南方汉族等候肾移植终末期肾功能衰竭患者HLA基因多态性分析

Analysis of HLA polymorphisms in 3911 ESRD patients awaiting kidney transplantation

目的对我国南方地区3911例等候肾脏移植的患者进行HLA-A,B,DRB1基因表达的回顾性研究,以探讨在因肾脏疾病导致患者最终并发终末期肾功能衰竭(ESRD)进程中的HLA免疫遗传易感性及其相对风险作用。方法采用聚合酶链反应-序列特异性引物扩增(PCR-SSP)技术进行HLA-A,B,DR基因分型,应用SPPS13.0软件包统计分析ESRD患者中HLA抗原频率、基因频率、HLA-A,B,DR三个位点的单倍型频率(HF)、连锁不平衡参数、相对危险度(RR)及优势比(OR)。结果ESRD患者中表达出HLA-A抗原19个,HLA-B抗原40个,HLA-DR抗原14个;其中呈现抗原频率显著增高(PC<0.0001,PC值即P值乘以所检测的某一位点的抗原数)的是HLA-B75(RR=1.222,OR=1.479)、DR4(RR=1.146,OR=1.294),DR17(RR=1.541,OR=2.639);呈现出抗原频率显著降低(PC<0.0001)的是HLA-DR8(RR=0.812,OR=0.697)、DR9(RR=0.878,OR=0.793);ESRD患者中具有显著连锁不平衡单倍型(HF>0.5%)10条,分别为A1-B37-DR10,A2-B7-DR17,A29-B7-DR10,A30-B13-DR7,A33-B13-DR17,A33-B44-DR17,A33-B46-DR17,A33-B58-DR17,A33-B60-DR17和A33-B75-DR17,其中A33-B75-DR17、A33-B58-DR17频率高达7.93%和11.74%。结论研究发现HLA-B75、DR4和DR17可能对南方地区肾脏疾病患者最终并发ESRD具有独立易感关联,而表达HLA-DR8、DR9的肾脏病患者将可能不易并发ESRD;单倍型A33-B75-DR17高频率出现说明HLA-B75,DR17不仅具有独立易感作用还可能对肾脏病患者最终并发ESRD具有集合易感作用。这个发现对于等候肾脏移植患者选择合适供体以提高移植后患者生存时间和远期移植效果具有临床指导意义。

Objective The expression of HLA-A,B and DRB1 alleles of end-stage renal disease （ESRD） patients awaiting kidney transplantation, in Southern Chinese Han population was analysed in order to explore HLA polymorphisms as immune and genetic factors in the pathogenesis of ESRD. Methods DNA was extracted by salting-out method. Poly-merase chain reaction-sequence specific primer（PCR-SSP） were used to analyze the type of HLA-A , B and DRB1 alleles of 3 911 ESRD patients. The phenotype frequencies, gene frequencies,haplotypes frequencies, relative risk（RR ）, and odd ratio （OR） were calculated with a statistic software named SPSS13.0. Results 19 HLA-A,40 HLA-B,and 14 HLA-DR were detected in 3911 patients. The antigens HLA-B75 （RR = 1. 222 and OR = 1. 479）, HLA-DR4 （ RR = 1. 149 and OR = 1. 294） and HLA-DR17 （RR = 1. 541 and OR=2. 639）） were at significantly higher frequencies among patients compared with controls. However, the antigens, HLA-DR8 （RR = 0. 812 and OR = 0. 697） and HLA-DR9 （RR = 0. 878 and OR = 0. 793） were at a significantly lower frequency among patients. There were 10 haplotypes with significant linkage disequilibrium observed in ESRD patients, of which the frequencies were more than 0. 005, including A1-B37-DR10, A2-B7-DR17, A29-B7-DR10, A30-B13-DR7, A33-B13- DR17 ,A33-B44-DR17,A33-B46-DR17, A33-B58-DR17,A33-B60-DR17and A33-B75-DR17. The haplotype A33-B75-DR17 and A33-B58-DR17 showed a frequency of 7.93% and 11.74% respectively. Conclusions The susceptible HLA antigens in patients with renal diseases complicated with ESRD were HLA-B75, DR4, and DR17 in Southern China, while the protective ones were HLA-DR8 and DR9. The haplotype A33-B75-DR17 showed high frequency , indicating HLA-B75, DR17 are not only the independent susceptible genes but also the compound susceptible ones. The founding were helpful for ESRD patients awaiting kidney transplantation to choose suitable donors in order to increase their survival time and improve efficacy of transplantation in a long time.