Wuttke Matthias, Wong Craig S, Wühl Elke, Epting Daniel, Luo Li, Hoppmann Anselm, Doyon Anke, Li Yong, Sözeri Betül, Thurn Daniela, Helmstädter Martin, Huber Tobias B, Blydt-Hansen Tom D, Kramer-Zucker Albrecht, Mehls Otto, Melk Anette, Querfeld Uwe, Furth Susan L, Warady Bradley A, Schaefer Franz, Köttgen Anna
Renal Division, Department of Internal Medicine, Medical Center, University of Freiburg, Freiburg im Breisgau, Germany.
Division of Pediatric Nephrology, University of New Mexico Children's Hospital, Albuquerque, NM, USA.
Nephrol Dial Transplant. 2016 Feb;31(2):262-9. doi: 10.1093/ndt/gfv342. Epub 2015 Sep 28.
Chronic kidney disease (CKD) in children is characterized by rapid progression and a high incidence of end-stage renal disease and therefore constitutes an important health problem. While unbiased genetic screens have identified common risk variants influencing renal function and CKD in adults, the presence and identity of such variants in pediatric CKD are unknown.
The international Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) and Cardiovascular Comorbidity in Children with CKD (4C). Clean genotype data from > 10 million genotyped or imputed single-nucleotide polymorphisms (SNPs) were available for 1136 patients with measurements of serum creatinine at study enrollment. Genome-wide association studies were conducted to relate the SNPs to creatinine-based estimated glomerular filtration rate (eGFR crea) and proteinuria (urinary albumin- or protein-to-creatinine ratio ≥ 300 and ≥ 500 mg/g, respectively). In addition, European-ancestry PediGFR patients (cases) were compared with 1347 European-ancestry children without kidney disease (controls) to identify genetic variants associated with the presence of CKD.
SNPs with suggestive association P-values < 1 × 10(-5) were identified in 10 regions for eGFR crea, four regions for proteinuria and six regions for CKD including some plausible biological candidates. No SNP was associated at genome-wide significance (P < 5 × 10(-8)). Investigation of the candidate genes for proteinuria in adults from the general population provided support for a region on chromosome 15 near RSL24D1/UNC13C/RAB27A. Conversely, targeted investigation of genes harboring GFR-associated variants in adults from the general population did not reveal significantly associated SNPs in children with CKD.
Our findings suggest that larger collaborative efforts will be needed to draw reliable conclusions about the presence and identity of common variants associated with eGFR, proteinuria and CKD in pediatric populations.
儿童慢性肾脏病（CKD）的特点是进展迅速且终末期肾病发病率高，因此是一个重要的健康问题。虽然无偏倚的基因筛查已确定了影响成人肾功能和CKD的常见风险变异，但小儿CKD中此类变异的存在情况和具体身份尚不清楚。
国际儿童肾脏进展相关遗传因素研究（PediGFR）联盟包括三个小儿CKD队列：儿童慢性肾脏病（CKiD）、严格血压控制和ACE抑制对小儿患者慢性肾功能衰竭进展的影响（ESCAPE）以及CKD患儿心血管合并症研究（4C）。对于1136例在研究入组时测量了血清肌酐的患者，可获得超过1000万个基因分型或推算的单核苷酸多态性（SNP）的干净基因型数据。进行全基因组关联研究，以将SNP与基于肌酐的估计肾小球滤过率（eGFRcrea）和蛋白尿（尿白蛋白或蛋白与肌酐比值分别≥300和≥500mg/g）相关联。此外，将欧洲血统的PediGFR患者（病例）与1347名无肾脏疾病的欧洲血统儿童（对照）进行比较，以确定与CKD存在相关的基因变异。
在10个区域中发现了与eGFRcrea提示性关联P值<1×10⁻⁵的SNP，在4个区域中发现了与蛋白尿相关的SNP，在6个区域中发现了与CKD相关的SNP，其中包括一些合理的生物学候选基因。没有SNP达到全基因组显著性水平（P<5×10⁻⁸）。对一般人群中成人蛋白尿候选基因的研究为15号染色体上靠近RSL24D1/UNC13C/RAB27A的一个区域提供了支持。相反，对一般人群中成人携带与GFR相关变异基因的靶向研究未在小儿CKD患者中发现显著相关的SNP。
我们的研究结果表明，需要更大规模的合作努力，才能就小儿人群中与eGFR、蛋白尿和CKD相关的常见变异的存在情况和具体身份得出可靠结论。
