Interaction of T - cell and antigen presenting - cell co - stimulatory genes in childhood IgE 1 2 3 4

43 It is likely that multiple genes contribute to IgE production. Co-stimulatory molecules are crucial 44 for the cross-talk between antigen presenting cells and T-lymphocytes which drives the IgE 45 response. We evaluated gene-gene interactions of haplotype tagging polymorphisms in a pathway 46 of 24 co-stimulatory genes in relation to serum IgE levels. We assessed this at ages 1-2 years and 47 6-8 years in 3,062 Dutch children from a pooled data set of three birth cohorts PIAMA, 48 PREVASC and KOALA. Singleand multilocus associations with serum IgE levels (3 vs. 1 49 tertile) were evaluated by Chi-tests and multidimensionality-reduction method (MDR) in co50 stimulatory genes VTCN1, TNFRSF4, TNFRSF18, TNFRSF14, TNFSF18, TNFSF4, CD28, 51 CTLA4, ICOS, PDCD1, BTLA, CD80, CD86, HLA-G, CD274, PDCD1LG2, CD276, LILRA4, 52 LILRB1, LILRB2, LILRB4, CD40, ICOSLG, and CD40LG. We found multiple statistically 53 significant single (S) and multilocus (M) associations for the genes VTCN1, TNFSF18, 54 TNFSF4, CD28, CTLA4, ICOS, BTLA, CD80, CD86, CD274, PDCD1LG2, 55 LILRA4, LILRB4, and CD40 with serum IgE. Two-locus interactions of CD86 with VTCN1 56 and CD274 with LILRA4 were confirmed by logistic regression. In conclusion, serum IgE levels 57 are regulated by multiple gene-gene interaction effects in the co-stimulatory pathway. We suggest 58 using research strategies that model multiple gene-gene interactions in genetic studies. (200 59 words) 60 61