Medical Genomics, UCL Cancer Institute, University College London, London, UK.
BMC Med Genomics. 2010 Aug 5;3:33. doi: 10.1186/1755-8794-3-33.
Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease.
We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes.
Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy.
This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy.
糖尿病肾病是糖尿病的严重并发症，与相当高的发病率和死亡率有关。越来越多的证据表明，表观基因组的失调与糖尿病肾病有关。我们在一项对 192 名爱尔兰 1 型糖尿病患者（T1D）的病例对照研究中评估了 DNA 甲基化的表观遗传修饰是否与糖尿病肾病有关。病例组有 T1D 和肾病，而对照组有 T1D 但没有肾脏疾病的证据。
我们使用最近开发的 Illumina Infinium HumanMethylation27 BeadChip 在病例和对照组的亚硫酸氢盐转化 DNA 中进行 DNA 甲基化谱分析，该芯片可直接研究基因组中 27578 个 CpG 位点的单个胞嘧啶，这些位点集中在 14495 个基因的启动子区域。
奇异值分解（SVD）分析表明，DNA 甲基化变异的显著成分与患者年龄、糖尿病肾病发病时间和性别相关。使用多元 Cox 回归分析调整混杂因素，并使用 False Discovery Rate（FDR）为 0.05，我们观察到 19 个 CpG 位点与糖尿病肾病发展时间相关。值得注意的是，其中包括一个位于 UNC13B 转录起始位点上游 18bp 的 CpG 位点，该基因的第一个内含子 SNP rs13293564 最近被报道与糖尿病肾病有关。
该高通量平台能够成功地检测单个胞嘧啶的甲基化状态，并确定了 19 个与糖尿病肾病风险相关的前瞻性 CpG 位点。这些 DNA 甲基化差异值得在有和没有肾病的更大队列的糖尿病患者中进行进一步的复制研究。
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