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.


CONCLUSIONS
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.
Bottema
Renske W B
RW
Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Kerkhof
Marjan
M
Reijmerink
Naomi E
NE
Thijs
Carel
C
Smit
Henriette A
HA
van Schayck
Constant P
CP
Brunekreef
Bert
B
van Oosterhout
Antoon J
AJ
Postma
Dirkje S
DS
Koppelman
Gerard H
GH
D000485:Allergens / Q000009:adverse effects; D001249:Asthma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004843:Epistasis, Genetic / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D056426:Genetic Loci / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007223:Infant; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D016015:Logistic Models; D008297:Male; D008957:Models, Genetic; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology
D000485:Allergens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; C508594:IL2 protein, human; C508017:IL2RA protein, human; C508600:IL6 protein, human; C508603:IL6R protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D007073:Immunoglobulin E; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human