Graça Guerra

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.

Association of ADAMTS7 gene polymorphism with cardiovascular survival in coronary artery disease.

Recent genetic studies have revealed an association between polymorphisms at the ADAMTS7 gene locus and coronary artery disease (CAD) risk. Functional studies have shown that a CAD-associated polymorphism (rs3825807) affects ADAMTS7 maturation and vascular smooth muscular cell (VSMC) migration. Here, we tested whether ADAMTS7 (A/G) SNP is associated with cardiovascular (CV) survival in patients with established CAD. A cohort of 1,128 patients with angiographic proven CAD, who were followed up prospectively for a mean follow-up period of 63 (range 6-182) mo, were genotyped for rs3825807 A/G. Survival statistics (Cox regression) compared heterozygous (AG) and wild-type (AA) with the reference homozygous GG. Kaplan-Meier (K-M) survival curves were performed according to ADAMTS7 genotypes for CV mortality. Results showed that 47.3% of patients were heterozygous (AG), 36.5% were homozygous for the wild-type allele (AA) and only 16.2% were homozygous for the GG genotype. During the follow-up period, 109 (9.7%) patients died, 77 (6.8%) of CV causes. Survival analysis showed that AA genotype was an independent risk factor for CV mortality compared with reference genotype GG (HR = 2.7, P = 0.025). At the end of follow-up, the estimated survival probability (K-M) was 89.8% for GG genotype, 82.2% for AG and 72.3% for AA genotype (P = 0.039). Carriage of the mutant G allele of the ADAMTS7 gene was associated with improved CV survival in patients with documented CAD. The native overfunctional ADAMTS7 allele (A) may accelerate VSMC migration and lead to neointimal thickening, atherosclerosis progression and acute plaque events. ADAMTS7 gene should be further explored in CAD for risk prediction, mechanistic and therapeutic goals.

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.

6C.07: INCREASE THE PREDICTIVE CAPACITY OF CORONARY RISK WITH A GENETIC SCORE.

Objective: Genes associated with coronary artery disease (CAD) and traditional cardiovascular risk factors (TCRF) present a limited individual predictive value. It is expected that the inclusion in global scores may increase the predictive ability. In genetic terms, there are no validated risk scores to predict the occurrence of cardiovascular disease or its complications. Objective: Evaluate the ability of a multifactorial genetic risk score (GRS) be able to add predictive power, for the development of CAD, to the model developed only with TCRF. Design and method: A case-control study was performed with 1321 consecutive coronary patients (mean age 53.4 ± 8.1 years, 78.8% male) and 1148 controls selected to be similar to cases in terms of gender and age. Traditional risk factors (hypertension, diabetes, dyslipidemia, smoking, obesity, sedentary lifestyle, family history) were evaluated according to the International criteria. The genetic variants were analyzed with specific primers and the GRS was determined in the entire population, based on 29 genetic polymorphisms previously associated with atherosclerotic disease in general and, in particular, with CAD. A multiplicative model was then used based on risk multiplication (odds ratio - OR) of each genotype of the 29 studied genes. Subsequently, a multivariate analysis was done with the TCRF only or the TCRF with the GRS and a ROC curve was constructed for both situations. Results: After multivariate analysis, the GRS was found to be an independent predictor for CAD (OR = 2.1; CI: 1.7–2.5; p < 0.0001). The AUC increased from 0.71 to 0.74 after the inclusion of GRS to the TCRF in the multivariate analysis (Figure). Figure. No caption available. Conclusions: In our population, the multiplicative GRS was an independent predictor for CAD. When analyzed together with traditional risk factors, it adds little predictive value. Its usefulness, in clinical practice, may be directed to the intermediate risk group, in which a possible risk reclassification can have different therapeutic measures.

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.

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.