Genomic and Proteomic Markers on the Developmental Pathogenesis of Childhood Asthma (I)

Prevalence of childhood asthma in Taiwan has increased 8 to 10 times from 1.3% to 10-14% in the past two decades. Epidemiological studies indicate that childhood asthma is a highly heritable disease since monozygotic twins are more frequently affected simultaneously than heterozygotic twins, and offspring of affected parents also has a higher risk for developing the disease. Many studies worldwide have demonstrated that many genes in different chromosomes are implicated in atopic asthma in different ethnic populations. A growing body of evidence suggests that allergic sensitization could occur in utero and might be related to future development of atopic asthma. Now, important issues unresolved are the genetic basis and gene-environmental interactions for prenatal allergy sensitization? And which gene(s) are the real determinants of the later development of overt asthma phenotype under influence of gender, age, and certain environmental factors? Linkage-based case control studies that reflect outcomes but not interacting process failed to answer these questions. Resolution of the complex questions may require a cohort study from prenatal to postnatal follow up. In a pilot study with 655 core families with pregnant parents, our previous studies had shown that the immune braking gene CTLA-4 +49 A/G, but not -318 T/C, polymorphism correlated to elevation of cord blood IgE (CBIgE) was only found in female infants. Further studies revealed that maternal but not paternal atopy was significantly correlated with elevation CBIgE and infant atopy. Interestingly, we also found that babies from atopic mothers can interact with the IL-13, 2044 A/G polymorphism to affect prenatal allergy sensitization as reflected on elevated CBIgE. Extending from these promising results published, we hypothesize that many genes can affect prenatal allergy sensitization, but only certain of them is(are) the real determinants of the postnatal development of asthma, under influence of gender, age and environmental factors such as smoking, feeding types, or allergen exposure. To prove this hypothesis for defining a better preventive strategy of childhood asthma, we plan to conduct a large perinatal cohort study to recruit 1200 pregnant parents for this study on identifying potential genetic (DNA polymorphisms), genomic (RNA differential displays), and proteomic (proteomic profiles) markers of childhood asthma during the 6-year course of perinatal cohort study. In a kinetic follow-up with genomic and proteomic approaches, we attempt to reach the following 3 specific aims: 1. To evaluate the relationship between the genetic polymorphisms (60 SNPs) in 35 important candidate genes and prenatal allergy sensitization as well as final asthma development. 2. To determine the functional genomics of prenatal allergy sensitization in newborn stage by the use of a two-tier approach, wherein differential gene expression patterns will be identified in a selected group of subjects as the primary event, followed by additional screening and validation in an expanded population using customized genechip arrays. 3. To kinetically assess the critical changes of genomic markers and proteomic profiles in the development of allergic phenotypes during this cohort follow up from age of 0 month, 6 months, 18 months, 3 years to age of 6 years. The crucial genomic marker or proteomic profiles may be useful for early prediction or prevention of childhood asthma. After clarifying the natural course of the genomic and proteomic profiles in prenatal allergy sensitization and postnatal development of childhood asthma, certain early predictor(s) and preventive regimens for atopic asthma or other atopic disorders may be made possible. This cohort study will also provide a study model to identify certain gene-gene, gene-gender and gene-environmental interactions on other complex disorders in addition to childhood asthma.

Project ID:PA9405-0116
External Project ID:NSC94-3112-B182-003