Savage D A, Patterson C C, Deloukas P, Whittaker P, McKnight A J, Morrison J, Boulton A J, Demaine A G, Marshall S M, Millward B A, Thomas S M, Viberti G C, Walker J D, Sadlier D, Maxwell A P, Bain S C
Nephrology Research Laboratory, Queen's University, Belfast, BT9 7AB, Northern Ireland, UK.
Diabetologia. 2008 Nov;51(11):1998-2002. doi: 10.1007/s00125-008-1142-5. Epub 2008 Sep 5.
AIMS/HYPOTHESIS: Diabetic nephropathy, characterised by persistent proteinuria, hypertension and progressive kidney failure, affects a subset of susceptible individuals with diabetes. It is also a leading cause of end-stage renal disease (ESRD). Non-synonymous (ns) single nucleotide polymorphisms (SNPs) have been reported to contribute to genetic susceptibility in both monogenic disorders and common complex diseases. The objective of this study was to investigate whether nsSNPs are involved in susceptibility to diabetic nephropathy using a case-control design.
White type 1 diabetic patients with (cases) and without (controls) nephropathy from eight centres in the UK and Ireland were genotyped for a selected subset of nsSNPs using Illumina's GoldenGate BeadArray assay. A chi (2) test for trend, stratified by centre, was used to assess differences in genotype distribution between cases and controls. Genomic control was used to adjust for possible inflation of test statistics, and the False Discovery Rate method was used to account for multiple testing.
We assessed 1,111 nsSNPs for association with diabetic nephropathy in 1,711 individuals with type 1 diabetes (894 cases, 817 controls). A number of SNPs demonstrated a significant difference in genotype distribution between groups before but not after correction for multiple testing. Furthermore, neither subgroup analysis (diabetic nephropathy with ESRD or diabetic nephropathy without ESRD) nor stratification by duration of diabetes revealed any significant differences between groups.
CONCLUSIONS/INTERPRETATION: The nsSNPs investigated in this study do not appear to contribute significantly to the development of diabetic nephropathy in patients with type 1 diabetes.
目的/假设：糖尿病肾病以持续性蛋白尿、高血压和进行性肾衰竭为特征，影响一部分易患糖尿病的个体。它也是终末期肾病（ESRD）的主要原因。据报道，非同义（ns）单核苷酸多态性（SNP）在单基因疾病和常见复杂疾病的遗传易感性中均起作用。本研究的目的是采用病例对照设计，研究nsSNP是否与糖尿病肾病易感性有关。
来自英国和爱尔兰8个中心的1型糖尿病白种患者，有肾病的（病例组）和无肾病的（对照组），使用Illumina的GoldenGate BeadArray检测法对选定的nsSNP子集进行基因分型。采用按中心分层的趋势卡方检验，评估病例组和对照组之间基因型分布的差异。采用基因组对照调整检验统计量可能的膨胀，并采用错误发现率方法处理多重检验。
我们在1711例1型糖尿病患者（894例病例，817例对照）中评估了1111个nsSNP与糖尿病肾病的相关性。一些SNP在多重检验校正前显示组间基因型分布有显著差异，但校正后无差异。此外，亚组分析（伴有ESRD的糖尿病肾病或不伴有ESRD的糖尿病肾病）和按糖尿病病程分层均未显示组间有任何显著差异。
结论/解读：本研究中所研究的nsSNP似乎对1型糖尿病患者糖尿病肾病的发生没有显著贡献。
