Unidad de Investigación Médica en Bioquímica, Unidad Médica de Alta Especialidad "Dr. Bernardo Sepúlveda", Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México, México; Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Ciudad de México, México.
Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Ciudad de México, México.
Nefrologia (Engl Ed). 2023 Sep-Oct;43(5):546-561. doi: 10.1016/j.nefroe.2022.06.010. Epub 2023 Nov 22.
Early biomarkers search for Diabetic Kidney Disease (DKD) in patients with Type 2 Diabetes Mellitus (T2DM), as genetic markers to identify vulnerable carriers of the disease even before Glomerular Filtration Rate (GFR) decline or microalbuminuria development, has been relevant during the last few years. The rs5186 (A116C) polymorphism of the Angiotensin II Receptor Type I gene (AGTR1), has been associated to multiple effects of renal injury risk, commonly detected in patients with Diabetes Mellitus (DM). It has been described that rs5186 could have an effect in stability proteins that assemble Angiotensin II Receptor Type I (AT1), modifying its action, which is why it should be considered as a risk factor for Chronic Kidney Disease (CKD), characterized by a GFR progressive reduction. Even though, the association between rs5186 AGTR1 gene polymorphism and DKD in patients with T2DM has been controversial, inconclusive, and even absent. This disputable issue might be as a result of association studies in which many and varied clinical phenotypes included are contemplated as CKD inductors and enhancers. Although, the sample sizes studied in patients with T2DM are undersized and did not have a strict inclusion criteria, lacking of biochemical markers or KDOQI classification, which have hindered its examination.
The aim of our study was to establish an association between rs5186 AGTR1 gene polymorphism and GFR depletion, assessed as a risk factor to DKD development in patients with T2DM.
We analyzed 297 not related patients with T2DM, divided into 221 controls (KDOQI 1) and 76 cases (KDOQI 2). Arterial pressure, anthropometric and biochemical parameters were measured. rs5186 of AGTR1 genotyping was performed by TaqMan assay real-time PCR method. Allele and genotype frequencies, and Hardy-Weinberg equilibrium were measured. Normality test for data distribution was analyzed by Shapiro-Wilk test, variable comparison by Student's t-test for continuous variables, and Chi-squared test for categorical variables; ANOVA test was used for mean comparison of more than two groups. Effect of rs5186 to DKD was estimated by multiple heritability adjustment models for risk variables of DKD. Statistical significance was indicated by p<0.05. Data was analyzed using Statistical Package STATA v11 software.
Dominant and Over-dominant models showed a likelihood ratio to GFR depletion of 1.89 (1.05-3.39, p=0.031) and 2.01 (1.08-3.73, p=0.023) in patients with T2DM. Risk factor increased to 2.54 (1.10-5.89) in women in Over-dominant model.
In clinical practice, most of nephropathies progress at a slow pace into a total breakdown of renal function, even asymptomatic. This is the first study, reporting that rs5186 polymorphism of AGTR1 gene contribution to GFR depletion, and this could be evaluated as a predisposing factor for DKD in patients with T2DM.
在 2 型糖尿病（T2DM）患者中，早期生物标志物可用于寻找糖尿病肾脏疾病（DKD），作为遗传标志物，即使在肾小球滤过率（GFR）下降或微量白蛋白尿发展之前，也可以识别疾病的易患携带者。近年来，血管紧张素 II 受体 1 型基因（AGTR1）的 rs5186（A116C）多态性与多种肾脏损伤风险的效应相关，在糖尿病（DM）患者中通常可以检测到。已经描述了 rs5186 可能对组装血管紧张素 II 受体 1 型（AT1）的稳定性蛋白具有作用，从而改变其作用，这就是为什么它应该被视为慢性肾脏病（CKD）的危险因素，其特征为 GFR 进行性降低。尽管如此，T2DM 患者中 rs5186 AGTR1 基因多态性与 DKD 之间的关联一直存在争议，尚无定论，甚至不存在。这个有争议的问题可能是由于关联研究所致，其中考虑了许多和不同的临床表型作为 CKD 的诱导和增强因素。尽管如此，在 T2DM 患者中研究的样本量较小，并且没有严格的纳入标准，缺乏生化标志物或 KDOQI 分类，这阻碍了其检查。
我们的研究旨在建立 rs5186 AGTR1 基因多态性与 GFR 耗竭之间的关联，作为 T2DM 患者 DKD 发展的危险因素。
我们分析了 297 名无亲缘关系的 T2DM 患者，分为 221 名对照组（KDOQI 1）和 76 例病例（KDOQI 2）。测量了动脉压、人体测量和生化参数。通过 TaqMan 实时 PCR 方法进行 AGTR1 基因的 rs5186 基因分型。测量等位基因和基因型频率以及 Hardy-Weinberg 平衡。通过 Shapiro-Wilk 检验分析数据分布的正态性检验，通过学生 t 检验比较连续变量，通过卡方检验比较分类变量；使用方差分析检验两组以上的均值比较。通过 DKD 风险变量的多重遗传调整模型估计 rs5186 对 DKD 的影响。p<0.05 表示具有统计学意义。使用统计软件 STATA v11 分析数据。
在 T2DM 患者中，显性和超显性模型显示 GFR 耗竭的似然比分别为 1.89（1.05-3.39，p=0.031）和 2.01（1.08-3.73，p=0.023）。在超显性模型中，女性的风险因素增加到 2.54（1.10-5.89）。
在临床实践中，大多数肾病以缓慢的速度进展为肾功能完全衰竭，即使是无症状的。这是第一项报告 AGTR1 基因 rs5186 多态性与 GFR 耗竭相关的研究，这可能被评估为 T2DM 患者 DKD 的易患因素。
