全基因组表观遗传关联研究鉴定出与肾功能相关的 DNA 甲基化。
Epigenome-wide association studies identify DNA methylation associated with kidney function.
机构信息
The Population Sciences Branch, Division of Intramural Research, NHLBI, NIH, Bethesda, MD, 20892, USA.
NHLBI's Framingham Heart Study, Framingham, MA, 01702, USA.
出版信息
Nat Commun. 2017 Nov 3;8(1):1286. doi: 10.1038/s41467-017-01297-7.
Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). Previous genetic studies have implicated regulatory mechanisms contributing to CKD. Here we present epigenome-wide association studies of eGFR and CKD using whole-blood DNA methylation of 2264 ARIC Study and 2595 Framingham Heart Study participants to identify epigenetic signatures of kidney function. Of 19 CpG sites significantly associated (P < 1e-07) with eGFR/CKD and replicated, five also associate with renal fibrosis in biopsies from CKD patients and show concordant DNA methylation changes in kidney cortex. Lead CpGs at PTPN6/PHB2, ANKRD11, and TNRC18 map to active enhancers in kidney cortex. At PTPN6/PHB2 cg19942083, methylation in kidney cortex associates with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis. The regions containing the 243 eGFR-associated (P < 1e-05) CpGs are significantly enriched for transcription factor binding sites of EBF1, EP300, and CEBPB (P < 5e-6). Our findings highlight kidney function associated epigenetic variation.
慢性肾脏病 (CKD) 的定义是肾小球滤过率 (eGFR) 降低。先前的遗传研究表明，调节机制与 CKD 有关。在这里，我们使用 2264 名 ARIC 研究和 2595 名弗雷明汉心脏研究参与者的全血 DNA 甲基化进行了 eGFR 和 CKD 的全基因组关联研究，以确定肾功能的表观遗传特征。在与 eGFR/CKD 显著相关（P < 1e-07）并复制的 19 个 CpG 位点中，有 5 个也与 CKD 患者活检中的肾纤维化相关，并且在肾皮质中表现出一致的 DNA 甲基化变化。PTPN6/PHB2、ANKRD11 和 TNRC18 处的先导 CpG 位于肾皮质的活性增强子上。在 PTPN6/PHB2 cg19942083 处，肾皮质中的甲基化与较低的肾 PTPN6 表达、较高的 eGFR 和较少的肾纤维化相关。包含与 243 个 eGFR 相关 (P < 1e-05) 的 CpG 的区域显着富含 EBF1、EP300 和 CEBPB 的转录因子结合位点（P < 5e-6）。我们的研究结果强调了与肾功能相关的表观遗传变异。
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