Co-occurrence of Type 1 Diabetes and Celiac Disease Autoimmunity

Abstract

BACKGROUND AND OBJECTIVES Few birth cohorts have prospectively followed development of type 1 diabetes (T1D) and celiac disease (CD) autoimmunities to determine timing, extent of co-occurrence, and associated genetic and demographic factors. METHODS In this prospective birth cohort study, 8676 children at high genetic risk of both diseases were enrolled and 5891 analyzed in median follow-up of 66 months. Along with demographic factors and HLA-DR-DQ, genotypes for HLA-DPB1 and 5 non-HLA loci conferring risk of both T1D and CD were analyzed. RESULTS Development of persistent islet autoantibodies (IAs) and tissue transglutaminase autoantibodies (tTGAs), as well as each clinical disease, was evaluated quarterly from 3 to 48 months of age and semiannually thereafter. IAs alone appeared in 367, tTGAs alone in 808, and both in 90 children. Co-occurrence significantly exceeded the expected rate. IAs usually, but not always, appeared earlier than tTGAs. IAs preceding tTGAs was associated with increasing risk of tTGAs (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.15–1.91). After adjusting for country, sex, family history, and all other genetic loci, significantly greater co-occurrence was observed in children with a T1D family history (HR: 2.80), HLA-DR3/4 (HR: 1.94) and single-nucleotide polymorphism rs3184504 at SH2B3 (HR: 1.53). However, observed co-occurrence was not fully accounted for by all analyzed factors. CONCLUSIONS In early childhood, T1D autoimmunity usually precedes CD autoimmunity. Preceding IAs significantly increases the risk of subsequent tTGAs. Co-occurrence is greater than explained by demographic factors and extensive genetic risk loci, indicating that shared environmental or pathophysiological mechanisms may contribute to the increased risk.

Type 1 Diabetes and Celiac Disease: Causal Association or True, True, Unrelated?

“…There are preclinical studies demonstrating that a gluten-free diet prevents or delays diabetes onset in nonobese diabetic mice, 13 and changes the composition of the innate immune system, 14 which is in contrast to results reported by Hagopian et al 10 in which autoimmunity to CD was not significantly associated with development of T1D autoimmunity. Two clinical trials have been conducted to evaluate the relationship between gluten exposure and T1D.…”

“…In this issue, Hagopian et al 10 find that the co-occurrence of T1D autoimmunity and CD autoimmunity is higher than would be expected in the general population. In a crosssectional analysis, individuals with autoantibodies to 1 disease had increased prevalence of antibodies to the other disease.…”

Incidence and risk of celiac disease after type 1 diabetes: A population‐based cohort study using the health improvement network database

“…Our finding of increased risk of CD with younger-onset diabetes is in agreement with previous studies of children with diabetes. 2,12,13,15 The mechanism underlying increased risk of CD with younger age at diabetes diagnosis may be related to the hypothesis of common determinants for both diseases, 13 including environmental exposures, genetic background (including HLA and non-HLA variants), 31,32 and the gut microbiome. 33 Combined exposure history and genetic predisposition may impact autoimmunity: for example, timing of cereal introduction to infants genetically susceptible to diabetes or CD is associated with seropositivity, and certain viral infections have been linked to diabetes and CD risk.…”

Screening for coeliac disease in children

“…Further unanswered questions are the right age for the first screening to optimise diagnostic yield and prevent permanent complications and how seronegative cases should be followed up. Interestingly, evidence provided by The Environmental Determinants of Diabetes in the Young, a prospective multicentre birth cohort study published in 2017, indicated that the great majority of genetically at‐risk children developed coeliac disease autoantibodies before 10 years of age . However, this may not be generalisable to all populations and it must be realised that new cases of celiac disease can appear at any age.…”