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 appearance 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. Norwalk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.

Graphical abstract

Figure 1

Age-specific incidence of IAA, GADA, and IA-2A as the first-appearing autoantibody (A) and GIEs (B).

Figure 2

IAA risk irrespective of age (solid horizontal line, OR [95% CI]) and by age (×, OR) when GIE was reported at <1 year of age (A), 1 to <2 years of age (B), and 2 to <3 years of age (C). Time lag correlation at 0–11 months (D) 12–23 months (E), and 24–35 months (F) between GIEs and subsequent risk of IAA-first development irrespective of age (solid horizontal line, OR [95% CI]) and at the age when children developed IAA (×, OR). Period of autoantibody development is defined as time after a scheduled blood draw visit up until the next blood draw visit when autoantibodies can be first detected.

Figure 3

Common viruses in stools (n = 7,202) collected monthly from 751 children 3–24 months of age and association with the odds of GIE report within ±2 weeks from stool sample collection date (A). Percentage of stool samples (B) (separate bars for virus-positive and virus-negative samples) with a reported GIE within ±2 weeks from stool sample collection date.

Figure 4

Common viruses (>2.5% of samples) in stools of children between 3 and 12 months of age (A and B) and 13–24 months of age (C) in relation to risk of IAA-first appearance between the 6 and 24 months of age (A) (n = 127 IAA-first case and match control pairs) and between 25 and 60 months of age (B and C) (n = 52 IAA-first case and match control pairs). Viruses in relation to IAA-first were examined separately, adjusting for HLA-DR genotype and matching factors (sex, site, and family history of T1D). Associations with P < 0.05 are shown in color. #Significant interaction between virus and age of seroconversion.