IgE-mediated reaction is the central component of allergic diseases. Five key inflammatory genes affecting IgE levels, including IL13, IL4, IL4RA, FCER1B and ADRB2 [10,11,12], have been demonstrated associated with asthma or atopy by more than ten different studies . Our previous study has found that gene–gene interactions on asthma exist between these genes in Chinese Han children . This study attempted to determine whether the interactions begin in utero, and whether these genes interact with prenatal environmental factors to increase CBIgE levels and induce subsequent allergic diseases. Of the models tested using GMDR approach, the four-way gene–gene interaction model consisting of IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713 was chosen as the optimal one for CBIgE elevation based on its TBA and P value. Among the four SNPs, only IL13 rs20541 was identified to have an independent effect on CBIgE elevation, while the other three had small but synergistic effects. Carriers of IL13 rs20541 TT, IL13 rs1800925 CT/TT, IL4 rs2243250 TT and ADRB2 rs1042713 AA were estimated to be at more than fourfold higher risk for CBIgE elevation. Among these genes and prenatal environmental factors, only IL4 rs2243250 and maternal atopy were found to have interactions on elevated CBIgE. This is the first study to elucidate genetic and environmental determinants of CBIgE in Han population of mainland China.
To our knowledge, this study is also the first to identify gene–gene interactions between IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713 on CBIgE elevation. IL13 and IL4 genes encode cytokines interleukin 13 (IL13) and IL4, which share a common signaling pathway in binding to their receptors on human B cells, and switch immunoglobulin production from IgM to IgE . ADRB2 gene encodes Beta2-adrenergic receptor (ADRB2). Stimulation of ADRB2 on B cells responding to allergen enhances IgE production via a unique signaling pathway, independently of class switch recombination [17, 18]. IL13, IL4 and ADRB2 are all associated with IgE levels. IL13 rs20541 TT genotype, IL13 rs1800925 T allele, IL4 rs2243250 TT genotype and ADRB2 rs1042713 AA genotype have been associated with increased IL13 concentration , enhanced IL13 promoter activity , augmented IL4 levels , and decreased downregulation of ADRB2 , respectively. How these four varients interact with each other biologically to promote IgE production in prenatal stage need further functional studies in vitro and in vivo.
In this study, gene-environment interaction on elevated CBIgE was found between IL4 rs2243250 and maternal atopy. Maternal atopy has been reported to modify cord blood immune response and it may provide an intrauterine environment that influences fetal immune development and results in allergic predisposition [23,24,25]. IL4 gene polymorphism affects cytokine IL4 levels . How maternal atopy interacts with IL4 gene variants to enhance antenatal IgE production need future biological studies.
Our study confirmed the independent role of IL13 rs20541 and rs1295686 on CBIgE elevation, and also found the association of cesarean section and male gender with elevated CBIgE levels, consistent with previous reports [3, 5,6,7, 27]. However, no interactions were identified among them. To date, only a few studies have explored gene–gene and gene-environment interactions on CBIgE elevation. One study in a predominantly black sample reported that three IL13 SNPs (rs1295686, rs1800925 and rs206974) could jointly influence CBIgE concentration . One study in a birth cohort in Korea identified interactions between reactive oxygen species genes, prenatal exposure to home renovation and maternal atopy on CBIgE response . Another study, in a Chinese population in Taiwan, found that IL13 rs20541, male sex and prenatal environmental tobacco smoke interacted on antenatal IgE production . In this study, we found a four-way genetic interactions among IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713, and a two-way gene-environment interactions between IL4 rs2243250 and maternal atopy on CBIgE elevation. The variation of the gene–gene and gene-environment interactions on fetal IgE production may be in part explained by different populations and different genetic and environmental factors focused in different studies. Therefore, when we move forward to identify constellations of interacting genes and environments that influence antenatal IgE production, replication studies in different populations are required.
There are some limitations in this study. First, only five genes (IL13, IL4, IL4RA, FCER1B and ADRB2) were chosen as candidate genes. However, these five genes are susceptible genes of asthma and atopy replicated in more than ten different studies , and our previous study has found that gene–gene interactions on asthma exist between these genes in Chinese Han children . Second, the subjects’ environmental exposures were evaluated using a self-reported questionnaire, which might lead to an underestimation of the associations of certain environmental exposures. Genes and environmental factors interact to elevate CBIgE concentrations [5,6,7], with the heritability estimated around 84–95% . In our future studies, more candidate genes especially those from genome-wide association studies should be included and direct measurement of certain environmental exposures is needed. Third, cord blood IgA concentrations were not measured to exclude subjects whose circulation was contaminated by maternal blood. However, previous studies using cord blood IgA levels as an indicator of maternal contamination have reported a very low rate of contamination . Therefore CBIgE is unlikely to be contaminated by maternal IgE .
In summary, Gene–gene interaction between IL13 rs20541, IL13 rs1800925, IL4 rs2243250 and ADRB2 rs1042713, and gene-environment interaction between IL4 rs2243250 and maternal atopy begin in fetal stage to increase IgE production in Chinese Han children. After future functional and replication studies, these findings may be translated into specific strategies for early prediction and prevention of allergy.