Variable number of tandem repeats polymorphism of MUC20 is associated with the progression of IgA nephropathy

目的 MUC20基因是在IgA肾病(IgA nephropathy,IgAN)患者肾组织中筛选出来的高表达基因.对不同细胞系检测发现它具有可变数目串联重复片段(variable number of tandem repeats,VNTR)多态性.本研究检测MUC20基因在正常人群是否存在VNTR多态性及其分布情况,并探讨MUC20基因VNTR多态性与中国北方汉族人群IgA肾病临床病理表现及预后的关系.方法选取282名健康献血员和503名IgA肾病患者,采用PCR方法确定MUC20基因VNTR多态性,并对有代表性的结果进行测序验证.分析健康献血员的MUC20不同串联重复次数的等位基因和基因型分布情况.按重复次数多少分为小等位基因(S,重复次数<3次)与大等位基因(L,重复次数4次以上),IgA肾病病人相应分为SS、SL与LL组.收集IgA肾病患者临床病理资料,对其中113名患者进行3.5年±1.5年的随访.分析不同基因型与IgA肾病发病、临床、病理和预后的关系.结果 (1) 在健康人群中存在MUC20基因VNTR多态性,重复片段长度为57bp,重复次数为2～6次.其中重复次数为3次(R3)和4次(R4)的等位基因最多, 6次(R6)最少;基因型以R3R4最多见,其次为R3R3,R4R4,而R2R2,R3R6和R5R5最少见.(2)IgA肾病患者中MUC20等位基因及基因型的分布与健康对照之间没有明显差异.(3)SS、SL与LL基因型的IgA肾病患者之间性别、肾穿时年龄、血尿、高血压、蛋白尿、肾功能、血清IgA水平无明显差异.同时这三组之间肾穿时尿渗透压、尿NAG酶、α1-MG水平以及肾脏间质纤维化,小管萎缩等病理表现之间无明显差异.(4)SL/LL基因型较SS基因型进入终点事件(终末期肾衰竭/肌酐倍增)的危险性明显增高(OR=7.29, 95 % CI:1.68～31.60,P=0.008).结论在健康人群存在MUC20基因VNTR多态性,R3和R4等位基因最多见,基因型以R3R4最多见.MUC20基因VNTR多态性与IgA肾病患者发病及临床表型无关,SL/LL基因型可能是IgA肾病进展的危险因子.The MUC20 gene is a novel up-regulated gene that was identified in renal tissues of patients with IgA nephropathy (IgAN) by restriction endonucleolytic analysis of differentially expressed sequences. The variable number of tandem repeats (VNTR) polymorphism of MUC20 was detected in different cell lines. In this study we determined the distribution of MUC20 VNTR polymorphism in the healthy population, and the association between the MUC20 VNTR polymorphism and the pathogenesis or progression of IgAN.282 healthy and 503 proved IgAN patients by biopsy were involved in this investigation. 113 patients had been followed-up for 3.5 +/- 1.5 years. Genomic DNAs were extracted from peripheral blood leucocytes. MUC20 VNTR polymorphism was detected by PCR amplification and several representational PCR products were confirmed by sequencing. The MUC20 genes were divided into small alleles (repeat times <or= 3) and large alleles (repeat times > 3) according to the repeat times of MUC20 VNTR. These patients were classified into group SS, SL and LL. MUC20 allele frequencies and genotypes of IgAN patients were analyzed and compared with healthy population. In addition, the associations of MUC20 polymorphism with the clinical and pathological parameters at the time of renal biopsy were analyzed. The data followed up in different groups were compared.There was MUC20 VNTR polymorphism in healthy population with 2 - 6 repeats. The repeat fragment was 57bp. The most frequent alleles included 3(R(3)) and 4(R(4)) repeats; otherwise the least ones included 6(R(6)) repeats. The most frequent genotype was R(3)R(4), then R(3)R(3) and R(4)R(4); the least ones were R(2)R(2), R(3)R(6) and R(5)R(5). The frequencies of MUC20 alleles and genotypes in the IgAN patients were similar to healthy population. Initial ages, blood pressure, proteinuria, and renal function did not differ significantly among the three groups. There was no difference of the urinary osmotic pressure, urinary NAG (N-acetyl-B-D-glucosaminidase) and alpha1 microglobulin (alpha1-MG), and the semiquantitative scores of renal interstitial fibrosis and tubular atrophy in the three groups. IgAN patients with SL/LL genotype had higher odds ratio for progression of renal function (OR = 7.29, 95% CI: 1.68 - 31.60, P = 0.008) than the SS genotype.There were MUC20 VNTR polymorphisms in the healthy population. The polymorphism did not associate with the pathogenesis and the clinico-pathological parameters at the time of renal biopsy. The SL/LL genotype was likely to be a risk factor for rapid progression of renal function in the patients with IgAN.首都医学发展科研项目; 国家"211"工程建设项目PubMed中文核心期刊要目总览(PKU)中国科学引文数据库(CSCD)0191333-13388