High Concentrations of Immunoglobulin G Against Cow Milk Proteins and Frequency of Cow Milk Consumption Are Associated With the Development of Islet Autoimmunity and Type 1 Diabetes: The Trial to Reduce Insulin-dependent Diabetes Mellitus (IDDM) in the Genetically at Risk (TRIGR) Study

Background: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) (NCT00179777) found no difference type 1 diabetes risk between hydrolyzed and regular infant formula. However, cow milk consumption during childhood is consistently linked to type 1 diabetes risk in prospective cohort studies. Objectives: Our primary aim was to study whether humoral immune responses to cow milk and cow milk consumption are associated with type 1 diabetes in TRIGR children. Methods: TRIGR comprised 2159 children with genetic susceptibility to type 1 diabetes born between 2002 and 2007 in 15 countries. Children were randomly assigned into groups receiving extensively hydrolyzed casein or a regular cow milk formula and followed up until age 10 y. Type 1 diabetes-related autoantibodies and antibodies to cow milk proteins were analyzed. Infant formula intake was measured by structured dietary interviews and milk consumption with a food frequency questionnaire. Associations of milk antibodies and milk consumption with risk to develop type 1 diabetes were analyzed using Cox survival model. Results: Cow milk antibody concentrations both in cord blood [hazards ratio (HR) for islet autoimmunity: 1.30; 95% CI: 1.05, 1.61; HR for type 1 diabetes: 1.32; 95% CI: 1.02, 1.71] and longitudinally from birth to 3 years (HR for islet autoimmunity: 1.39; 95% CI: 1.07, 1.81; HR for type 1 diabetes: 1.43; 95% CI: 1.04, 1.96) were associated with increased risk of developing type 1 diabetes. The amount of regular infant formula was associated with reduced islet autoimmunity risk in the regular infant formula group (HR: 0.92; 95% CI: 0.85, 0.99). Furthermore, frequent liquid milk consumption after infancy was associated with increased risk of islet autoimmunity or type 1 diabetes. Conclusions: Elevated cow milk antibody concentrations and high consumption of liquid milk after infancy are related to type 1 diabetes development in children with an increased genetic susceptibility to type 1 diabetes. Enhanced antibody concentrations to cow milk may provide a biomarker of immune system prone to develop islet autoimmunity. This trial was registered at clinicaltrials.gov as NCT00179777.