Genetic heterogeneity may affect the analysis of risk factors associated with type 1 diabetes (T1D). We studied the effect of the INS -23A/T, PTPN22 1858C/T, and CTLA-4 +49A/G polymorphisms on the emergence of T1D-associated autoimmunity in children exposed to cow's milk (CM) based formula during early or late infancy. The study comprised of 156 children from the Finnish DIPP cohort who had developed >or= 2 types of autoantibodies (ICA, IAA, GADA or IA-2A) or clinical T1D and 563 control children. The PTPN22 1858T allele was associated with the appearance of the autoantibodies and clinical T1D among children exposed to CM formula before the age of 6 months (PTPN22: for all P <or= 0.001, Log Rank test), but not among children exposed later on. Cox regression analysis showed an interaction between early CM exposure and 1858T allele and enhanced appearance of ICA, IAA and IA-2A (for all P <or= 0.04). Our results imply that the PTPN22 polymorphism affects the development of T1D-associated autoimmunity only if children are exposed to CM formula during early infancy suggesting an interplay between genetic and environmental factors. This may provide an explanation for the contradictory findings on the significance of CM formula exposure in T1D.