Nephrology Research; Centre for Public Health; Queen's University of Belfast; Belfast Northern Ireland.
Epigenetics. 2014 Mar;9(3):366-76. doi: 10.4161/epi.27161. Epub 2013 Nov 19.
Genetic risk factors for chronic kidney disease (CKD) are being identified through international collaborations. By comparison, epigenetic risk factors for CKD have only recently been considered using population-based approaches. DNA methylation is a major epigenetic modification that is associated with complex diseases, so we investigated methylome-wide loci for association with CKD. A total of 485,577 unique features were evaluated in 255 individuals with CKD (cases) and 152 individuals without evidence of renal disease (controls). Following stringent quality control, raw data were quantile normalized and β values calculated to reflect the methylation status at each site. The difference in methylation status was evaluated between cases and controls with resultant P values adjusted for multiple testing. Genes with significantly increased and decreased levels of DNA methylation were considered for biological relevance by functional enrichment analysis using KEGG pathways in Partek Genomics Suite. Twenty-three genes, where more than one CpG per loci was identified with Padjusted<10(-8), demonstrated significant methylation changes associated with CKD and additional support for these associated loci was sought from published literature. Strong biological candidates for CKD that showed statistically significant differential methylation include CUX1, ELMO1, FKBP5, INHBA-AS1, PTPRN2, and PRKAG2 genes; several genes are differentially methylated in kidney tissue and RNA-seq supports a functional role for differential methylation in ELMO1 and PRKAG2 genes. This study reports the largest, most comprehensive, genome-wide quantitative evaluation of DNA methylation for association with CKD. Evidence confirming methylation sites influence development of CKD would stimulate research to identify epigenetic therapies that might be clinically useful for CKD.
通过国际合作，正在鉴定慢性肾脏病（CKD）的遗传风险因素。相比之下，最近才开始使用基于人群的方法来研究 CKD 的表观遗传风险因素。DNA 甲基化是一种主要的表观遗传修饰，与复杂疾病有关，因此我们研究了全基因组甲基化位点与 CKD 的关联。在 255 名 CKD 患者（病例）和 152 名无肾脏疾病证据的个体（对照）中评估了总共 485,577 个独特特征。经过严格的质量控制，对原始数据进行了分位数归一化，并计算了β值以反映每个位点的甲基化状态。通过比较病例和对照之间的甲基化状态，并用 Partek Genomics Suite 中的 KEGG 途径对结果进行了多重检验调整后的 P 值评估。对具有显著增加和减少 DNA 甲基化水平的基因进行了功能富集分析，以评估其生物学相关性。在 Partek Genomics Suite 中使用 KEGG 途径进行了功能富集分析，其中有 23 个基因，每个基因都有超过一个 CpG 被鉴定为 Padjusted<10(-8)，这些基因的 DNA 甲基化与 CKD 相关，并且从已发表的文献中寻找这些相关基因座的额外支持。与 CKD 具有显著差异甲基化的强生物学候选基因包括 CUX1、ELMO1、FKBP5、INHBA-AS1、PTPRN2 和 PRKAG2 基因；一些基因在肾脏组织中表现出不同的甲基化，并且 RNA-seq 支持 ELMO1 和 PRKAG2 基因中差异甲基化的功能作用。本研究报告了迄今为止最大、最全面的全基因组定量评估与 CKD 相关的 DNA 甲基化。确认甲基化位点影响 CKD 发生的证据将激发研究，以确定可能对 CKD 具有临床应用价值的表观遗传疗法。
