Genetic risk factors affecting mitochondrial function are associated with kidney disease in people with Type 1 diabetes.
Genetic risk factors affecting mitochondrial function are associated with kidney disease in people with Type 1 diabetes.
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DOI：
10.1111/dme.12763
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发表时间：
2015-08
期刊：
影响因子：
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通讯作者：
GENIE Consortium
中科院分区：
文献类型：
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作者：
Swan EJ;Salem RM;Sandholm N;Tarnow L;Rossing P;Lajer M;Groop PH;Maxwell AP;McKnight AJ;GENIE Consortium
目的探讨单核苷酸多态(SNPs)与糖尿病肾病的关系，这些SNPs可能导致线粒体功能障碍。采用病例组(n=2823例糖尿病肾病患者)和对照组(n=903例糖尿病非肾脏疾病患者)的方法对线粒体基因组和1039个与线粒体功能有关的核基因进行了研究。所有纳入分析的人都是欧洲白人血统，并在31岁之前被诊断出患有1型糖尿病。在5093人中进行了复制，这些人的表型与发现集合的人相似。使用PLINK遗传分析工具集进行关联分析，并对相关协变量进行调整。总共评估了线粒体基因组中的25个SNP，但没有一个与糖尿病肾脏疾病或终末期肾脏疾病显著相关。在影响线粒体功能的核基因中，共有38个SNP与糖尿病肾脏疾病名义上相关，16个SNP与继发于糖尿病肾脏疾病的终末期肾脏疾病相关，Meta分析证实了相同的影响方向。三个独立的信号(七个SNP)对于1型糖尿病和持续性蛋白尿或终末期肾病的两种表型的复制数据都是共同的。我们的结果表明，在欧洲白人人群中，影响线粒体功能的核基因中的SNPs与糖尿病肾病显著相关。线粒体功能障碍已经在糖尿病肾病中被发现，但相对大规模的以线粒体为重点的遗传学和表观遗传学研究尚未被描述。我们报道了一种新的病例对照分析，通过独立的重复，对线粒体基因组和1039个对线粒体功能重要的核基因进行了遗传变异的分析。影响线粒体功能的核基因的单核苷酸多态(SNPs)与糖尿病肾病相关。突出显示的SNPs位于与表观遗传过程调控有关的基因内。进一步研究高血糖、尿毒症和基因组的表观遗传修饰之间的相互作用，可能会为这些核基因组SNPs如何与肾脏疾病相关提供新的线索。
To evaluate the association with diabetic kidney disease of single nucleotide polymorphisms (SNPs) that may contribute to mitochondrial dysfunction. The mitochondrial genome and 1039 nuclear genes that are integral to mitochondrial function were investigated using a case (n = 823 individuals with diabetic kidney disease) vs. control (n = 903 individuals with diabetes and no renal disease) approach. All people included in the analysis were of white European origin and were diagnosed with Type 1 diabetes before the age of 31 years. Replication was conducted in 5093 people with similar phenotypes to those of the discovery collection. Association analyses were performed using the plink genetic analysis toolset, with adjustment for relevant covariates. A total of 25 SNPs were evaluated in the mitochondrial genome, but none were significantly associated with diabetic kidney disease or end-stage renal disease. A total of 38 SNPs in nuclear genes influencing mitochondrial function were nominally associated with diabetic kidney disease and 16 SNPS were associated with end-stage renal disease, secondary to diabetic kidney disease, with meta-analyses confirming the same direction of effect. Three independent signals (seven SNPs) were common to the replication data for both phenotypes with Type 1 diabetes and persistent proteinuria or end-stage renal disease. Our results suggest that SNPs in nuclear genes that influence mitochondrial function are significantly associated with diabetic kidney disease in a white European population. 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, with independent replication, of genetic variation focused on the mitochondrial genome and 1039 nuclear genes that are important for mitochondrial function. Single nucleotide polymorphisms (SNPs) in nuclear genes affecting mitochondrial function were found to be associated with diabetic kidney disease. The highlighted SNPs were within the genes implicated in regulation of epigenetic processes. Further research to explore the interactions between hyperglycaemia, uraemia and epigenetic modifications of the genome could shed new light on how these nuclear genome SNPs are associated with kidney disease.