PREDICTIVE FACTORS FOR ACUTE REJECTION IN A POPULATION OF KIDNEY TRANSPLANTED PATIENTS
PREDICTIVE FACTORS FOR ACUTE REJECTION IN A POPULATION OF KIDNEY TRANSPLANTED PATIENTS
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发表时间：
2004-07
期刊：
影响因子：
6.2
通讯作者：
G. La Manna;M. Cappuccilli;A. Faenza;G. Mina;E. Persici;S. Nascetti;F. Bianchi;M. Ortolani;G. Comai;G. Donati;G. Feliciangeli;M. Scolari;S. Stefoni
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作者：
G. La Manna;M. Cappuccilli;A. Faenza;G. Mina;E. Persici;S. Nascetti;F. Bianchi;M. Ortolani;G. Comai;G. Donati;G. Feliciangeli;M. Scolari;S. Stefoni
目的：本研究的目的是通过分析与细胞凋亡和炎症过程有关的基因多态性来鉴定急性排斥反应（AR）相对风险较高的基因型。AR仍然是导致器官功能障碍的重要并发症，特别是如果发生较晚。许多研究强调炎性分子和凋亡介质在AR发病机制中的关键作用。一些细胞因子，如IL-4、IL-6和IL-10，携带基因多态性（单核苷酸多态性，SNP），负责分子的个体产生水平。这些多态性通常位于基因的启动子区，决定了一般人群中存在被定义为“低、中和高生产者”的基因型，这些基因型与AR的风险相关。此外，编码凋亡分子的基因表达增加与AR的发病率和严重程度之间似乎可能存在相关性。研究方法：对凋亡相关基因中的粒酶B（Gzm B）、穿孔蛋白1（PRF 1）和丝氨酸蛋白酶抑制剂9（PI 9）的多态性以及炎症相关基因中IL-10基因启动子区的3个SNP进行了基因型分析。对于每种多态性，通过比较AR组（n 29）和非AR组（n 41）之间的等位基因频率，在1998年至2002年期间在博洛尼亚圣奥尔索拉大学医院肾病研究所接受尸体肾移植的70例患者中进行病例对照研究。病例组和对照组在年龄和HLA-DR错配数量上相匹配。通过限制性片段长度多态性（RFLP）和引物延伸/变性高效液相色谱法进行基因型分析。结果如下：通过方差分析（ANOVA e Student's t检验），已经确定哪些变量（临床参数、不可修改的因素和基因型分布）在病例组和对照组中显示出显著差异。在本研究中，凋亡基因的多态性似乎不影响急性肾排斥反应的发生。相反，IL-10/G-1082 A多态性的杂合基因型在非AR组中显示出更高的频率。当考虑IL-10基因的三个SNPs对细胞因子产生的单基因效应时，高/中间生产者基因型突出了与肌酐血浆水平的负正相关。结论：这些结果似乎表明IL-10/G-1082 A多态性杂合基因型对AR的保护作用，以及肾移植受者肾功能与IL-10高/中等产生之间的可能关系。
Aims: The purpose of the present study is the identification of genotypes at higher relative risk of Acute Rejection (AR) by the analysis of gene polymorphisms implicated in apoptosis and inflammation processes. AR still represents an important complication leading to organ dysfunction, especially if it occurs late. Many studies have emphasized a key role of inflammatory molecules and apoptosis mediators in the pathogenesis of AR. Some cytokines, such as IL-4, IL-6 and IL-10, carry gene polymorphisms (Single Nucleotide Polymorphisms, SNPs) responsible for the individual production levels of the molecule. These polymorphisms, generally located in the promoter region of the gene, determine the presence in the general population of genotypes defined as “low, intermediate and high producers”, that have been associated with the risk of AR. Moreover, a correlation between the increased expression of genes encoding for apoptosis molecules and the incidence and severity of AR appears to be likely. Methods: Genotype analysis has been carried out for polymorphisms of Granzyme B (GzmB), Perforin (PRF1) and Serine Proteinase Inhibitor member 9 (PI9) amongst apoptosis genes and three SNPs located in the promoter region of IL-10 gene amongst inflammatory molecules. For each polymorphism, a case-control study was conducted within a panel of 70 patients who had received cadaveric kidney transplants between 1998 and 2002 at the Institute of Nephrology of the St. Orsola University Hospital of Bologna by comparing the allele frequencies between AR group (n 29) and non-AR group (n 41). Cases and controls were matched for age and number of HLA-DR mismatches. Genotype analysis was performed by RFLP (Restriction Fragment Lenght Polymorphism) and Primer Extension/denaturing High-Performance Liquid Chromatography assay. Results: By variance analysis (ANOVA e Student’s t-test), it has been established which variables (clinical parameters, unmodifiable factors and distribution of genotypes) showed significative differences in case and control groups. In this study, the polymorphisms of apoptosis genes do not seem to influence acute kidney rejection episodes. In contrast, the heterozygous genotype for IL-10/G–1082A polymorphism showed a higher frequency in the non-AR group. When considering the sinergistic effect of the three SNPs of IL-10 gene on the cytokine production, the high/intermediate producer genotypes highlighted an inversely positive association with creatinine plasma levels. Conclusions: These results seem to indicate a protective effect towards AR of the heterozygous genotype for IL-10/G–1082A polymorphism and a possible relationship between renal function and IL-10 high/intermediate production in kidney transplant recipients.