IgA肾病患者TANK结合激酶1基因多态性与临床和病理表型的关系

Association of single nucleotide TANK binding kinase-1 gene polymorphism with clinical features and histological phenotypes in IgA nephropathy

目的探讨TANK结合激酶1(TBK1)基因多态性与IgA肾病患者临床和病理表型的关系。方法收集2010—2013年上海交通大学医学院附属新华医院肾脏科收治的经肾活组织病理学检查明确诊断为原发性IgA肾病的患者134例(IgA肾病组)和同期进行健康普查的健康志愿者140名(健康对照组)。应用聚合酶链反应产物直接测序法筛选TBK1基因21个外显子单核苷酸多态性(SNP)位点,对筛选到的SNP位点与IgA肾病患者的临床和病理表型进行相关性分析。结果 TBK1第8外显子c.1137T>A存在基因多态性,健康对照组TT、AT和AA基因型频率分别为40.7%、45.7%、13.6%,IgA肾病组分别为47.8%、42.5%、29.7%,两组间差异无统计学意义(χ=1.804,P=0.406);健康对照组等位基因T和A频率分别为63.6%、236.4%,IgA肾病组分别为69.0%、31.0%,两组间差异无统计学意义(χ=1.824,P=0.177)。IgA肾病组中,与AT基因型和TT基因型比较,AA基因型的收缩压(P=0.015)、24h尿蛋白定量(P=0.041)和血尿酸水平(P=0.006)均显著升高,IgA/C3比值(P=0.014)和Cockcorft-Gault方程计算的肾小球滤过率(P=0.048)显著降低。3种基因型间牛津病理分类系膜细胞增生积分的差异有统计学意义2(χ=6.336,P=0.042),其中AA基因型>50%肾小球出现系膜细胞增生的比例最高(M1为92.3%),AT基因型的比例最低(M1为54.5%)。结论 TBK1基因c.1137T>A与lgA肾病患者肾功能下降显著相关,提示TBK1在IgA肾病的发病和进展中可能起一定作用。

Objective To explore the relationship between TANK binding kinase-1 （TBK1） gene polymorphism and clinical features and histological phenotypes of IgA nephropathy. Methods A total of 134 renal-biopsy proven sporadic IgA nephropathy cases of Chinese Han nationality from 2010 to 2013 in Xinhua Hospital and 140 normal volunteers of health screening were recruited in the study. Polymorphism of 21 exons of TBK1 gene was detected and one candidate single nucleotide polymorphism （SNP, frequency 〉 5%） were genotyped with polymerase chain reaction （PCR）-direct sequencing. A case-control association study was carried out. Results The genotype frequencies of TT, AT and AA in the 8th exon of TBK1 gene c. 1137T〉A were 40.7%, 45.7% and 13.6% in healthy volunteers and were 47.8%, 42.5% and 9.7% in patients. The frequencies of T and A allele were 63.6% and 36.4% in healthy volunteers and 69. in IgA nephropathy patients, respectively. There were no significant differences in genotype or a between patients and healthy controls （X2 = 1. 804, P = 0.406; X2 = 1. 824, P = 0. 177）. In J gA nephropathy 0% and 31.0% lele frequencies gA nephropathy cases, the levels of systolic pressure （ P = 0.015）, 24-hour urine protein （ P = 0.041 ） and uric acid （ P = 0. 006）were significantly increased in AA genotype as compared with AT and TT genotypes, while the levels of IgA/C3 （P=0. 014） and estimated glomerular filtration rate （eGFR） calculated by the Cockcorft-Gault equation （P= 0. 048） were significantly decreased in AA genotype. There was significant difference in mesangial hypercellularity identified by the Oxford Classification between the three genotypes （X2 = 6. 336, P = 0. 042）. The mesangial cell proliferation in more than 50% glomerulus had the highest proportion in AA genotype （M1 = 92.3% ） but the lowest level in AT genotype （M1 = 54. 5%）. Conclusion The SNP of c. 1137T〉A is significantly associated with reduced renal function of IgA nephropathy patients, which indicates that TBK1 may play a role in the pathogenesis and development of IgA nephropathy.