Identification and Characterization of Genetic Risk Variants for Chronic Kidney Disease and Related Traits

慢性肾脏疾病（CKD）是全球范围内患病率和发病率不断上升的严重公共卫生负担。它可以发展为终末期肾脏疾病，并大大增加心血管发病率和死亡率的风险。尽管有强有力的证据表明CKD的遗传成分，但迄今为止已经确定的CKD的遗传易感性位点很少。了解肾脏疾病遗传易感性的基础可以为重要的生理途径和疾病机制提供有价值的见解。因此，本提案的目的是扩展先前的工作，以发现和表征肾功能障碍和CKD的新型常见和罕见遗传易感性变异。这一目标将首先在一个大型国际联盟中进行CKD全基因组关联研究和约45,000名欧洲血统个体的肾功能测量来解决。接下来，我们将在更少的个体中对最有希望的基因进行有针对性的重测序，包括我们之前发现的UMOD基因。风险变异的随访基因分型及其特征将在基于人群和ckd特异性研究样本中进行。最后，由于表型的精确测量对于全面的变异鉴定至关重要，一种新的CKD生物标志物血清FGF-23将在一项基于人群的研究中对3000名参与者进行测量。将研究FGF-23水平与CKD及其并发症的关系，并确定FGF-23和FGF-23途径其他组分的遗传和非遗传相关性。综合起来，拟议的研究将为慢性肾脏疾病的遗传学提供新的见解。

Chronic kidney disease (CKD) constitutes a serious public health burden of increasing prevalence and incidence worldwide. It can progress to end-stage renal disease and increases the risk for cardiovascular morbidity and mortality substantially. Despite strong evidence for a genetic component, few genetic susceptibility loci for CKD have been identified to date. Understanding the underpinnings of genetic susceptibility to kidney disease can provide valuable insights into important physiological pathways and disease mechanisms. The objective of this proposal is therefore to expand on previous work to discover and characterize novel common and rare genetic susceptibility variants for kidney dysfunction and CKD. This objective will be addressed by first conducting genome-wide association studies of CKD and measures of kidney function in ~45,000 individuals of European ancestry within a large international consortium. Discovery will be followed by targeted resequencing of the most promising genes in fewer individuals, including the UMOD gene we identified previously. Follow-up genotyping of risk variants and their characterization will be conducted in population-based and CKD-specific study samples. Finally, because exact measurement of the phenotype is essential for comprehensive variant identification, a novel CKD biomarker, serum FGF-23, will be measured in 3,000 participants of a population-based study. Associations of FGF-23 levels with CKD and its complications will be studied, and genetic and non-genetic correlates of FGF-23 and other components of the FGF-23 pathway will be identified. Combined, the proposed studies will provide novel insights into the genetics of chronic kidney disease.