Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes
Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes
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DOI：
10.2337/diabetes.54.4.1238
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发表时间：
2005-04-01
期刊：
影响因子：
7.7
通讯作者：
Zinman, B
中科院分区：
文献类型：
--
作者：
Boright, AP;Paterson, AD;Zinman, B
微血管并发症的发生和进展已在糖尿病控制和并发症试验（DCCT）中招募的I型糖尿病受试者队列中得到广泛记录，并在糖尿病干预和并发症流行病学（EDIC）研究中进行了随访。我们描述了1，365例DCCT/EDIC受试者中ACE基因的遗传变异与持续性微量白蛋白尿（n = 312）和严重肾病（n = 115）的相关性。我们研究了ACE基因中的三个标记（rs 1800764、插入/缺失和rs 9896208），这些标记使我们能够捕获高加索人中频率> 5%的常见单倍型中的遗传变异。在多变量模型中，与更常见的插入/缺失多态性基因型（D/I）相比，I/I基因型导致持续性微量白蛋白尿（风险比[HR] 0.62 [95%CI 0.43-0.89]，P = 0.009）和严重肾病（0.56 [0.32-0.96]，P = 0.033）的风险较低。另外两个标志物rs 1800764和rs 9896208的变化也与这些肾脏结局相关。此外，常见单倍型TIC的纯合性与CDT/TIC单倍型对相比，CDT/TIC单倍型对（分别对应于三个标记rs 1800764、插入/缺失和rs 9896208处的T、插入和C等位基因）与持续性微量白蛋白尿的发生风险较低相关（HR 0.49 [0.32-0.75]，P = 0.0009）和重度肾病（0.41 [0.22-0.78]，P = 0.006）。我们在DCCT/EDIC队列中的发现提供了强有力的证据，表明ACE基因的遗传变异与I型糖尿病患者肾病的发生相关。
The development and progression of microvascular complications have been extensively documented in a cohort of type I diabetic subjects enrolled in the Diabetes Control and Complications Trial (DCCT) and followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. We describe the association of genetic variation in the ACE gene in 1,365 DCCT/EDIC subjects with incident persistent microalbuminuria (n = 312) and severe nephropathy (n = 115). We studied three markers (rs1800764, insertion/deletion, and rs9896208) in the ACE gene that allowed us to capture genetic variation in the common haplotypes occurring at frequencies of > 5% in Caucasians. Compared with the more frequent genotype (D/I) for the insertion/deletion polymorphism, in multivariate models, the I/I genotype conferred a lower risk for persistent microalbuminuria (hazard ratio [HR] 0.62 [95% CI 0.43-0.89], P = 0.009) and severe nephropathy (0.56 [0.32-0.96], P = 0.033). Variation at the two other markers, rs1800764 and rs9896208, were also associated with these renal outcomes. In addition, homozygosity for the common haplotype TIC (which corresponded to the T, insertion, and C alleles at the three markers, rs1800764, insertion/deletion, and rs9896208, respectively) versus the CDT/TIC haplotype pair was associated with lower risk for development of persistent microalbuminuria (HR 0.49 [0.32-0.75],P = 0.0009) and severe nephropathy (0.41 [0.22-0.78], P = 0.006). Our findings in the DCCT/EDIC cohort provide strong evidence that genetic variation at the ACE gene is associated with the development of nephropathy in patients with type I diabetes.