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

R.W. Bottema, M. Kerkhof, N.E. Reijmerink, C. Thijs, H.A. Smit, C.P. van Schayck, B. Brunekreef, A. J. van Oosterhout, D.S. Postma, G.H. Koppelman

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Abstract

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.
Original languageEnglish
Pages (from-to)338-346.e10
Number of pages19
JournalJournal of Allergy and Clinical Immunology
Volume126
Issue number2
DOIs
Publication statusPublished - Aug 2010

Keywords

  • T regulatory cells
  • atopy
  • IgE
  • asthma
  • MDR
  • polymorphism
  • interaction
  • birth cohort
  • MULTIFACTOR-DIMENSIONALITY REDUCTION
  • TRANSFORMING GROWTH-FACTOR-BETA-1
  • PROMOTER POLYMORPHISMS
  • AIRWAY INFLAMMATION
  • ALLERGIC DISEASE
  • SERUM IGE
  • IMMUNOGLOBULIN-E
  • BIRTH COHORT
  • CHILDREN
  • ASSOCIATION

Cite this

Bottema, R.W. ; Kerkhof, M. ; Reijmerink, N.E. ; Thijs, C. ; Smit, H.A. ; van Schayck, C.P. ; Brunekreef, B. ; van Oosterhout, A. J. ; Postma, D.S. ; Koppelman, G.H. / Gene-gene interaction in regulatory T-cell function in atopy and asthma development in childhood. In: Journal of Allergy and Clinical Immunology. 2010 ; Vol. 126, No. 2. pp. 338-346.e10.
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abstract = "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.",
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author = "R.W. Bottema and M. Kerkhof and N.E. Reijmerink and C. Thijs and H.A. Smit and {van Schayck}, C.P. and B. Brunekreef and {van Oosterhout}, {A. J.} and D.S. Postma and G.H. Koppelman",
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Bottema, RW, Kerkhof, M, Reijmerink, NE, Thijs, C, Smit, HA, van Schayck, CP, Brunekreef, B, van Oosterhout, AJ, Postma, DS & Koppelman, GH 2010, 'Gene-gene interaction in regulatory T-cell function in atopy and asthma development in childhood', Journal of Allergy and Clinical Immunology, vol. 126, no. 2, pp. 338-346.e10. https://doi.org/10.1016/j.jaci.2010.04.024

Gene-gene interaction in regulatory T-cell function in atopy and asthma development in childhood. / Bottema, R.W.; Kerkhof, M.; Reijmerink, N.E.; Thijs, C.; Smit, H.A.; van Schayck, C.P.; Brunekreef, B.; van Oosterhout, A. J.; Postma, D.S.; Koppelman, G.H.

In: Journal of Allergy and Clinical Immunology, Vol. 126, No. 2, 08.2010, p. 338-346.e10.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Gene-gene interaction in regulatory T-cell function in atopy and asthma development in childhood

AU - Bottema, R.W.

AU - Kerkhof, M.

AU - Reijmerink, N.E.

AU - Thijs, C.

AU - Smit, H.A.

AU - van Schayck, C.P.

AU - Brunekreef, B.

AU - van Oosterhout, A. J.

AU - Postma, D.S.

AU - Koppelman, G.H.

PY - 2010/8

Y1 - 2010/8

N2 - 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.

AB - 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.

KW - T regulatory cells

KW - atopy

KW - IgE

KW - asthma

KW - MDR

KW - polymorphism

KW - interaction

KW - birth cohort

KW - MULTIFACTOR-DIMENSIONALITY REDUCTION

KW - TRANSFORMING GROWTH-FACTOR-BETA-1

KW - PROMOTER POLYMORPHISMS

KW - AIRWAY INFLAMMATION

KW - ALLERGIC DISEASE

KW - SERUM IGE

KW - IMMUNOGLOBULIN-E

KW - BIRTH COHORT

KW - CHILDREN

KW - ASSOCIATION

U2 - 10.1016/j.jaci.2010.04.024

DO - 10.1016/j.jaci.2010.04.024

M3 - Article

VL - 126

SP - 338-346.e10

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 2

ER -