慢性肾脏病是一种严重危害人群健康的常见慢性病，以肾功能下降为主要表现，导致心血管疾病和死亡的风险增加，并且相当数量的患者最终进展至终末期肾病。虽然慢性肾脏病存在较大的疾病异质性，但研究表明肾功能下降具有独立于原发病的作用机制，且受到遗传因素的影响。国外全基因组关联研究识别了大量与慢性肾脏病相关的易感基因位点，并且基因表达研究显示它们主要集中于人体炎症和代谢通路，上述通路基因对中国人群的影响尚未有相关研究。本研究基于中国慢性肾脏病队列研究，系统收集慢性肾脏病患者的医疗信息、流行病学资料及生物标本，进行随访并监测多种终点事件发生情况。基于队列研究的优势，本研究拟系统评价候选基因多态性与肾功能下降等表型的关系。在确认遗传易感基因的基础上，综合遗传和环境两方面的危险因素，采用多种统计方法建立预测肾功能进展的风险评估模型。本研究结果将为筛选高危慢性肾脏病患者，开展个性化的疾病防治提供依据。

Chronic kidney disease is a common non-communicable chronic disease, which exert a huge hazard on people’s health. The patients with chronic kidney disease have a significantly increased risk of cardiovascular diseases and death, besides a large proportion of them can ultimately enter end stage kidney disease, which would need dialysis or kidney transplantation to sustain life. Although chronic kidney disease can be caused by a series of diseases with different etiology, recent studies have shown that common molecular pathways may exist for the decline of kidney function. The genome-wide association studies have detected several candidate single nucleotide polymorphisms from the European descent chronic kidney disease patients. Further gene expression studies found the inflammation and metabolic pathways may cover the effect of the candidate genetic variants. Given the great progress of genetic susceptibility study among Caucasians on CKD, none of studies have been conducted to detect or replicate the susceptible genetic polymorphisms among Chinese population. Based on the Chinese Cohort Study of Chronic Kidney Disease, we aim to evaluate the association between candidate genetic variants detected by genome-wide association studies with the decline of kidney function and occurrence of end stage kidney disease among Chinese chronic kidney disease patients. The study population was systematically investigated by structured questionnaire, clinical investigation and biochemical examination. The blood samples were collected and stored according to the standard protocol. Whole genome DNA will be extracted and the genotypes of the candidate single nucleotide polymorphisms will be got by Time of Flight Mass Spectrometer method of using Sequenom MassARRAY system. Genetic association studies will be used to detect the susceptible genetic variants and gene by environment interaction will be investigated as well. Combined with the systematic examination of environmental risk factors, we will try to build the prediction model on the CKD progression and ESRD occurrence among the study participants. The findings of our study will provide solid evidence to select high risk CKD patients and provide them personalized intervention.

慢性肾脏病是一种严重危害人群健康的常见慢性病，以肾功能下降为主要表现，导致心血管疾病和死亡的风险增加，并且相当数量的患者最终进展至终末期肾病。虽然慢性肾脏病存在较大的疾病异质性，但研究表明肾功能下降具有独立于原发病的作用机制，且受到遗传因素的影响。国外全基因组关联研究识别了大量与慢性肾脏病相关的易感基因位点，并且基因表达研究显示它们主要集中于人体炎症和代谢通路，上述通路基因对中国人群的影响尚未有相关研究。本研究基于中国慢性肾脏病队列研究，系统收集慢性肾脏病患者的医疗信息、流行病学资料及生物标本，进行随访并监测多种终点事件发生情况。基于GWAS研究的发现，探索炎症和代谢通路候选基因SNP位点与CKD患者肾功能进展和ESKD发生情况的关系。综合环境危险因素以及遗传关联研究识别的易感基因多态性位点，建立预测中国CKD患者肾功能进展和ESKD发生的风险预测模型。本研究共检测480名慢性肾脏病患者的12个SNP位点，位于UMOD和SHROOM3等与肾脏功能密切相关的蛋白基因上。基于单个位点和UMOD及SHROOM3基因单倍型的描述性分析未发现上述SNP位点的基因型/单倍型与终末期肾脏病、心血管疾病和全因死亡相关。通过以肾功能进展为表型的混合线性模型分析，发现BCAS3基因rs9895661多态性的T等位基因在隐性模型下增加肾功能的下降（eGFR多下降5.59ml/min/1.73m2，P值=0.036）。将rs9895661多态性纳入与终点事件（终末期肾脏病、心血管疾病和全因死亡）的Cox比例风险回归模型，调整年龄和性别后，T等位基因增加终末期肾脏病和全因死亡的风险，风险比为1.36(95%置信区间：0.93-1.98)和2.39(95%置信区间：0.83-6.89)，但没有达到统计学显著性水平，因此未再进一步调整其他环境危险因素。本研究结果可为慢性肾脏病患者肾功能进展的机制研究提供一定线索，也可为筛选慢性肾脏病患者中肾功能快速进展表型提供一定依据，但尚需要在更大样本量中做进一步研究。