科研之友
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摘要
AimsEpigenetic 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 Type1 diabetes. MethodsA 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 Type1 diabetes before 31years 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 () were calculated and quality control was conducted, including evaluating blind duplicate DNA samples. ResultsFifty-four Cytosine-phosphate-Guanine probes across 51 unique genes were significantly associated (P10(-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 (P10(-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 (=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)). ConclusionsDifferential methylation in genes that influence mitochondrial function are associated with kidney disease in individuals with Type1 diabetes. What's new? Mitochondrial dysfunction has been identified in diabetic kidney disease, but relatively large-scale genetic and epigenetic studies focused on mitochondria have not yet been described. We report a novel case-control analysis of DNA methylation in 442 individuals, with Type1 diabetes, for 780 mitochondrial proteins. Stringent quality control was applied and different chemistry employed for two different methylation arrays. Fifty-one genes demonstrated genome-wide significance (P10(-8)) for association with diabetic kidney disease, 46 of which were also supported by subgroup analysis for end-stage renal disease. Genetic and epigenetic risk variants in mitochondrial related genes are associated with kidney disease in individuals with Type1 diabetes.
- 出版日期2015-8
