影响线粒体功能的基因中不同的甲基化模式与1型糖尿病患者血液来源DNA中的肾脏疾病有关。

Distinct methylation patterns in genes that affect mitochondrial function are associated with kidney disease in blood-derived DNA from individuals with Type 1 diabetes.

作者信息

Swan E J, Maxwell A P, McKnight A J

机构信息

Centre for Public Health, Queen's University of Belfast.

Regional Nephrology Unit, Belfast City Hospital, Belfast, UK.

出版信息

Diabet Med. 2015 Aug;32(8):1110-5. doi: 10.1111/dme.12775. Epub 2015 May 10.

DOI:10.1111/dme.12775

PMID:25850930

Abstract

AIMS

Epigenetic modifications, such as DNA methylation, can influence the risk of developing kidney disease. We studied methylation profiles in genes related to mitochondrial function to assess whether differences in these epigenetic features were associated with diabetic kidney disease in people with Type 1 diabetes.

METHODS

A case-control association study was undertaken (n = 196 individuals with diabetic kidney disease vs. n = 246 individuals without renal disease). Participants were White and diagnosed with Type 1 diabetes before 31 years of age. Genes that encode mitochondrial proteins (n = 780) were downloaded from mitoproteome.org. DNA methylation profiles from blood-derived DNA were generated using the Illumina Infinium HumanMethylation450 (262 samples) and Illumina Infinium HumanMethylation27 (192 samples) arrays. Beta values (β) were calculated and quality control was conducted, including evaluating blind duplicate DNA samples.

RESULTS

Fifty-four Cytosine-phosphate-Guanine probes across 51 unique genes were significantly associated (P ≤ 10(-8) ) with diabetic kidney disease across both the 450K and the 27K methylation arrays. A subanalysis, employing the 450K array, identified 755 Cytosine-phosphate-Guanine probes in 374 genes that were significantly associated (P ≤ 10(-8) ) with end-stage renal disease. Forty-six of the top-ranked variants for diabetic kidney disease were also identified as being differentially methylated in individuals with end-stage renal disease. The largest change in methylation (Δβ = 0.2) was observed for cg03169527 in the TAMM41 gene, chromosome 3p25.2. Three genes, PMPCB, TSFM and AUH, were observed with differential methylation at multiple Cytosine-phosphate-Guanine sites each (P < 10(-12) ).

CONCLUSIONS

Differential methylation in genes that influence mitochondrial function are associated with kidney disease in individuals with Type 1 diabetes.

摘要

目的

表观遗传修饰，如DNA甲基化，可影响患肾病的风险。我们研究了与线粒体功能相关基因的甲基化谱，以评估这些表观遗传特征的差异是否与1型糖尿病患者的糖尿病肾病相关。

方法

进行了一项病例对照关联研究（n = 196例糖尿病肾病患者与n = 246例无肾病患者）。参与者为白人，在31岁之前被诊断为1型糖尿病。从mitoproteome.org下载编码线粒体蛋白的基因（n = 780个）。使用Illumina Infinium HumanMethylation450（262个样本）和Illumina Infinium HumanMethylation27（192个样本）芯片生成来自血液DNA的DNA甲基化谱。计算β值并进行质量控制，包括评估盲法重复DNA样本。

结果

在450K和27K甲基化芯片上，51个独特基因中的54个胞嘧啶-磷酸-鸟嘌呤探针与糖尿病肾病显著相关（P≤10^(-8)）。使用450K芯片进行的亚分析在374个基因中鉴定出755个胞嘧啶-磷酸-鸟嘌呤探针，这些探针与终末期肾病显著相关（P≤10^(-8)）。糖尿病肾病排名靠前的46个变异体也被鉴定为在终末期肾病患者中存在差异甲基化。在3号染色体p25.2的TAMM41基因中的cg03169527观察到最大的甲基化变化（Δβ = 0.2）。观察到三个基因，PMPCB、TSFM和AUH，在多个胞嘧啶-磷酸-鸟嘌呤位点存在差异甲基化（P < 10^(-12)）。