BACKGROUND Several genetic susceptibility loci associated with diabetic nephropathy have been documented, but no causative variants implying novel pathogenetic mechanisms have been elucidated. METHODS We carried out whole-genome sequencing of a discovery cohort of Finnish siblings with type 1 diabetes who were discordant for the presence (case) or absence (control) of diabetic nephropathy. Controls had diabetes without complications for 15-37 years. We analyzed and annotated variants at genome, gene, and single-nucleotide variant levels. We then replicated the associated variants, genes, and regions in a replication cohort from the Finnish Diabetic Nephropathy study that included 3531 unrelated Finns with type 1 diabetes. RESULTS We observed protein-altering variants and an enrichment of variants in regions associated with the presence or absence of diabetic nephropathy. The replication cohort confirmed variants in both regulatory and protein-coding regions. We also observed that diabetic nephropathy-associated variants, when clustered at the gene level, are enriched in a core protein-interaction network representing proteins essential for podocyte function. These genes include protein kinases (protein kinase C isoforms ε and ι) and protein tyrosine kinase 2. CONCLUSIONS Our comprehensive analysis of a diabetic nephropathy cohort of siblings with type 1 diabetes who were discordant for kidney disease points to variants and genes that are potentially causative or protective for diabetic nephropathy. This includes variants in two isoforms of the protein kinase C family not previously linked to diabetic nephropathy, adding support to previous hypotheses that the protein kinase C family members play a role in diabetic nephropathy and might be attractive therapeutic targets.

中文翻译：

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芬兰1型糖尿病兄弟姐妹肾脏疾病的全基因组测序揭示了与糖尿病性肾病相关的DNA变异。

背景技术已经报道了与糖尿病性肾病相关的几种遗传易感基因座，但是尚未阐明暗示新的致病机制的致病性变体。方法我们对芬兰1型糖尿病兄弟姐妹的发现队列进行了全基因组测序，这些兄弟姐妹因糖尿病肾病的存在（病例）或不存在（对照）而不一致。对照组患有糖尿病且无并发症15-37年。我们在基因组，基因和单核苷酸变异水平上分析并注释了变异。然后，我们在芬兰糖尿病肾病研究的复制队列中复制了相关的变异体，基因和区域，该研究包括3531个与1型糖尿病无关的芬兰人。结果我们观察到与糖尿病性肾病存在或不存在相关的区域中，蛋白质改变的变体和变体的富集。复制队列在调节区和蛋白质编码区均证实了变异。我们还观察到，与糖尿病肾病相关的变异体在基因水平上聚集时，富含核心蛋白相互作用网络，该网络代表足细胞功能所必需的蛋白。这些基因包括蛋白激酶（蛋白激酶C亚型ε和η）和蛋白酪氨酸激酶2。结论我们对患有肾脏疾病的1型糖尿病兄弟姐妹的糖尿病肾病队列进行的综合分析指出了潜在的变异和基因或对糖尿病肾病有保护作用。