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SLC12A3基因Arg913Gln促进中国2型糖尿病终末期肾病的发生和进展
Arg913Gln of SLC12A3 Gene Promotes Development and Progression of End-stage Renal Disease in Chinese Type 2 Diabetes Mellitus
【作者】 张荣；
【导师】 刘丽梅；
【作者基本信息】 上海交通大学 ， 内科学（内分泌与代谢病学）， 2019， 博士
【摘要】 目的:SLC12A3,是钠和氯化物共转运蛋白,负责调节钠和氯化物在肾脏远端小管中的重吸收,与血压的调节相关,并作为噻嗪类利尿剂的作用靶点。SLC12A3的Arg913Gln变异(rs11643718,G/A)是否促进2型糖尿病肾脏病(DKD)的发病仍存在争议。我们进行病例-对照研究,以评估SLC12A3 Arg913Gln变异与中国接受维持性血液透析治疗的2型糖尿病(T2DM)患者发生终末期肾病(ESRD)风险的相关性,并分析基因型-表型间的相互作用。研究设计和方法:将合并糖尿病视网膜病、无血缘关系的中国T2DM患者(n=372)分为非糖尿病肾脏病对照组(non-DKD组,n=151,糖尿病病程>15年,无肾病)和T2DM导致的ESRD组(DKD-ESRD组,n=221,终末期肾病接受维持性血液透析治疗)。应用PCR-直接测序方法,对所有372名受试者的SLC12A3-Arg913Gln变异进行基因型分型。结果:1)DKD-ESRD组患者的GA+AA基因型频率显著高于非DKD对照组[23.1%vs.9.9%;校正OR值为2.2(95%CI,1.3-4.5;P=0.019)];2)non-DKD组中,与GG基因型携带者相比,GA+AA基因型携带者的尿白蛋白排泄率(UAER)和舒张压(DBP)水平显著升高(均P<0.05)。结论:SLC12A3 Arg913Gln变异可能与血压和UAER升高相关,因此可能预测进行血液透析的中国T2DM患者DKD-ESRD的发生和发展。
【Abstract】 OBJECTIVE: SLC12A3 is a sodium-chloride cotransporter,which regulates re-absorption of sodium ions and chloride ions in the renal distal convoluted tubules,associates with regulation of blood pressure and is the target of thiazide diuretics.Whether Arg913 Gln variation(rs11643718,G/A)of SLC12A3 contributes to type 2 diabetic kidney disease(DKD)remains controversial.We undertook a case-control study to evaluate the association of the SLC12A3-Arg913 Gln variation with the risk of ESRD in Chinese type 2 diabetes(T2DM)patients undergoing hemodialysis and analyzed the genotype-phenotype interaction.RESEARCH DESIGN AND METHODS: Unrelated Chinese T2 DM patients(n=372)with diabetic retinopathy were classified into the non-diabetic nephropathy control group(non-DKD group,n=151,duration of diabetes >15 years,no signs of renal involvement)and the ESRD group due to T2DM(DKD-ESRD group,n=221;ESRD patients who are receiving hemodialysis).PCR-direct sequencing was used to genotype SLC12A3-Arg913 Gln variation for all 372 subjects.RESULTS: 1)The frequenciey of the GA+AA genotype in DKD-ESRD subjects was significantly higher than that of non-DKDgroup(23.1% vs.9.9%;adjusted OR 2.2(95% CI,1.3-4.5;P=0.019);2)In the non-DKD group,GA+AA carriers had a significantly higher urinary albumin excretion rate(UAER)and diastolic blood pressure(DBP)compared with GG carriers(both P<0.05).CONCLUSIONS: The SLC12A3-Arg913 Gln variation may be associated with elevated blood pressure and UAER,and therefore may predict the development and progression of DKD-ESRD in Chinese T2 DM patients undergoing hemodialysis.