Cilião Heloísa Lizotti, Camargo-Godoy Rossana Batista Oliveira, de Souza Marilesia Ferreira, Dos Reis Mariana Bisarro, Iastrenski Lorena, Alvares Delfino Vinicius Daher, Rogatto Silvia Regina, de Syllos Cólus Ilce Mara
a Department of General Biology, Center of Biological Sciences , State University of Londrina , Londrina , Paraná , Brazil.
b Center of Health Sciences , State University of Londrina , Londrina , Paraná , Brazil.
J Toxicol Environ Health A. 2017;80(13-15):661-671. doi: 10.1080/15287394.2017.1286922. Epub 2017 May 19.
Despite advances in testing compatibility between donor and recipient, graft rejection remains a current concern. Single-nucleotide polymorphisms (SNPs) that codify altered enzymes of metabolism, drug transport, and the immune system may contribute to graft rejection in transplant patients. This study examined the association between SNPs present in genes of these processes and occurrence of graft rejection episodes in 246 kidney transplant patients, 35% of which were diagnosed with rejection. Genotype-gene expression associations were also assessed. Peripheral blood samples were used for genotyping of 24 SNPs on the following genes: CYP3A4, CYP3A5, CYP2E1, POR, UGT2B7, UGT1A9, ABCB1, ABCC2, ABCG2, SLCO1B1, TNF, IL2, IRF5, TGFB1, NFKBIA, IL10, IL23R, NFAT, and CCR5 by real-time PCR. The analysis of gene expression was performed by RT-qPCR. The association between graft rejection episodes and polymorphic variants was assessed using odds ratios. Polymorphisms rs7662029 (UGT2B7) and rs6714486 (UGT1A9) were associated with occurrence of graft rejection episodes, rs7662029 (UGT2B7) exhibited a protective effect (1.85-fold), and rs6714486 (UGT1A9) an increased 1.6-fold increased risk of graft rejection. Among drug transporter genes, only rs2231142 (ABCG2) demonstrated an association with a 1.92-fold decrease in the risk of graft rejection. The immunological SNP rs10889677 (IL23R) was associated with a 1.9-fold enhanced risk of graft rejection. Association between genotypes and gene expression was not detected. Therefore, SNPs of UGT2B7, UGT1A9, ABCG2, and IL23R genes may be useful as candidate markers for screening of risk graft rejection in renal transplant patients. These markers may improve medical decisions, avoiding adverse effects.
尽管在检测供体与受体之间的兼容性方面取得了进展，但移植排斥仍然是当前令人关注的问题。编码代谢、药物转运和免疫系统中酶改变的单核苷酸多态性（SNP）可能导致移植患者发生移植排斥。本研究调查了这些过程相关基因中的SNP与246例肾移植患者移植排斥发作之间的关联，其中35%的患者被诊断为排斥反应。还评估了基因型与基因表达的关联。外周血样本用于对以下基因上的24个SNP进行基因分型：CYP3A4、CYP3A5、CYP2E1、POR、UGT2B7、UGT1A9、ABCB1、ABCC2、ABCG2、SLCO1B1、TNF、IL2、IRF5、TGFB1、NFKBIA、IL10、IL23R、NFAT和CCR5，采用实时PCR法。基因表达分析通过RT-qPCR进行。使用优势比评估移植排斥发作与多态性变体之间的关联。多态性rs7662029（UGT2B7）和rs6714486（UGT1A9）与移植排斥发作的发生有关，rs7662029（UGT2B7）表现出保护作用（1.85倍），而rs6714486（UGT1A9）使移植排斥风险增加1.6倍。在药物转运蛋白基因中，只有rs2231142（ABCG2）显示与移植排斥风险降低1.92倍有关。免疫SNP rs10889677（IL23R）与移植排斥风险增加1.9倍有关。未检测到基因型与基因表达之间的关联。因此，UGT2B7、UGT1A9、ABCG2和IL23R基因的SNP可能作为肾移植患者移植排斥风险筛查的候选标志物。这些标志物可能改善医疗决策，避免不良反应。
