臍帶血免疫球蛋白E升高的預測因子: 基因、產前居家環境、與受性別修飾之基因-環境交互作用

Abstract

The dissertation includes a review for cord blood biomarkers and a research on predictors of cord blood IgE elevation. The review aimed to evaluate the importance of cord blood biological markers in predicting the development of childhood atopic dermatitis. Two sub-studies were conducted to investigate the association of genetic variants of the IL-13, IL-4, and STAT6 genes from the cord blood and the association of prenatal environmental factors with cord blood IgE (cIgE) elevation, and to examine the influences of the potential gene by environment interactions on cIgE level in a population of Taiwanese term neonates. Review. Biological markers in cord blood to predict atopic dermatitis in childhood Atopic dermatitis, a chronic inflammatory skin disease that usually occurs in the first few years of life, is an important risk factor for the subsequent development of asthma. While genetic and early environmental risk factors for expression of atopic dermatitis have been widely investigated and reviewed, relatively little attention has been paid to whether different biologic compositions of cord blood could increase or reduce the risk of developing atopic dermatitis in childhood. At birth, collection of cord blood is an easy and non-invasive procedure. This mini-review attempts to search and evaluate which biomarkers in cord blood may be able to predict atopic dermatitis in childhood. Among studies related to this issue, most showed inconsistent or contradictory results. The biological markers which have been studied in cord blood include IgE, T helper 1 and T helper 2 cytokines, macrophage inflammatory protein β (MIP-1β), and fatty acids. Among them, IL-13 responses and MIP-1β in cord blood may be important predictors for the development of atopic dermatitis in childhood. Although many studies recognized the mutations of filaggrin gene (FLG) as major genetic determinants for atopic dermatitis, none of these studies detected FLG from the cord bloods. Moreover, epigenetic modification perhaps is another substantial predictor for atopic dermatitis, but the association between them remains unclear. To verify the significance of previously examined biomarkers and to identify new biological predictor in cord blood, such as FLG mutations or epigenetic modifications, a large-scaled birth cohort design is needed. Study I. Environmental tobacco smoke and male sex modify the influence of IL-13 genetic variants on cord blood IgE levels Elevated cord blood IgE (cIgE) levels enhance the risk of childhood atopic diseases. However, genetic determinants of cIgE elevation and their potential modifiers remain inconclusive. We aimed to investigate the associations of single nucleotide polymorphisms (SNPs) in the IL-13 gene (IL-13) with cIgE elevation and their interactions with prenatal environmental tobacco smoke (ETS) and neonatal sex. A structured questionnaire regarding prenatal environmental exposures was completed during pregnancy. Birth information was extracted from the medical records. Cord blood from 794 term neonates were genotyped for three SNPs (rs1800925, rs20541, and rs848) of IL-13 and measured for cIgE levels. SNP rs20541 and a 3-SNP haplotype containing rs1800925, rs20541, and rs848 (denoted as h011) were significantly associated with cIgE elevation (p = 0.04 and 0.003, respectively). Two-way interaction analysis revealed that the associations of IL-13 rs20541 and h011 with cIgE elevation were synergistically enhanced by prenatal ETS (p for interaction = 0.03 and 0.03, respectively), but not by male sex. If the association analyses were stratified by prenatal ETS and neonatal sex simultaneously, IL-13 rs20541 and h011 had the highest risks for cIgE elevation in male babies prenatally exposed to ETS, with adjusted odds ratios (95% confidence interval) being 3.03 (1.56-5.88) and 2.81 (1.54-5.15), respectively. When three-way interactions were examined, both IL-13 rs20541 and h011 exhibited significant interactions with male sex and ETS (p for interaction = 0.03 and 0.007, respectively). In conclusion, the influence of IL-13 genetic variants on cIgE elevation was modified by male sex and prenatal ETS. Study II. Sex-modified interaction between IL4/IL13 pathway genes and prenatal household environment on cord blood IgE levels Elevated cord blood IgE (cIgE), a predictor of childhood atopic diseases, is influenced by genetic and environmental factors. However, gene-environment interactions on cIgE elevation and their difference by sex remain largely unexplored. We aimed to determine if there are interactions between genetic variants in the IL4/IL13 pathway and prenatal household environments on cIgE elevation, and if such interactions are modified by sex. In 1107 Han-Chinese mother-fetus pairs, comprehensive information on environmental tobacco smoke (ETS), home dampness (indexed by combining mildewy odor, visible mold, and water stamp on the wall), and other prenatal household environments was obtained using a structured questionnaire during the third trimester of pregnancy. Cord blood was collected for measuring cIgE levels, with elevation defined as > or = 0.5 IU/mL, and for genotyping of five single nucleotide polymorphisms (IL-13 rs1800925, rs20541, rs848, IL-4 rs2243250, and STAT6 rs324011) of three candidate genes. Several gene-environment interactions on cIgE elevation in neonatal sex-stratified analyses were observed only in male newborns, including those between ETS and IL13 rs20541, between cumulative home dampness and STAT6 rs324011, and between composite environmental exposures (combined ETS and the three home dampness indices) and STAT6 rs324011 (P for interaction = .03, .006, and .001, respectively). Only male newborns carrying particular genotypes of IL4/IL13 pathway genes manifested with dose-response effects of prenatal environments on cIgE elevation. In conclusion, male sex modifies the gene-environment interactions involving IL4/IL13 pathway genes and prenatal household environments for cIgE production.