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Background: Exposure to cow’s milk protein in early infancy could lead to increased rates of allergic diseases later in life. We investigated whether feeding a protein-hydrolyzed formula (HF) in the first 6 months of life decreased allergic diseases up to 36 months later. Methods: Newborns who had at least 1 first-degree family member with a history of atopy and could not breast-feed were enrolled. They were fed with HF or cow’s milk infant formula (CM) for at least 6 months via an open-label protocol and were monitored prospectively at 6, 18 and 36 months of age to assess allergy sensitization and allergic diseases. Results: A total of 1,002 infants were enrolled and 679 infants were consistently fed the same formula for the first 6 months of life (345 HF and 334 CM). The percentage of food sensitization (especially to milk protein) was significantly lower in the HF group than in the CM group at 36 months (12.7 vs. 23.4%, p = 0.048). There was no significant difference in the prevalence of aeroallergen sensitization between the groups. Occurrence of allergic diseases during the first 3 years of life was significantly correlated with aeroallergen sensitization, but not to food allergen sensitization, parental atopy or feeding types. Conclusions: Infants fed with HF during the first 6 months of life had a significantly lower percentage of sensitization to milk protein allergens, but not allergic diseases during the first 3 years of life. Avoidance of cow’s milk protein alone in infancy is not enough to decrease rates of allergic diseases.

To cite this article: Yang KD, Chang J-C, Chuang H, Liang H-M, Kuo H-C, Lee Y-S, Hsu T-Y, Ou C-Y. Gene–gene and gene–environment interactions on IgE production in prenatal stage. Allergy 2010; 65: 731–739. Abstract Background: Prevalence of allergic diseases in children has increased worldwide over the past decades. Allergy sensitization may occur in fetal life. This study investigated whether gene–gene and gene–environment interactions affected cord blood IgE (CBIgE) levels. Methods: A total of 575 cord blood DNA samples were subjected to a multiplex microarray for 384 single nucleotide polymorphisms (SNPs) in 159 allergy candidate genes. Genetic association was initially assessed by univariate and multivariate analyses. Multifactor dimensionality reduction (MDR) was used to identify gene–gene and gene–environment interactions. Environmental factors for analysis included maternal atopy, paternal atopy, parental smoking, gender, and prematurity. Results: Twenty-one SNPs in 14 genes were associated with CBIgE elevation (≥0.5 KU/l) in univariate analysis. Multivariate analysis identified eleven genes (IL13, IL17A, IL2RA, CCL17, CXCL1, PDGFRA, FGF1, HAVCR1, GNAQ, C11orf72, and ADAM33) which were significantly associated with CBIgE elevation. MDR analyses of gene–gene interactions identified IL13 interacted with IL17A and/or redox genes on CBIgE elevation with the prediction accuracy of 62.52%. Analyses of gene–environment interactions identified that maternal atopy combined with IL13, rs1800925 and CCL22, rs170359 SNPs had the highest prediction accuracy of 67.15%. All the high and low risk classifications on gene–gene and gene–environment interactions by MDR analyses could be validated by Chi-square test. Conclusions: Gene–gene (e.g. immune and redox genes) and gene–environment (e.g. maternal atopy and FGF1or redox genes) interactions on IgE production begin in prenatal stage, suggesting that prevention of IgE-mediated diseases may be made possible by control of maternal atopy and redox responses in prenatal stage.

Background Wheezing episodes are common in young infants. However, the molecular mechanism of wheezing is unclear, and very few therapeutic regimens are effective. Objective This study investigated the genetic and environmental factors predisposing to infant wheezing in a birth cohort study. Methods A cohort of 1211 pregnant women was recruited for this study. Infant wheezing episodes during the first 18 months of life were correlated to parental atopic history, parental smoking, prematurity, CB IgE levels, and the sequence variant (G+38A) of the Clara cell protein 10 (CC10) gene encoding a secretary anti-inflammatory CC10 protein. Results Nine hundred eighty-three infants completed umbilical cord blood collection, and 813 infants completed the 18-month postnatal follow-up. Twenty-two percent of the infants experienced at least 1 wheezing episode, and 6.6% of the infants experienced frequent wheezing (≥3 episodes). Multivariate logistic regression showed that male sex and the CC10 G+38A polymorphism, but not prematurity, CB IgE level, passive smoking, or parental atopy, were predictors of frequent wheezing. Further studies found that infant frequent wheezing was significantly associated with the CC10 +38AA genotype and lower plasma CC10 levels at 18 months of age ( P = .046), and infants with acute wheezing episodes had significantly lower CC10 levels than those without ( P = .023). No association of wheezing episodes with allergic sensitization was observed in this cohort population. Conclusion Infant frequent wheezing is associated with the CC10 G+38A polymorphism and lower CC10 levels but not infant atopy. Clinical implications Lower CC10 expression, but not allergy sensitization, is involved in the pathogenesis of infant frequent wheezing.

Summary Background Genetic heritability and maternal atopy have been correlated to antenatal IgE production, but very few studies have studied gene–maternal atopy interaction on antenatal IgE production. This study investigated the interaction of CTLA-4 polymorphism with prenatal factors on the elevation of cord blood IgE (CBIgE). Methods Pregnant women were antenatally recruited for collection of prenatal environmental factors by a questionnaire. Umbilical cord blood samples were collected for CBIgE detection by fluorescence-linked enzyme assay and CTLA-4 polymorphism measurement by restriction fragment length polymorphism. Results A total of 1104 pregnant women initially participated in this cohort study, and 898 of them completed cord blood collection. 21.4% of the newborns had elevation of CBIgE (0.5 kU/L). The CTLA-4+49A allele (P=0.021), maternal atopy (P

Elevation of serum IgE levels has long been associated with allergic diseases. Many genes have been linked to IgE production, but few have been linked to the developmental aspects of genetic association with IgE production. To clarify developmental genetic association, we investigated what genes and gene-gene interactions affect IgE levels among fetus, infancy and childhood in Taiwan individuals. A birth cohort of 571 children with completion of IgE measurements from newborn to 1.5, 3, and 6 years of age was subject to genetic association analysis on the 384-customized SNPs of 159 allergy candidate genes. Fifty-three SNPs in 37 genes on innate and adaptive immunity, and stress and response were associated with IgE production. Polymorphisms of the IL13, and the HLA-DPA1 and HLA-DQA1 were, respectively, the most significantly associated with the IgE production at newborn and 6 years of age. Analyses of gene-gene interactions indentified that the combination of NPSR1, rs324981 TT with FGF1, rs2282797 CC had the highest risk (85.7%) of IgE elevation at 1.5 years of age (P=1.46 × 10(-4)). The combination of IL13, CYFIP2 and PDE2A was significantly associated with IgE elevation at 3 years of age (P=5.98 × 10(-7)), and the combination of CLEC2D, COLEC11 and CCL2 was significantly associated with IgE elevation at 6 years of age (P=6.65 × 10(-7)). Our study showed that the genetic association profiles of the IgE production among fetus, infancy and childhood are different. Genetic markers for early prediction and prevention of allergic sensitization may rely on age-based genetic association profiles.