Sousa Ana Célia, Reis Roberto Palma, Pereira Andreia, Borges Sofia, Freitas Ana Isabel, Guerra Graça, Gouveia Sara, Góis Teresa, Nóbrega Lino, Rodrigues Mariana, Henriques Eva, Freitas Sónia, Ornelas Ilídio, Pereira Décio, Brehm António, Mendonça Maria Isabel
Unidade de Investigação. Hospital Doutor Nélio Mendonça. Funchal. Portugal.
Faculdade de Ciências Médicas. Universidade Nova de Lisboa. Lisboa. Portugal.
Acta Med Port. 2018 Oct 31;31(10):542-550. doi: 10.20344/amp.9184.
Arterial hypertension is a complex, multifactorial disease, controlled by genetic and environmental factors.
Evaluate the genetic susceptibility for developing arterial hypertension and its association with the traditional risk factors in the outbreak of this pathology.
Case-control study with 1712 individuals, mean age of 51.0 ± 7.9 years (860 hypertensive patients and 852 controls). Biochemical and traditional risk factors, and genetic variants were evaluated: ACE I/D rs4340, ACE A2350G rs4343, AGT T174M rs4762, AGT M235T rs699 AGTR1 A1166C rs5186, CYP11B2 -344 C/T rs1799998, ADRB1 R389G rs1801253, ADRB2 R16G rs1042713, ADD1 G460W rs4961, SCNN1G G173A rs5718, GNB3 C825T rs5443, ATP2B1 A/G rs2681472, CYP17A1 T/C rs11191548, SLC4A2 C/T rs2303934. The risk of each gene for hypertension was estimated by the dominant, recessive, co-dominant and multiplicative models. By logistic regression, variables associated with hypertension were evaluated. ROC curves were first performed with traditional risk factors and then adding the genetic variants associated with hypertension. Data were analyzed by SPSS for Windows 19.0 and MedCalc v. 13.3.3.0.
The genetic variants ADD1 G460W, GNB3 C825T, ACE I/D, ACE A2350G were associated with hypertension. ROC curve with traditional risk factors and these variants showed an increase in the predictive capacity of hypertension (p = 0.018).
According to the results of our study, the genetic variants found to be associated with hypertension were: ACE I/D rs4340, ACE A2350G rs4343, ADD1 G460W rs4961 and GNB3 C825T rs5443. The first two variants are associated with hypertension by interfering with the renin-angiotensin-aldosterone system, which plays an important role in regulating blood pressure. It should be noted that genes encoding the components of renin-angiotensin-aldosterone system are natural candidates for the development and progression of hypertension. In our population alpha-aducin polymorphism (ADD1 G460W rs4961) was also associated with hypertension. In a Portuguese population, known to have high salt intake, it makes sense that this polymorphism which is relevant in salt and water management may consequently be relevant in the onset of hypertension. The genetic variant GNB3 C825T rs5443 that affects intracellular signalling was also found to be a strong risk candidate for hypertension. Initially, with the elaboration of the ROC curve and calculation of the AUC using only with traditional risk factors and later by adding the variants ADD1 G460W, GNB3 C825T, ACE I/D and ACE A2350G to the traditional risk factors, we verified that genetic polymorphisms increased the predictive risk of hypertension, when compared to the risk given only by traditional risk factors, with statistical significance (p = 0.018). This suggests that hypertension is a multifactorial disease that results from the interaction of environmental, genetic and lifestyle factors that interact with each other and lead to the advent of this important pathology.
In our study, the hypertension-associated polymorphisms are linked to the renin-angiotensin-aldosterone axis (ACE I/D, ACE A2350G), as well as to salt and water management (ADD1 G460W, GNB3 C825T). Through a multivariate analysis, it was concluded that these two last genetic variants together with four of the traditional risk factors (smoking, alcohol consumption, obesity and diabetes) are associated in a significant and independent way with essential hypertension. In a predictive model of hypertension, the introduction of genetic variants slightly increases the predictive value of the model.
动脉高血压是一种复杂的多因素疾病，受遗传和环境因素控制。
评估发生动脉高血压的遗传易感性及其与该疾病发作时传统危险因素的关联。
对1712名个体进行病例对照研究，平均年龄为51.0±7.9岁（860名高血压患者和852名对照）。评估生化和传统危险因素以及基因变异：ACE I/D rs4340、ACE A2350G rs4343、AGT T174M rs4762、AGT M235T rs699、AGTR1 A1166C rs5186、CYP11B2 -344 C/T rs1799998、ADRB1 R389G rs1801253、ADRB2 R16G rs1042713、ADD1 G-460W rs4961、SCNN1G G173A rs5718、GNB3 C825T rs5443、ATP2B1 A/G rs2681472、CYP17A1 T/C rs11191548、SLC4A2 C/T rs2303934。通过显性、隐性、共显性和乘法模型估计每个基因患高血压的风险。通过逻辑回归评估与高血压相关的变量。首先用传统危险因素绘制ROC曲线，然后添加与高血压相关的基因变异。数据用SPSS for Windows 19.0和MedCalc v. 13.3.3.0进行分析。
基因变异ADD1 G460W、GNB3 C825T、ACE I/D、ACE A2350G与高血压相关。传统危险因素与这些变异的ROC曲线显示高血压预测能力有所提高（p = 0.018）。
根据我们的研究结果，发现与高血压相关的基因变异为：ACE I/D rs4340、ACE A2350G rs4343、ADD1 G460W rs4961和GNB3 C825T rs5443。前两个变异通过干扰肾素 - 血管紧张素 - 醛固酮系统与高血压相关，该系统在调节血压中起重要作用。应该注意的是，编码肾素 - 血管紧张素 - 醛固酮系统成分的基因是高血压发生和发展的天然候选基因。在我们的人群中，α - 内收蛋白多态性（ADD1 G460W rs4961）也与高血压相关。在已知盐摄入量高的葡萄牙人群中，这种与盐和水管理相关的多态性可能与高血压的发病有关是有道理的。影响细胞内信号传导的基因变异GNB3 C825T rs5443也被发现是高血压的一个强有力的风险候选因素。最初，仅用传统危险因素绘制ROC曲线并计算AUC，后来将变异ADD1 G460W、GNB3 C825T、ACE I/D和ACE A2350G添加到传统危险因素中，我们验证了与仅由传统危险因素给出的风险相比，基因多态性增加了高血压的预测风险，具有统计学意义（p = 0.018）。这表明高血压是一种多因素疾病，由环境、遗传和生活方式因素相互作用导致这种重要疾病的出现。
在我们的研究中，与高血压相关的多态性与肾素 - 血管紧张素 - 醛固酮轴（ACE I/D、ACE A2350G）以及盐和水管理（ADD1 G460W、GNB3 C825T）有关。通过多变量分析得出，这两个最后的基因变异与四个传统危险因素（吸烟、饮酒、肥胖和糖尿病）一起以显著且独立的方式与原发性高血压相关。在高血压预测模型中，引入基因变异略微增加了模型的预测价值。
