Interaction of T-cell and antigen presenting cell co-stimulatory genes in childhood IgE

Abstract

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 (3rdversus1st 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, andCD40LG. We found multiple statistically significant single-locus(S)and multi-locus(M)associations for the genesVTCN1SM,TNFSF18SM,TNFSF4S,CD28S,CTLA4M,ICOSS,BTLAM,CD80M,CD86SM,CD274SM,PDCD1LG2M,LILRA4SM,LILRB4M, andCD40SMwith serum IgE. Two-locus interactions ofCD86withVTCN1andCD274withLILRA4were 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.

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

“…The MDR approach has been described previously [37][38][39] and applied in this cohort. [40][41][42] The TLR2 gene has been studied in relation to other TLRs and atopy development by MDR (Reijmerink et al, unpublished data, May 2010). A detailed description of the MDR method is included in the Online Repository at www.jacionline.org, ''MDR'' section.…”

B7x in the Periphery Abrogates Pancreas-Specific Damage Mediated by Self-reactive CD8 T Cells

“…Recently a genome-wide association analysis identifies 10 single-nucleotide polymorphisms (SNPs) in non-coding regions of the B7x gene that are strongly associated with juvenile idiopathic arthritis (9). In addition, two SNPs in the B7x gene are significantly associated with increased serum IgE in children (10). Despite these recently discovered genetic data linking the B7x gene to different autoimmune diseases, it is unclear how B7x contributes to peripheral tolerance and autoimmunity.…”

A Genome-Wide Association Study of Total Serum and Mite-Specific IgEs in Asthma Patients

“…[2], [4], [12], [15], [29], this study confirmed a significant association between CD28 SNPs and total IgE in asthmatics (minimum P  = 0.001, data not shown). Serum total IgE levels have been elucidated to be correlated with CD28, an important regulator of T-cell activation and subsequent IgE production [30], [31]. In this study, differences in the results between present and previous GWASs might be attributed to population and/or ethnic differences, limitation and mismatch of the tested SNP markers (albeit only SNPs in the C11orf30 - LRRC32 region were matched with those of this GWAS), and a diversity of clinical phenotypes among asthma patients.…”