Association of Polymorphisms in the Angiotensin-Converting Enzyme, Palsminogen Activator Inhibitor-1, and Tumor Necrosis Factor-α with Renal Progression in Children with Vesicoureteral Reflux

Abstract

本研究的目的在探討血管收縮素轉化酶(ACE)、第一型纖維蛋白溶解酶原活化物抑制物(PAI-1)、腫瘤球死因子α(TNF-α)等基因多型性與臺灣孩童膀胱輸尿管逆流(VUR)發生及病程進展的相關性。ACE基因的A-240T、Alu I/D多型性及TNF-α基因的T-1031C、C-863A、C-857T、G-308A、G-238A等多型性係藉限制酶切割PCR放大產物及洋菜膠體電泳等技術來分析，PAI-1基因的4G/5G多型性則藉異偶合分析及對偶基因專一PCR等技術來檢測。結果發現各多型性基因座之遺傳情形均處於哈溫平衡。ACE基因的A-240T、Alu I/D多型性間呈現非逢機的組合，顯示ACE基因的重組率很低。TNF-α基因的T-1031C、C-863A多型性間亦呈現強烈的連鎖不平衡。在正常人族群和VUR患者群間，上述8個多型性對偶基因頻率均無顯著差異，顯示和VUR的發生不相關。當VUR患者依尿毒症的有無區分為二群時，ACE基因的A-240T和Alu I/D多型性、PAI-1基因的4G/5G多型性、TNF-α基因的T-1031C和C-863A多型性對偶基因頻率皆有顯著的差異，顯示和VUR患者為程的進展相關。

In this study, the angiotensin-converting enzyme (ACE), palsminogen activator inhibitor-1 (PAI-1), and tumor necrosis factor-α (TNF-α) gene polymorphisms were evaluated for association with vesicoureteral reflux (VUR) susceptibility and progression in Taiwanese children. The ACE gene A-240T and Alu I/D polymorph isms and TNF-α gene T-1031C, C-863A, C-857T, G-308A and G-238A polymorphisms were analyzed by restriction enzyme digestion and/or gel electrophoresis of polymerase chain reaction (PCR)-amplified products. The PAI-1 4G/5G polymorphism was examined by heteroduplex analysis and allele specific PCR. All the polymorph isms examined were in Hardy-Weinberg equilibrium. The strong non-random association among A-240T and Alu I/D polymorphisms suggests low levels of intragenic recombination in the ACE gene. Similar strong linkage disequilibrium between the TNF-α gene T-1031C and C-863A was also observed. None of these polymorphisms showed association with VUR susceptibility. However, the allele frequency distribution of ACE A-240T and Alu I/D, PAI-1 4G/5G, and TNF-α T-1031C and C-863A among VUR patients with or without uremia was statistically different (P < 0.05). The data suggest the etiologic effect of the ACE A-240T and Alu I/D, PAI-1 4G/5G, as well as TNF-a T-1031C and C-863A polymorphisms on progressive renal deterioration in Taiwanese VUR children.