Prognostic value of angiotensin-1 converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: A prospective study
Prognostic value of angiotensin-1 converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: A prospective study
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DOI：
10.1681/asn.v123541
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发表时间：
2001-03-01
影响因子：
13.6
通讯作者：
Marre, M
中科院分区：
文献类型：
--
作者：
Hadjadj, S;Belloum, R;Marre, M
血管紧张素- 1转换酶（ACE）调节肾脏血流动力学。它的插入/缺失（I/D）多态性决定了ACE的大部分个体间变异，被认为是糖尿病肾病的遗传标记。血管紧张素原（AGT）的替代（M235T）多态性可能与ACE I/D多态性相互作用，影响糖尿病肾病的风险，但其预后价值有待于后续研究确定。共有310名I型糖尿病患者在昂热（法国）的糖尿病诊所参加了一项前瞻性、观察性、随访研究。定期测定糖蛋白、血压、血浆肌酐和尿白蛋白排泄量。肾病分为不存在、早期（微量白蛋白尿）、确诊（蛋白尿）、晚期（血浆肌酐大于或等于150 mu mol/L）和晚期（肾脏替代治疗）。主要终点是肾脏事件的发生，定义为进展到更高阶段的糖尿病肾病。在基线时，251名（81%）患者无肾病，35名（11%）患者为早期肾病，18名（6%）患者为已确诊肾病，6名（2%）患者为晚期肾病。ACE I/D和M235T AGT多态性在患者中处于Hardy-Weinberg平衡。中位随访时间为6年（范围2 - 9年）。肾事件的发生受ACE基因型的显著影响（log-rank II vs . ID vs . DD, P < 0.03），其中D等位基因的显性有害影响：ID或DD vs . II（校正风险比5.0；95%可信区间为1.5 ~ 16.6）。其他因素包括高糖蛋白和收缩压。在最初无肾病的患者中，进展为微量白蛋白尿的患者的基线血浆ACE浓度较高（571 +/- 231对466 +/- 181 g/L， P = 0.0032）；D等位基因独立支持早期肾病的发生（校正风险比为4.5；95%可信区间为1.1 ~ 19.4）；其他影响因素包括男性、基线收缩压和尿白蛋白排泄。AGT M235T多态性与肾脏事件无关。ACE VD多态性的D等位基因是1型糖尿病患者糖尿病肾病发生和发展的独立危险因素。
Angiotensin-I converting enzyme (ACE) regulates renal hemodynamics. Its insertion/deletion (I/D) polymorphism, which determines most of ACE interindividual variance, was proposed as a genetic marker for diabetic nephropathy. A substitution (M235T) polymorphism in angiotensinogen (AGT) may interact with ACE I/D polymorphism for the risk of diabetic nephropathy, but their prognostic values have to be established by follow-up studies. A total of 310 type I diabetes mellitus patients who attended the diabetic clinic in Angers (France) took part in a prospective, observational, follow-up study. Glycohemoglobin, BP, plasma creatinine, and urinary albumin excretion were determined periodically. Nephropathy was classified as absent, incipient (microalbuminuria), established (proteinuria), advanced (plasma creatinine greater than or equal to 150 mu mol/L), and terminal (renal replacement therapy). The main end point was the occurrence of a renal event defined as the progression to a higher stage of diabetic nephropathy. At baseline, 251 (81%) patients had no nephropathy, 35 (11%) had incipient nephropathy, 18 (6%) had established nephropathy, and 6 (2%) had advanced nephropathy. The ACE I/D and M235T AGT polymorphisms were in Hardy-Weinberg equilibrium in the patients. The median duration of follow-up was 6 yr (range, 2 to 9 yr). The occurrence of renal events was significantly influenced by ACE genotype (log-rank II versus ID versus DD, P < 0.03) with a dominant deleterious effect of the D allele: ID or DD versus II (adjusted hazard ratio, 5.0; 95% confidence interval, 1.5 to 16.6). Other contributors were high glycohemoglobin and systolic BP. In the patients who initially were free of nephropathy, baseline plasma ACE concentration was higher in patients who progressed to microalbuminuria (571 +/- 231 versus 466 +/- 181 g/L; P = 0.0032); the D allele independently favored the occurrence of incipient nephropathy (adjusted hazard ratio, 4.5; 95% confidence interval, 1.1 to 19.4); other contributors were male gender, baseline systolic BP, and urinary albumin excretion. The AGT M235T polymorphism was not associated with renal events. The D allele of the ACE VD polymorphism is an independent risk factor for both the onset and the progression of diabetic nephropathy in type 1 diabetes mellitus patients.