Al-Kateb Hussam, Boright Andrew P, Mirea Lucia, Xie Xinlei, Sutradhar Rinku, Mowjoodi Alireza, Bharaj Bhupinder, Liu Michelle, Bucksa Jean M, Arends Valerie L, Steffes Michael W, Cleary Patricia A, Sun Wanjie, Lachin John M, Thorner Paul S, Ho Michael, McKnight Amy Jayne, Maxwell A Peter, Savage David A, Kidd Kenneth K, Kidd Judith R, Speed William C, Orchard Trevor J, Miller Rachel G, Sun Lei, Bull Shelley B, Paterson Andrew D
Program in Genetics and Genome Biology, The Hospital for Sick Children, TMDT Building East Tower, Rm. 15-707, 101 College St., Toronto, Ontario, Canada.
Diabetes. 2008 Jan;57(1):218-28. doi: 10.2337/db07-1059. Epub 2007 Oct 3.
Despite familial clustering of nephropathy and retinopathy severity in type 1 diabetes, few gene variants have been consistently associated with these outcomes.
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 multivariate 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.
We observed association between rs17880135 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 x 10(-5), q = 0.06) and persistent microalbuminuria (1.82 [1.29-2.57], P = 6.4 x 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 rs17880135 and rs17881180 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.
Multiple variations in SOD1 are significantly associated with persistent microalbuminuria and severe nephropathy in the DCCT/EDIC study.
尽管1型糖尿病患者的肾病和视网膜病变严重程度存在家族聚集现象，但很少有基因变异与这些结局始终相关。
我们对糖尿病控制与并发症试验/糖尿病干预与并发症流行病学研究（DCCT/EDIC）中1362例1型糖尿病白人先证者进行了一项基于个体的基因关联研究，观察肾脏和视网膜病变结局的发生时间。具体而言，我们对1411个单核苷酸多态性（SNP）进行基因分型，这些SNP涵盖了212个与长期并发症相关的候选基因中的常见变异，并使用多变量Cox比例风险模型分析它们与从DCCT基线到肾脏和视网膜病变结局发生事件的时间之间的关联。为解决多重检验问题并辅助结果解释，我们分别为每个结局计算了错误发现率q值。
我们观察到超氧化物歧化酶1（SOD1）3'区域的rs17880135与严重肾病的发生率（风险比[HR] 2.62 [95%可信区间1.64 - 4.18]，P = 5.6×10⁻⁵，q = 0.06）以及持续性微量白蛋白尿的发生率（1.82 [1.29 - 2.57]，P = 6.4×10⁻⁴，q = 0.46）均相关。测序和精细定位确定了其他SOD1变异，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rs17880135和rs17881180与严重肾病的发生同样相关。在三项横断面病例对照研究中尝试重复这些发现，结果并不明确。我们未观察到风险基因型在血清SOD活性、血清SOD1质量或淋巴母细胞系中SOD1 mRNA表达方面存在显著差异。
在DCCT/EDIC研究中，SOD1的多个变异与持续性微量白蛋白尿和严重肾病显著相关。
