Roberto Palma dos Reis

RAS gene polymorphisms, classical risk factors and the advent of coronary artery disease in the Portuguese population

BackgroundSeveral polymorphisms within the renin-angiotensin system cluster of genes have been associated with the advent of coronary artery disease (CAD) or related pathologies. We investigated the distribution of 5 of these polymorphisms in order to find any association with CAD development and distinguish if any of the biochemical and behavioural factors interact with genetic polymorphisms in the advent of the disease.MethodsACE I/D (rs4340), ACE A11860G (rs4343), AT1R A1166C (rs5186), AGT T174M (rs4762) and AGT M235T (rs699) gene polymorphisms were PCR-RFLP analysed in 298 CAD patients and 510 controls from Portugal. Several biochemical and behavioural markers were obtained.ResultsACE I/D DD and ACE11860 GG genotypes are risk factors for CAD in this population. The simultaneous presence of ACE I/D I and ACE11860 A alleles corresponds to a significant trend towards a decrease in CAD incidence. We found several synergistic effects between the studied polymorphisms and classical risk factors such as hypertension, obesity, diabetes and dyslipidaemia: the presence of the DD genotype of ACE I/D (and also ACE11860 GG) increases the odds of developing CAD when associated to each one of these classical risk factors, particularly when considering the male and early onset CAD subgroup analysis; AGT235 TT also increases the CAD risk in the presence of hypertension and dyslipidaemia, and AT1R1166 interacts positively with hypertension, smoking and obesity.ConclusionACE polymorphisms were shown to play a major role in individual susceptibility to develop CAD. There is also a clear interaction between RAS predisposing genes and some biochemical/environmental risk factors in CAD onset, demonstrating a significant enhancement of classical markers particularly by ACE I/D and ACE11860.

Methylenetetrahydrofolate reductase gene, homocysteine and coronary artery disease: The A1298C polymorphism does matter. Inferences from a case study (Madeira, Portugal)

Elevated levels of plasma homocysteine, an independent risk factor and a strong predictor of mortality in patients with coronary artery disease (CAD), can result from nutritional deficiencies or genetic errors, including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms. The contribution of these polymorphisms in the development of CAD remains controversial. We analysed the impact of MTHFR C677T and A1298C on fasting homocysteine and CAD in 298 CAD patients proved by angiography and 510 control subjects from the Island of Madeira (Portugal). After adjustment for other risk factors, plasma homocysteine remained independently correlated with CAD. Serum homocysteine was significantly higher in individuals with 677TT and 1298AA genotypes. There was no difference in the distribution of MTHFR677 genotypes between cases and controls but a significant increase in 1298AA prevalence was found in CAD patients. In spite of the clear effect of C677T mutation on elevated homocysteine levels we only found an association between 1298AA genotype and CAD in this population. The simultaneous presence of 677CT and 1298AA genotypes provides a significant risk of developing the disease, while the 1298AC genotype, combined with 677CC, shows a significant trend towards a decrease in CAD occurrence. The data shows an independent association between elevated levels of homocysteine and CAD. Both MTHFR polymorphisms are associated with increased fasting homocysteine (677TT and 1298AA genotypes), but only the 1298AA variant shows an increased prevalence in CAD group. Odds ratio seem to indicate that individuals with the MTHFR 1298AA genotype and the 677CT/1298AA compound genotype had a 1.6-fold increased risk for developing CAD suggesting a possible association of MTHFR polymorphisms with the risk of CAD in Madeira population.

Hematological evaluation in males with obstructive sleep apnea before and after positive airway pressure

Obstructive sleep apnea syndrome (OSAS) is a systemic inflammatory disease associated with cardiovascular consequences. Red blood cell distribution width (RDW), mean platelet volume (MPV), and platelet distribution width (PDW) are recognized biomarkers of cardiovascular morbidity/mortality. Limited data is available on the association between these parameters and OSAS severity and the relationship with positive airway pressure therapy (PAP). In this prospective study of male OSAS patients we analyzed hematological data in order to evaluate their value in predicting OSAS severity, the relationship with sleep parameters, and their behavior under PAP. Seventy-three patients were included (mean age 46.5 years), of which 36 were mild (49.3%), 10 moderate (13.7%), and 27 severe (37%). The mean RDW increased significantly with OSAS severity and showed a positive correlation with respiratory disturbance index and hypoxemic burdens. Additionally, a group of 48 patients (mean age 47.2 years) were submitted to PAP. After six months, red blood cell count, hemoglobin, hematocrit, and platelet count showed a significant decrease (p<0.0001; p<0.0001; p=0.001; p<0.0001; respectively). Concerning OSAS severity, these parameters also significantly decreased in mild patients (p=0.003; p=0.043; p=0.020; p=0.014; respectively) but only hemoglobin, hematocrit, and platelet count decreased in severe cases (p<0.0001; p=0.008; p=0.018; respectively). This study demonstrated an association between RDW values and OSAS severity. Moreover, red cell and platelet parameters changed significantly after PAP, supporting its cardiovascular protective effect. RDW may become a simple/inexpensive blood biomarker, making it useful in prioritizing OSAS patients waiting for polysomnography, and red cell and platelet parameters could be useful in PAP follow up.

Relationship between ADD1 Gly460Trp gene polymorphism and essential hypertension in Madeira Island

Abstract Essential hypertension (EH) is a complex disease in which physiological, environmental, and genetic factors are involved in its genesis. The genetic variant of the alpha-adducin gene (ADD1) has been described as a risk factor for EH, but with controversial results. The objective of this study was to evaluate the association of ADD1 (Gly460Trp) gene polymorphism with the EH risk in a population from Madeira Island. A case-control study with 1614 individuals of Caucasian origin was performed, including 817 individuals with EH and 797 controls. Cases and controls were matched for sex and age, by frequency-matching method. All participants collected blood for biochemical and genotypic analysis for the Gly460Trp polymorphism. We further investigated which variables were independently associated to EH, and, consequently, analyzed their interactions. In our study, we found a significant association between the ADD1 gene polymorphism and EH (odds ratio 2.484, P = .01). This association remained statistically significant after the multivariate analysis (odds ratio 2.548, P = .02). The ADD1 Gly460Trp gene polymorphism is significantly and independently associated with EH risk in our population. The knowledge of genetic polymorphisms associated with EH is of paramount importance because it leads to a better understanding of the etiology and pathophysiology of this pathology.

A variante genética c825t da subunidade β3 da proteína G associa‐se com a hipertensão arterial numa população portuguesa

INTRODUCTION Hypertension is an important public health problem, affecting about 25% of the adult population worldwide.1 Genetic and environmental factors contribute to its pathogenesis. The T allele of the C825T polymorphism of the beta 3 subunit of G protein (rs5443) leads to the production of a truncated variant that enhances intracellular signaling and may interfere with the regulation of blood pressure. This genetic variant has been described as a risk factor for hypertension, although study results are controversial. OBJECTIVE The objective of this study was to analyze the association of the C825T polymorphism of the GNB3 gene with the occurrence of hypertension in a Portuguese population from the Madeira archipelago. METHODS A case-control study was performed with 1641 Caucasian individuals (mean age 50.6±8.1 years), 848 with hypertension and 793 controls. Blood was collected from all participants for biochemical and genetic analysis, including genotyping of the C825T polymorphism. Logistic regression analysis was performed to determine which variables were significantly associated with the onset of hypertension. Statistical analyses were performed using IBM SPSS version 19.0 and p-values <0.05 were considered statistically significant. RESULTS In our study, there was a significant association between the C825T polymorphism of the GNB3 gene and the occurrence of hypertension (odds ratio 1.275; 95% confidence interval 1.042-1.559; p=0.018) in the dominant model, after multivariate analysis. CONCLUSION We conclude that the C825T polymorphism of the beta 3 subunit of G protein is significantly and independently associated with the occurrence of hypertension in the study population.

Good agreement between echocardiography and impedance cardiography in the assessment of left ventricular performance in hypertensive patients

ABSTRACT Background: Impedance cardiography (ICG) is a noninvasive hemodynamic monitoring tool which can define hypertensive patients’ hemodynamic profiles and help to tailor antihypertensive therapy. This study assesses the concordance between ICG-derived indexes used to evaluate left ventricular performance and transthoracic echocardiography (TTE) in hypertensive patients. Methods: In this IMPEDDANS post-hoc analysis, the ICG-derived indexes are compared with TTE by Bland–Altman method. Statistical significance of the relationship between the values obtained was assessed by generalized linear mixed-effects models. Results: In supine position, Bland–Altman analysis showed good concordance for cardiac output (CO) (mean difference of 0.006 mL/min [−0.120; 0.133]), cardiac index (CI) (mean difference of 0.016 mL/min/m2 [−0.471; 0.504]), pre-ejection period (PEP) (mean difference of −0.216 ms [−4.510; 4.077]), left ventricular ejection time (LVET) (mean difference of −0.140 ms [−6.573; 6.293]), and systolic time ratio (STR) (mean difference of −0.00004 [−0.008; 0.008]). In orthostatic position, good concordance was found for CO (mean difference 0.028 mL/min [−2.036; 1.980]), CI (mean difference −0.012 mL/min/m2 [−1.063; 1.039]), and STR (mean difference −0.101 [0.296; 0.094]). No significant difference between methods was identified by the linear mixed-effects models. Conclusion: The ICG-derived indexes CO, CI, PEP, LVET, and STR in supine position have good agreement with TTE. Therefore, ICG can be used to accurately evaluate left ventricular performance.

Genetic Risk Analysis of Coronary Artery Disease in a Population-based Study in Portugal, Using a Genetic Risk Score of 31 Variants

Background Genetic risk score can quantify individual’s predisposition to coronary artery disease; however, its usefulness as an independent risk predictor remains inconclusive. Objective To evaluate the incremental predictive value of a genetic risk score to traditional risk factors associated with coronary disease. Methods Thirty-three genetic variants previously associated with coronary disease were analyzed in a case-control population with 2,888 individuals. A multiplicative genetic risk score was calculated and then divided into quartiles, with the 1st quartile as the reference class. Coronary risk was determined by logistic regression analysis. Then, a second logistic regression was performed with traditional risk factors and the last quartile of the genetic risk score. Based on this model, two ROC curves were constructed with and without the genetic score and compared by the Delong test. Statistical significance was considered when p values were less than 0.05. Results The last quartile of the multiplicative genetic risk score revealed a significant increase in coronary artery disease risk (OR = 2.588; 95% CI: 2.090-3.204; p < 0.0001). The ROC curve based on traditional risk factors estimated an AUC of 0.72, which increased to 0.74 when the genetic risk score was added, revealing a better fit of the model (p < 0.0001). Conclusions In conclusion, a multilocus genetic risk score was associated with an increased risk for coronary disease in our population. The usual model of traditional risk factors can be improved by incorporating genetic data.

Effects of positive airway pressure therapy on cardiovascular and metabolic markers in males with obstructive sleep apnea

INTRODUCTION Obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular/metabolic complications. Some analytical parameters (homocysteine, glycemic and lipidic profiles) are recognized markers of these consequences. Limited data is available on the association of these markers and OSASs severity/response to positive airway pressure therapy (PAP). MATERIAL AND METHODS In this prospective study we analyzed polysomnographic and analytical data of male patients admitted to sleep laboratory. The aim was to evaluate metabolic/cardiovascular markers in snorers and OSAS patients, to relate with sleep parameters and PAP response. One-hundred and three patients were included, and 73 (71%) were OSAS patients. OSAS patients were similar to snorers except for higher body mass index (BMI) and dyslipidemia. Severe OSAS patients showed higher glycemia, HbA1c, insulin, and insulin resistance, and lower HDL cholesterol in comparison to mild-moderate (p<0.05, p<0.05, p<0.001, p<0.001, p<0.05, respectively). Glycemic profile and triglycerides were slightly correlated with OSAS severity. 46 OSAS patients were submitted to 6 months of PAP, with a statistical decrease in mean values of homocysteine, glycemia, total and LDL cholesterol (p<0.05, p<0.05, p<0.05, respectively), and in glycemia and LDL cholesterol in severe group only (p<0.05, p<0.05, respectively). RESULTS This study demonstrated an association between glucose metabolism parameters and triglycerides with OSAS severity underlying the complexity of the process leading to cardiovascular/metabolic complications in this disorder. Moreover, homocysteine, glycemic and lipidic profiles changed significantly after 6 months of PAP therapy in OSAS, supporting its cardiovascular and metabolic protective effect. CONCLUSION Our study has reinforced the importance of analytical cardiovascular/metabolic evaluation as complementary tool of diagnosis/treatment response in OSAS.

Genetic risk score and cardiovascular mortality in a southern european population with coronary artery disease

Several genetic risk scores (GRS) have been associated with cardiovascular disease; their role, however, in survival from proven coronary artery disease (CAD) have yielded conflicting results.

Prediction of Coronary Heart Disease Risk in a South European Population: A Case-Control Study

Coronary heart disease (CHD) is the most common cause of death in the industrialized countries. Although the past two decades have brought considerable advances in its detection and treatment, it remains a leading cause of death and disability in Western countries (Mackay & Mensah, 2004). CHD is a complex disease, whose primary cause is atherosclerosis. It is a progressive chronic disease process with contributions from environment, lifestyle and genetic factors. This complex disease clusters in families, suggesting a substantial genetic predisposition (Marenberg et al., 1994) and we know that its susceptibility can be mediated by both genetic and environmental factors (Talmud, 2007).