The Study of Genetic Polymorphisms of IFN-γ, IRF1 and LTC4 Synthase in Asthmatic Children

• Main Authors: Tsai. Wei-Dung, 蔡維東
• Other Authors: Wamg. Jiu-Yao
• Format: Others
• Language: zh-TW
• Published: 2003
• Online Access: http://ndltd.ncl.edu.tw/handle/85651278784389346152

碩士 === 國立成功大學 === 分子醫學研究所 === 91 === [Abstract] Asthma, a chronic airway inflammatory disorder, is the most common chronic lung disease of childhood in Taiwan. The charac-teristic symptoms of asthma are bronchial hyperresponsiveness, and reversible obstruction of the airways. Most asthma in child-ren and teenagers is initiated by IgE-mediated hypersensiti-vity, resulting from inhaled allergens such as house dust mites, molds, or pollen grains. Based on the cytokine secretion patt-erns in the airwayof asthmatics, it has been indicated that the CD4+ T cells are of the TH 2 cells.Interferon (IFN)-gamma is a well-known potent immunomodulator, which plays an important role in the differentiation of TH 1 and TH 2 cytokines. Genome-wide linkage analysis has demonstrated that 12q14.1 (IFNG), and 5q31.1 (IRF1) were associated with atopic asthma. T to A trans-version at +999 IFNG single nucleotide polymorphism (SNP) has been shown to correlate with in vitro high IFN-gamma produc-tion. Besides, IFN-γ gene CA-repeat and IRF-1 gene GT- repeat polymorphisms have been observed to significantly associate with atopic asthma in the Japanese child population. The CA- repeat polymorphism within IFN-gamma gene was significantly associated with total serum IgE (TsIgE) levels in the Indian population. Previously, we have shown that in vivo serum IFN-gamma levels of asthmatic children were statistically signifi-cantly lower than those of healthy controls. In this study, we purposed to investigate association of genetic polymorphisms (SNPs: —2653 T/G, +999 T/A, +2110 A/G and +2322 T/C; microsa-tellite: CA repeat) in the IFN-gamma gene and GT-repeat poly-morphism in the IRF-1 gene with atopic asthma, in vivo and in vitro IFN-gamma production, and TsIgE levels in the Taiwanese child population. A novel SNP (T→G) was found at the upstream (—2653) of IFN-gamma promoter region by SSCP and was confirmed by sequence analysis. Recently, we revealed that only the dis-tribution of IFN-gamma gene +2110 A/G polymorphism significant-ly differs between asthmatics and healthy controls (p = 0.011) in those of investigated IFN-gamma gene SNPs, CA-repeat micro-satellite and IRF-1 gene GT-repeat microsatellite in our study; the distribution of +2110 A/G polymorphism was also associated with moderate asthma (p = 0.012) and severe asthma (p = 0.023), but not mild asthma. Two-by-two interactions between those of 4 SNP sites of IFN-γ gene could not increase the risk of asthma. Furthermore, the distribution of all of screened SNPs and the CA-repeat within IFN-γ gene and IRF1 GT-repeat failed to assoc-iate with in vivo and in vitro IFN-γ production and TsIgE levels through Kruskal-Wallis test. In the other hand, preliminary data have shown that urinary LTE4 and PGF2α levels were highly correlated in both acute and convalescent phase of asthma. In this report, we inspected the association of LTC4 synthase (LTC4S) promoter SNP, —444 A/C with urinary LTE4 and PGF2α levels in acute and convalescent phase of asthma. We also investigated the distribution of LTC4S —444 SNP between atopic asthmatics and healthy controls. The result indicated that there was a significantly association between LTC4S —444 A/C polymorphism and urinary LTE4 levels in the convalescent phase of asthma (p = 0.026). Besides, urinary LTE4 levels in the convalescent phase of asthma were signifi-cantly higher in asthmatics without —444 C allele than in asthmatics with —444 C allele. But there was no association between LTC4S —444 SNP and atopic asthma (p = 0.026).