Polimorfismos Genéticos Associados ao Aparecimento de Hipertensão Arterial Numa População Portuguesa

Abstract

Introduction: Arterial hypertension is a complex, multifactorial disease, controlled by genetic and environmental factors.Objective: Evaluate the genetic susceptibility for developing arterial hypertension and its association with the traditional risk factors in the outbreak of this pathology.Material and Methods: 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.Results: 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).Discussion: 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.Conclusion: 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.

Association Between M235T-AGT and I/D-ACE Polymorphisms and Carotid Atheromatosis in Hypertensive Patients: A Cross-Sectional Study

“…I/D represents the insertion/deletion of a fragment of the ACE gene, which results in an increase in plasma ACE levels and activity. This genetic variation closely correlates with EHT (23, 24).…”

“…It has been established that M235T-AGT and I/D-ACE gene variants play a role in the etiology of IHD and the development of MI in Caucasian and Japanese subjects (24,36,37). Ethnicity, geographical area, and environmental factors influence this association (21).…”

Polymorphism of ACE, AGT, AGTR1 genes as genetic predictors of hypertension

“…Рас пространенность данного полиморфизма среди европеоидной расы достаточно широка и составляет 27%. Исследования показали, что лица, страдающие АГ, достоверно чаще имели генотип А/С или С/С гена AGTR1 по сравнению со здоровыми людьми [38][39][40].…”

Association of the I/D polymorphism of angiotensinconverting enzyme gene with the development of essential hypertension

“…подтверждающих результатов получено не было [8][9][10][11][12][13]. В других же наблюдениях сообщалось о значимом влиянии I/D полиморфизма АСЕ на развитие заболевания, чаще у мужчин [14][15][16][17][18][19][20][21]. В популяционном Фрамингемском исследовании была выявлена взаимосвязь полиморфизма I/D гена АСЕ c АГ и повышенным уровнем диастолического АД (ДАД) у мужчин в отличие от женщин [22].…”