RAS系統和TGF-β1的基因多型性與原發性VUR疾病發生和腎病進行的相關性研究

Study of Association of RAS and TGF-β1 Gene Polymorphisms with Primary VUR Development and Progression

劉國保(Liu Kuo-Pao)

指導教授 ： 李桂楨

國立臺灣師範大學/理學院/生物學系/碩士(2002年)

摘要

無資料

關鍵字

膀胱輸尿管逆流 ； 腎素-血管收縮素系統 ； 基因多型性

並列摘要

Vesicoureteral reflux (VUR) is a common pediatric disease that may lead to severe end-stage renal disease (ESRD) in part of patients. The development of VUR is highly familial inherited and the disease progression is variable. The renin-angiotensin system (RAS) and transforming growth factor-b1 (TGF-b1) involve in the development of urinary system and may also be the potential candidate prognostic factors in the progression of ESRD. In this study, the RAS related angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R) as well as TGF-b1 gene polymorphisms were investigated for association with VUR susceptibility and progression in 74 Taiwanese children, including 16 with ESRD, and 117 normal controls. By polymerase chain reaction and directing sequencing, restriction enzyme digestion, or single strand conformation polymorphism analysis, a total of 25 polymorphisms within the AGT, ACE, AT1R, and TGF-b1 genes were studied. The novel ACE A-3692C was not formally reported, and no TGF-b1 A-880G, G-800A, R25P and T263I polymorphisms were detected. All the polymorphisms examined were in Hardy-Weinberg equilibrium. In the AGT gene, strong linkage disequilibrium between C-532T and G-217A, A-20C and T174M, A-6G and M235T were observed. The strong non-random association among the ACE gene T-5491C, A-5466C, T-3892C, A-3692C, A-240T, and Alu I/D polymorphisms spanning promoter to intron 16 suggests low levels of intragenic recombination within the ACE gene. Similar strong linkage disequilibrium was also seen in the AT1R gene A-1138T, T-810A, T-713G, C-521T, A-214C/G-213C, and A-153G polymorphisms. A statistically significant difference between primary VUR patients and normal controls was observed at the TGF-b1 gene -509 site, with T allele associated with primary VUR development. Furthermore, a significant allele association with ESRD was observed for the ACE loci, with the linked T-A-T-A-A-I haplotype as a risk factor for primary VUR progression. To assess the effect of polymorphism on gene expression, fragments containing the polymorphic haplotypes were fused to firefly luciferase reporter construct and transiently expressed in 293 cells. Within the 1.2 kb ACE and 1.4 kb AT1R promoter fragments, no appreciable effect on the gene expression was observed for the linked ACE A-240T and T-93C as well as the linked AT1R polymorphisms. However, reporter construct containing the AGT -152 G allele drove 2.4 times transcriptional activity compared with the -152 A allele.

參考文獻

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