY Study Group

PY - 2023

Y1 - 2023

N2 - OBJECTIVE To investigate gastrointestinal infection episodes (GIEs) in relation to the appear-ance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. RESEARCH DESIGN AND METHODS GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. RESULTS GIE reports (odds ratio [OR] 2.17 [95% CI 1.39–3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36–23.7]) at <1 year of age were associated with an increased IAA risk at 2–4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35–0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12–23 months prior [1.41–2.96]). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 [1.54–3.02]). CONCLUSIONS Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12–23 months prior to IAA. Nor-walk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.

AB - OBJECTIVE To investigate gastrointestinal infection episodes (GIEs) in relation to the appear-ance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. RESEARCH DESIGN AND METHODS GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. RESULTS GIE reports (odds ratio [OR] 2.17 [95% CI 1.39–3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36–23.7]) at <1 year of age were associated with an increased IAA risk at 2–4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35–0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12–23 months prior [1.41–2.96]). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 [1.54–3.02]). CONCLUSIONS Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12–23 months prior to IAA. Nor-walk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.

KW - Child

KW - Humans

KW - Infant

KW - Child, Preschool

KW - Autoantibodies

KW - Diabetes Mellitus, Type 1

KW - Case-Control Studies

KW - Insulin

KW - Insulin Antibodies

KW - Glutamate Decarboxylase

KW - Islets of Langerhans

U2 - 10.2337/dc23-0518

DO - 10.2337/dc23-0518

M3 - Article

C2 - 37607456

AN - SCOPUS:85175355699

SN - 0149-5992

VL - 46

SP - 1908

EP - 1915

JO - DIABETES CARE

JF - DIABETES CARE

IS - 11

ER -

Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study

Abstract

Funding

Keywords

Publication forum classification

ASJC Scopus subject areas

UN SDGs

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