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.


CONCLUSIONS
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.
Penders
John
J
Department of Epidemiology, Nutrition and Toxicology Research Institute Maastricht and Care and Public Health Research Institute, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. j.penders@epid.unimaas.nl
Thijs
Carel
C
Mommers
Monique
M
Stobberingh
Ellen E
EE
Dompeling
Edward
E
Reijmerink
Naomi E
NE
van den Brandt
Piet A
PA
Kerkhof
Marjan
M
Koppelman
Gerard H
GH
Postma
Dirkje S
DS
D002675:Child, Preschool; D003876:Dermatitis, Atopic / Q000235:genetics; D004926:Escherichia coli / Q000302:isolation & purification*; D005243:Feces / Q000382:microbiology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D018950:Lipopolysaccharide Receptors / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
D018950:Lipopolysaccharide Receptors; D051197:Toll-Like Receptor 4