Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy.

BACKGROUND: Both gastrointestinal microbiota composition and cesarean section have been linked to atopic manifestations. However, results are inconsistent, and the hypothesized intermediate role of the microbiota in the association between birth mode and atopic manifestations has not been studied yet. OBJECTIVES: We sought to investigate the relationship between microbiota composition, mode and place of delivery, and atopic manifestations. METHODS: The Child, Parent and Health: Lifestyle and Genetic Constitution Birth Cohort Study included data on birth characteristics, lifestyle factors, and atopic manifestations collected through repeated questionnaires from birth until age 7 years. Fecal samples were collected at age 1 month (n = 1176) to determine microbiota composition, and blood samples were collected at ages 1 (n = 921), 2 (n = 822), and 6 to 7 (n = 384) years to determine specific IgE levels. RESULTS: Colonization by Clostridium difficile at age 1 month was associated with wheeze and eczema throughout the first 6 to 7 years of life and with asthma at age 6 to 7 years. Vaginal home delivery compared with vaginal hospital delivery was associated with a decreased risk of eczema, sensitization to food allergens, and asthma. After stratification for parental history of atopy, the decreased risk of sensitization to food allergens (adjusted odds ratio, 0.52; 95% CI, 0.35-0.77) and asthma (adjusted odds ratio, 0.47; 95% CI, 0.29-0.77) among vaginally home-born infants was only found for children with atopic parents. Mediation analysis showed that the effects of mode and place of delivery on atopic outcomes were mediated by C difficile colonization. CONCLUSION: Mode and place of delivery affect the gastrointestinal microbiota composition, which subsequently influences the risk of atopic manifestations.

Interleukin-1 receptor-like 1 polymorphisms are associated with serum IL1RL1-a, eosinophils, and asthma in childhood.

BACKGROUND: IL-1 receptor-like 1 (IL1RL1) is a membrane receptor involved in T(H)2 inflammatory responses and eosinophilia. Single nucleotide polymorphisms (SNPs) in IL1RL1 have been associated with blood eosinophil counts in a genome-wide association study and with asthma in family-based and case-control studies. OBJECTIVE: We assessed in the prospective birth cohort Prevention and Incidence of Asthma and Mite Allergy (PIAMA) whether IL1RL1 SNPs associate with levels of its soluble transcript IL1RL1 (IL1RL1-a) in serum, blood eosinophil counts, and asthma prevalence from birth to age 8 years, and whether IL1RL1-a serum levels associate with blood eosinophil counts. METHODS: Fifteen IL1RL1 SNPs were genotyped. Serum IL1RL1-a levels were measured in 2 independent subsets within PIAMA, at 4 and 8 years. Blood eosinophil counts were measured in 4-year-old children. RESULTS: In 2 independent subsets of children, 13 of 15 SNPs were associated with serum IL1RL1-a levels at ages 4 and 8 years with a consistent direction of effect for each allele. Rs11685480 allele A and rs1420102 allele A were significantly associated with lower numbers of blood eosinophils. In the total cohort, rs1041973 allele A was associated with a decreased risk of developing asthma (odds ratio, 0.70; 95% CI, 0.54-0.90). Rs1420101, recently identified in a genome-wide association study in the Icelandic population, was not associated with asthma in this study. IL1RL1-a levels were not associated with eosinophil counts. CONCLUSION: We demonstrate that IL1RL1 polymorphisms are associated with serum IL1RL1-a, blood eosinophils, and asthma in childhood.

Intestinal lactobacilli and the DC-SIGN gene for their recognition by dendritic cells play a role in the aetiology of allergic manifestations.

Diminished exposure to harmless micro-organisms, such as lactobacilli, has been suggested to play a role in the increased prevalence of allergic disorders in Westernized communities. The development of allergies depends on both environmental factors and genetic variations, including polymorphisms in genes encoding pattern recognition receptors. The present study examines the effects of both colonization with specific Lactobacillus species and genetic variations in DC-SIGN, a pattern recognition receptor on dendritic cells that recognizes lactobacilli, on the development of atopic dermatitis (AD) and sensitization in infancy. Within the KOALA Birth Cohort Study, faecal samples of 681 one-month-old infants were collected and quantitatively screened for five Lactobacillus species: L. casei, L. paracasei, L. rhamnosus, L. acidophilus and L. reuteri. Eleven haplotype-tagging polymorphisms in the DC-SIGN gene were genotyped in these children. Allergic outcomes were a clinical diagnosis of AD and sensitization (specific IgE) at age 2 years. L. rhamnosus (31.5 %), L. paracasei (31.3 %) and L. acidophilus (14.4 %) were frequently detected in the faecal samples of one-month-old infants, whereas L. casei (2.5 %) and L. reuteri (<1 %) were rare. Colonization with L. paracasei decreased the risk of AD significantly (odds ratio 0.57, 95 % confidence interval 0.32-0.99), whereas effects of L. acidophilus were of borderline statistical significance (0.46, 0.20-1.04). Two DC-SIGN polymorphisms, rs11465413 and rs8112555, were statistically significantly associated with atopic sensitization. The present study supports the 'old friends' hypothesis suggesting that certain health-beneficial micro-organisms protect us from developing allergies and that these protective effects are species-dependent. Firm conclusions on the potential interaction between lactobacillus colonization and genetic variations in DC-SIGN in association with the development of allergic disorders cannot be drawn, given the limited power of our study. Therefore, incorporation of consecutive faecal sampling in newly started (birth) cohort studies would be a first requisite to further increase our understanding of host-microbial interactions in health and disease.

Gene-gene interaction in regulatory T-cell function in atopy and asthma development in childhood.

BACKGROUND: Regulatory T-cell dysfunction is associated with development of the complex genetic conditions atopy and asthma. Therefore, we hypothesized that single nucleotide polymorphisms in genes involved in the development and function of regulatory T cells are associated with atopy and asthma development. OBJECTIVE: To evaluate main effects and gene-gene interactions of haplotype tagging single nucleotide polymorphisms of genes involved in regulatory T-cell function-IL6, IL6R, IL10, heme-oxygenase 1 (HMOX1), IL2, Toll-like receptor 2 (TLR2), TGFB1, TGF-beta receptor (TGFBR)-1, TGFBR2, IL2RA, and forkhead box protein 3 (FOXP3)-in relation to atopy and asthma. METHODS: Single-locus and multilocus associations with total IgE (3rd vs 1st tertile); specific IgE to egg, milk, and indoor allergens; and asthma were evaluated by chi(2) tests and the multifactor dimensionality-reduction method in 3 birth cohorts (Allergenic study). RESULTS: Multiple statistically significant multilocus associations existed. IL2RA rs4749926 and TLR2 rs4696480 associated with IgE in both age groups tested (1-2 and 6-8 years). TGFBR2 polymorphisms associated with total and specific IgE in both age groups and with asthma. TGFBR2 rs9831477 associated with specific IgE for milk at age 1 to 2 years and indoor allergens at age 6 to 8 years. For milk-specific IgE, interaction between TGFBR2 and FOXP3 polymorphisms was confirmed by logistic regression and consistent in 2 birth cohorts and when stratified for sex, supplying internal replications. CONCLUSION: Genes involved in the development and function of regulatory T cells, specifically IL2RA, TLR2, TGFBR2, and FOXP3, associate with atopy and asthma by gene-gene interaction. Modeling of multiple gene-gene interactions is important to unravel further the genetic susceptibility to atopy and asthma.

Host-microbial interactions in childhood atopy: toll-like receptor 4 (TLR4), CD14, and fecal Escherichia coli.

BACKGROUND: Perturbations in the gut microbiota have been linked to atopic diseases. However, the development of atopic diseases depends not only on environmental factors (like microbial stimulation) but also on genetic factors. It is likely that particularly gene-environmental interactions in early life determine the development of atopy. OBJECTIVE: We examine the interaction between detection of fecal Escherichia coli and genetic variations in the CD14 and Toll-like receptor 4 (TLR4) genes in relation to atopic manifestations. METHODS: Within the Child, Parent and Health: Lifestyle and Genetic Constitution (KOALA) Birth Cohort Study, fecal samples of 957 one-month-old infants were collected and quantitatively screened for E coli. Fourteen haplotype-tagging polymorphisms in the genes TLR4 and CD14 were genotyped in 681 of the 957 children. Atopic outcomes were parentally reported eczema in the first 2 years of life and clinically diagnosed eczema and allergic sensitization at age 2 years. Multiple logistic regression was used to evaluate a multiplicative model of interaction. RESULTS: Most of the single nucleotide polymorphisms (SNPs) showed no significant interaction with E coli exposure for both eczema and allergic sensitization. A borderline significant multiplicative interaction was found between E coli and the rs2569190 (CD14/-159) SNP regarding allergic sensitization. Furthermore, a statistically significant multiplicative interaction was found for the TLR4 SNP rs10759932 (P for interaction = .001). E coli colonization was associated with a decreased risk of sensitization only in children with the rs10759932 TT genotype (adjusted odds ratio, 0.31; 95% CI, 0.14-0.68) and not in children with the minor C allele. This interaction remained statistically significant after controlling for multiple testing. CONCLUSION: The current study is the first to address the potential effect-modifying role of genetic variations in the relationship between the intestinal microbiota and allergy development.

CD14 polymorphisms in mother and infant, soluble CD14 in breast milk and atopy development in the infant (KOALA Study).

Different CD14 polymorphisms have been associated with atopic phenotypes in infants. In addition, CD14 genotypes of breastfeeding mothers have been associated with soluble CD14 (sCD14) levels in breast milk. The role of CD14 genotypes of infant and mother and their interaction with sCD14 levels in breast milk in atopy development remain to be established. We aimed to study the associations of CD14 single nucleotide polymorphisms (SNPs), and their interaction with breast milk sCD14, with atopy development until age two. In addition, we assessed whether levels of sCD14 in breast milk associated with SNPs in CD14. Four SNPs in CD14 gene were investigated in 698 infants and 188 mothers. Associations between these SNPs, sCD14 and atopy development were analyzed in multiple logistic or linear regression models. The CD14/-1619 SNP was associated with eczema. CC homozygotes showed a lower risk of eczema vs. TT homozygotes (adjusted odds ratio = 0.56, 95% confidence interval 0.33-0.96) in a co-dominant model. Breast milk sCD14 levels did not significantly modify the effect of the child's CD14 genotype on atopy development (p interaction > or =0.10). Maternal CD14 SNPs were not significantly associated with sCD14 levels in breast milk (anova, p > or = 0.48). We found only an association between CC homozygozity of SNP CD14/-1619 and eczema. Our data did not support a modifying role of breast milk sCD14 levels on the relationship between CD14 genotype and atopy development until age 2 yr.