BACKGROUND: Asthma is a chronic respiratory disease that often originates in early childhood. Although candidate gene studies have identified many potential asthma susceptibility genes in adult populations, few have studied associations with immune phenotypes in the first year that might be early clinical markers of asthma. OBJECTIVE: The aim of this study was to assess the contribution of genetic variation to cytokine response profiles and atopic phenotypes in the first year of life in the Childhood Origin of Asthma cohort. METHODS: Two hundred seven European American children participating in the Childhood Origin of Asthma study were genotyped for 61 single nucleotide polymorphisms in 35 genes involved in immune regulation. We examined the relationship between these single nucleotide polymorphisms and PHA-induced cytokine (IL-5, IL-10, IL-13, and IFN-gamma) response profiles at birth and at year 1, respiratory syncytial virus-induced wheezing and atopic dermatitis in the first year of life, and total IgE levels, peripheral blood eosinophil counts, and allergic sensitization at age 1 year. The data were analyzed by using censored regression for quantitative measurements and logistic regression for qualitative phenotypes. RESULTS: The 237Gly allele of the high-affinity IgE receptor beta chain (FCER1B) and a silent substitution in the nitric oxide synthase (NOS)2A gene were associated with reduced IL-13 responses in cord blood (P = .0025 and P = .0062, respectively). A significant gene-gene interaction between FCER1B 237Gly and NOS2A D346D was detected, with individuals carrying the minor allele for both polymorphisms having the lowest cord blood IL-13 levels. Furthermore, the IL13 110Gln allele showed an association with increased IgE levels at year 1 (P = .0026), and the colony-stimulating factor 2 (CSF2) 117Thr allele showed an association with a greater increase in IL-5 responses during the first year (P = .0092). The TGF-beta1 (TGFB1) -509T allele was associated with respiratory syncytial virus-related wheezing in the first year (P = .0005). None of the polymorphisms included in this study were associated with atopic dermatitis during the first year or a positive RAST result at 1 year of age. CONCLUSION: These data suggest that variations in genes involved in immune regulation are associated with biologic and clinical phenotypes in the first year of life that might increase the risk for the subsequent development of childhood asthma.