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- Genetic Risk Analysis of Coronary Artery Disease in a Population-based Study in Portugal, Using a Genetic Risk Score of 31 VariantsPublication . Pereira, Andreia; Mendonça, Maria Isabel; Borges, Sofia; Freitas, Sónia; Henriques, Eva; Rodrigues, Mariana; Freitas, Ana Isabel; Sousa, Ana Célia; Brehm, António; Palma dos Reis, RobertoBackground: 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.
- Association of ADAMTS7 gene polymorphism with cardiovascular survival in coronary artery diseasePublication . Pereira, A; Palma dos Reis, R; Rodrigues, R; Sousa, A C; Gomes, S; Borges, S; Ornelas, I; Freitas, A I; Guerra, G; Henriques, E; Rodrigues, M; Freitas, S; Freitas, C; Brehm, A; Pereira, D; Mendonça, M IRecent 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 IslandPublication . Sousa, Ana Célia; Palma dos Reis, Roberto; Pereira, Andreia; Borges, Sofia; Freitas, Ana Isabel; Guerra, Graça; Góis, Teresa; Rodrigues, Mariana; Henriques, Eva; Freitas, Sónia; Ornelas, Ilídio; Pereira, Décio; Brehm, António; Mendonça, Maria IsabelEssential 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.
- Synergistic Association of Genetic Variants with Environmental Risk Factors in Susceptibility to Essential HypertensionPublication . Sousa, Ana Célia; Mendonça, Maria I.; Pereira, Andreia; Gouveia, Sara; Freitas, Ana I.; Guerra, Graça; Rodrigues, Mariana; Henriques, Eva; Freitas, Sónia; Borges, Sofia; Pereira, Décio; Brehm, António; Palma dos Reis, RobertoEssential hypertension (EH) is a disease in which both environment and genes have an important role. This study was designed to identify the interaction model between genetic variants and environmental risk factors that most highly potentiates EH development.