Interaction of T-cell and antigen presenting cell co-stimulatory genes in childhood IgE.
It is likely that multiple genes contribute to immunoglobulin (Ig)E production. Co-stimulatory molecules are crucial for the cross-talk between antigen presenting cells and T-lymphocytes which drives the IgE response. We evaluated gene-gene interactions of haplotype tagging polymorphisms in a pathway of 24 co-stimulatory genes in relation to serum IgE levels. We assessed this at ages 1-2 yrs and 6-8 yrs in 3,062 Dutch children from a pooled data set of three birth cohorts: PIAMA (Prevention and Incidence Asthma and Mite Allergy), PREVASC (Prevention of Asthma in Children) and KOALA (Child, parents and health: lifestyle and genetic constitution). Single- and multi-locus associations with serum IgE levels (3rd versus 1st tertile) were evaluated by Chi-squared tests and the multifactor dimensionality reduction (MDR) method in the following co-stimulatory genes: VTCN1, TNFRSF4, TNFRSF18, TNFRSF14, TNFSF18, TNFSF4, CD28, CTLA4, ICOS, PDCD1, BTLA, CD80, CD86, HLA-G, CD274, PDCD1LG2, CD276, LILRA4, LILRB1, LILRB2, LILRB4, CD40, ICOSLG, and CD40LG. We found multiple statistically significant single-locus ((S)) and multi-locus ((M)) associations for the genes VTCN1(SM), TNFSF18(SM), TNFSF4(S), CD28(S), CTLA4(M), ICOS(S), BTLA(M), CD80(M), CD86(SM), CD274(SM), PDCD1LG2(M), LILRA4(SM), LILRB4(M), and CD40(SM) with serum IgE. Two-locus interactions of CD86 with VTCN1 and CD274 with LILRA4 were confirmed by logistic regression. In conclusion, serum IgE levels are regulated by multiple gene-gene interaction effects in the co-stimulatory pathway. We suggest using research strategies that model multiple gene-gene interactions in genetic studies.
Bottema
R W B
RW
Dept of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Postma
D S
DS
Reijmerink
N E
NE
Thijs
C
C
Stelma
F F
FF
Smit
H A
HA
van Schayck
C P
CP
Brunekreef
B
B
Koppelman
G H
GH
Kerkhof
M
M
D000938:Antigen-Presenting Cells / Q000502:physiology*; D002450:Cell Communication / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood* / Q000235:genetics*; D007223:Infant; D008297:Male; D011446:Prospective Studies; D013601:T-Lymphocytes / Q000502:physiology*
D007073:Immunoglobulin E