Human Leukocyte Antigen (HLA) Genotype and Probiotics Modify the Association between Early Infant Feeding and Islet Autoimmunity in the TEDDY Study

Abstract

Several studies have examined the duration of breastfeeding and timing of introduction of complementary foods in the development of type 1 diabetes (T1D) related islet autoimmunity (IA). The results have varied by country. This is the first attempt to study the association in a multi‐country setting.The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8676 children with T1D‐associated human leukocyte antigen (HLA) DR‐ and DQ‐alleles in the U.S., Finland, Germany, and Sweden. Blood samples were collected every 3 months from birth to evaluate the primary outcome of IA, defined as appearance of one or more of the islet cell antibodies to insulin, glutamic acid decarboxylase or insulinoma antigen‐2, confirmed in two laboratories at two consecutive visits. The age at introduction of solid foods was categorized: < 4, 4–5.9, and ≥ 6 months. Reported probiotic exposure via infant formula or via dietary supplements during the first year of life was collected. Children followed at least 1 year (n=7481) were included in the study. We used Cox regression model adjusting for country, family T1D status, HLA‐DR‐DQ genotype, and sex of the child to study the risk of IA.Significant interactions between the HLA‐DR‐DQ genotype, probiotic exposure before 6 months, and timing of solid foods (pinteraction=0.036) and gluten containing cereals (pinteraction=0.015) in relation to IA risk were detected. Early introduction of any solid food was associated with increased risk of IA (<4 months versus ≥6 months: HR 2.46; 95% CI 1.43, 4.22, p=0.001, and 4–5.9 months versus ≥ 6 months: HR 2.32; 95% CI 1.36, 3.94, p=0.002) if the child had DR3/4 genotype and had not received probiotics during the first 6 months of life. However, if probiotics were given before 6 months of age the risk of IA was lower among those with DR3/4 genotype: introduction of solid foods before 4 months of age: HR 0.44; 95% CI 0.20, 0.99, p=0.047 and at 4–5.9 months: HR 0.35; 95% CI 0.16, 0.77, p=0.009, respectively, when compared with introduction of solid foods at 6 months or later.We conclude that timing of solid food introduction may be associated with IA in TEDDY in a manner linked to HLA genotype and to the exposure of probiotics during the first 6 months.Support or Funding InformationFunded by NIH, NIDDK, NIAID, NICHD, NIEHS, JDRF and CDC.