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首页> 外文期刊>Diabetes >Multiple Superoxide Dismutase 1/Splicing Factor Serine Alanine 15 Variants Are Associated With the Development and Progression of Diabetic Nephropathy: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications
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Multiple Superoxide Dismutase 1/Splicing Factor Serine Alanine 15 Variants Are Associated With the Development and Progression of Diabetic Nephropathy: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications

机译：多种超氧化物歧化酶1 /剪接因子丝氨酸丙氨酸15变体与糖尿病性肾病的发展和进展有关：糖尿病的控制和并发症糖尿病的流行病学干预和并发症。

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BACKGROUND-Despite familial clustering of nephropathy and retinopathy severity in type 1 diabetes, few gene variants have been consistently associated with these outcomes. RESEARCH DESIGN AND METHODS-We performed an individual-based genetic association study with time to renal and retinal outcomes in 1,362 white probands with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Specifically, we genotyped 1,411 SNPs that capture common variations in 212 candidate genes for long-term complications and analyzed them for association with the time from DCCT baseline to event for renal and retinal outcomes using multivar-iate Cox proportion hazards models. To address multiple testing and assist interpretation of the results, false discovery rate q values were calculated separately for each outcome. RESULTS-We observed association between rsl7880135 in the 3' region of superoxide dismutase 1 (SOD1) and the incidence of both severe nephropathy (hazard ratio [HR] 2.62 [95% CI 1.64-4.18], P = 5.6 × 10~(-5), q = 0.06) and persistent microalbuminuria (1.82 [1.29-2.57], P = 6.4 × 10~(-4), q = 0.46). Sequencing and fine-mapping identified additional SOD1 variants, including rs202446, rs9974610, and rs204732, which were also associated (P ＜ 10~(-3)) with persistent microalbuminuria, whereas rsl7880135 and rsl7881180 were similarly associated with the development of severe nephropathy. Attempts to replicate the findings in three cross-sectional case-control studies produced equivocal results. We observed no striking differences between risk genotypes in serum SOD activity, serum SOD1 mass, or SOD1 mRNA expression in lymphoblastoid cell lines. CONCLUSIONS-Multiple variations in SOD1 are significantly associated with persistent microalbuminuria and severe nephropathy in the DCCT/EDIC study.
机译：背景技术尽管在1型糖尿病中肾病和视网膜病严重程度存在家族性聚集，但很少有基因变异与这些结果一致相关。研究设计和方法-我们进行了一项基于个体的遗传关联研究，研究了来自糖尿病控制与并发症试验/糖尿病干预与并发症流行病学（DCCT / EDIC）研究的1,362名1型糖尿病白人先证者的肾和视网膜预后。具体来说，我们对1,411个SNP进行了基因分型，这些SNPs捕获了212个候选基因的长期并发症的常见变异，并使用多变量Cox比例风险模型分析了它们与从DCCT基线到事件发生的时间相关的肾和视网膜结果。为了解决多个测试问题并帮助解释结果，针对每个结果分别计算了错误发现率q值。结果-我们观察到超氧化物歧化酶1（SOD1）3'区域中的rsl7880135与两种严重肾病的发生率相关（危险比[HR] 2.62 [95％CI 1.64-4.18]，P = 5.6×10〜（- 5），q = 0.06）和持续性微量白蛋白尿（1.82 [1.29-2.57]，P = 6.4×10〜（-4），q = 0.46）。测序和精细定位发现了另外的SOD1变体，包括rs202446，rs9974610和rs204732，它们也与持续性微量白蛋白尿相关（P ＜10〜（-3）），而rs1788035和rsl7881180与严重肾病的发展相似。试图在三项横断面病例对照研究中重复发现的结果产生了模棱两可的结果。我们观察到淋巴母细胞细胞系中血清SOD活性，血清SOD1质量或SOD1 mRNA表达的风险基因型之间没有显着差异。结论：在DCCT / EDIC研究中，SOD1的多种变异与持续性微量白蛋白尿和严重肾病显着相关。

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