SESARAM - C - Unidade de Investigação Dr.ª Maria Isabel Mendonça
Permanent URI for this collection
Browse
Browsing SESARAM - C - Unidade de Investigação Dr.ª Maria Isabel Mendonça by Title
Now showing 1 - 10 of 27
Results Per Page
Sort Options
- Additional value of a combined genetic risk score to standard cardiovascular stratificationPublication . Pereira, Andreia; Mendonca, Maria Isabel; Borges, Sofia; Sousa, Ana Célia; Freitas, Sónia; Henriques, Eva; Rodrigues, Mariana; Freitas, Ana Isabel; Guerra, Graça; Freitas, Carolina; Pereira, Décio; Brehm, António; Palma dos Reis, RobertoThe utility of genetic risk scores (GRS) as independent risk predictors remains inconclusive. Here, we evaluate the additive value of a multi-locus GRS to the Framingham risk score (FRS) in coronary artery disease (CAD) risk prediction. A total of 2888 individuals (1566 coronary patients and 1322 controls) were divided into three subgroups according to FRS. Multiplicative GRS was determined for 32 genetic variants associated to CAD. Logistic Regression and Area Under the Curve (AUC) were determined first, using the TRF for each FRS subgroup, and secondly, adding GRS. Different models (TRF, TRF+GRS) were used to classify the subjects into risk categories for the FRS 10-year predicted risk. The improvement offered by GRS was expressed as Net Reclassification Index and Integrated Discrimination Improvement. Multivariate analysis showed that GRS was an independent predictor for CAD (OR = 1.87; p<0.0001). Diabetes, arterial hypertension, dyslipidemia and smoking status were also independent CAD predictors (p<0.05). GRS added predictive value to TRF across all risk subgroups. NRI showed a significant improvement in all categories. In conclusion, GRS provided a better incremental value in intermediate subgroup. In this subgroup, inclusion of genotyping may be considered to better stratify cardiovascular risk.
- Associação independente da variante rs1333049, no locus 9p21, com a doença coronária, numa população portuguesaPublication . Mendonça, Isabel; Reis, RP; Pereira, A; Café, H; Serrão, M; Sousa, AC; Freitas, AI; Guerra, G; Freitas, S; Freitas, C; Ornelas, I; Brehm, A; Araújo, JJIntrodução: Estudos recentes de associação genómica em larga escala (GWAS) identificaram vários polimorfismos de um único nucleótido (SNP), localizados no locus 9p21, associados com doença arterial coronária (DAC). De entre eles o SNP rs1333049 demonstrou uma associação consistente com a DAC tendo sido reproduzida, com sucesso, em várias populações. Objectivo: Investigar se a nova variante rs1333049, no cromossoma 9p21, é um factor de risco independente para DAC, na população Portuguesa. Material e métodos: Estudo caso-controlo, que incluiu 1406 indivíduos, 723 doentes coronários internados consecutivamente (idade média de 53,7±8,9 anos 79,9% do sexo masculino) e 683 controlos sem doença coronária (idade média de 53,3±10,5 anos, 73,9 % do sexo masculino) seleccionados para não serem significativamente diferentes quanto ao sexo e idade. Estudou-se o SNP rs1333049, em todos os indivíduos, com recurso à técnica convencionada de PCR combinada com a técnica TaqMan (Applied Biosystems). Determinou-se a distribuição alélica e genotípica (C/G), odds ratio e respectivo intervalo de confiança para risco de DAC. Foi construído um modelo de regressão logística forward wald ajustado para a idade, sexo, factores de risco convencionais, marcadores bioquímicos e genótipos em estudo, afim de avaliar quais as variáveis associadas de forma significativa e independente com DAC. Resultados: 60% dos doentes coronários e 53% dos controlos apresentaram o alelo C (OR=1,33; p=0,0002), 35,7% dos doentes e 29,3% dos controlos tinham o genótipo homozigoto CC (OR=1,34;p=0,010). O heterozigoto CG estava presente em 48,1% dos doentes e 47% nos controlos, não atingindo significância estatística, para risco vascular (OR=1,05;p=0,670). Após análise multivariada de regressão logística o genótipo CC do cromossoma 9p21 ficou na equação com um OR=1,7, p=0,018 e o genótipo heterozigoto CG com um OR=1,5, p=0,048. Conclusão: Com o presente trabalho replicou-se, numa população portuguesa, o risco coronário ligado à nova variante rs1333049 do cromossoma 9p21. A robustez deste genótipo, tanto em homo como em heterozigotia, tem sido consistente e relevante na estratificação de risco para a DAC, mesmo em contextos populacionais muito diversos. Nestas circunstâncias, a utilização do genótipo CC ou CG poderá vir a revelar-se útil para a previsão do risco de DAC na nossa população.
- 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.
- Emergent Biomarkers of Residual Cardiovascular Risk in Patients with Low HDL-c and/or High Triglycerides and Average LDL-c Concentrations: Focus on HDL Subpopulations, Oxidized LDL, Adiponectin, and Uric AcidPublication . Mascarenhas-Melo, Filipa; Palavra, Filipe; Marado, Daniela; Sereno, José; Teixeira-Lemos, Edite; Freitas, Isabel; Mendonça, Maria Isabel; Pinto, Rui; Teixeira, Frederico; F, ReisThis study intended to determine the impact of HDL-c and/or TGs levels on patients with average LDL-c concentration, focusing on lipidic, oxidative, inflammatory, and angiogenic profiles. Patients with cardiovascular risk factors (n = 169) were divided into 4 subgroups, combining normal and low HDL-c with normal and high TGs patients. The following data was analyzed: BP, BMI, waist circumference and serum glucose, Total-c, TGs, LDL-c, oxidized-LDL, total HDL-c and HDL subpopulations, paraoxonase-1 (PON1) activity, hsCRP, uric acid, TNF- α , adiponectin, VEGF, and iCAM1. The two populations with increased TGs levels, regardless of the normal or low HDL-c, presented obesity and higher waist circumference, Total-c, LDL-c, Ox-LDL, and uric acid. Adiponectin concentration was significantly lower and VEGF was higher in the population with cumulative low values of HDL-c and high values of TGs, while HDL quality was reduced in the populations with impaired values of HDL-c and/or TGs, viewed by reduced large and increased small HDL subfractions. In conclusion, in a population with cardiovascular risk factors, low HDL-c and/or high TGs concentrations seem to be associated with a poor cardiometabolic profile, despite average LDL-c levels. This condition, often called residual risk, is better evidenced by using both traditional and nontraditional CV biomarkers, including large and small HDL subfractions, Ox-LDL, adiponectin, VEGF, and uric acid.
- Epicardial Adipose Tissue: The Genetics Behind an Emerging Cardiovascular Risk MarkerPublication . Sousa, João Adriano; Mendonca, Maria Isabel; Serrão, Marco; Borges, Sofia; Henriques, Eva; Freitas, Sónia; Tentem, Margarida; Santos, Marina; Freitas, Pedro; Ferreira, António; Guerra, Graça; Drumond, António; Palma Reis, RobertoEvidence points epicardial adipose tissue (EAT) as an emerging cardiovascular risk marker. Whether genetic polymorphisms linked with atherosclerosis are associated with higher EAT is still unknown. We aim to assess the role of genetic burden of atherosclerosis and its association to EAT in a cohort of asymptomatic individuals without coronary disease. A total of 996 participants were prospectively enrolled in a single Portuguese center. EAT volume was measured by Cardiac Computed Tomography and participants were distributed into 2 groups, above and below median EAT. SNPs were genotyped and linked to their respective pathophysiological axes. A multiplicative genetic risk score (mGRS) was constructed, representing the genetic burden of the studied SNPs. To evaluate the association between genetics and EAT, we compared both groups by global mGRS, mGRS by functional axes, and SNPs individually. Individuals above-median EAT were older, had a higher body mass index (BMI) and higher prevalence of hypertension, metabolic syndrome, diabetes, and dyslipidemia. They presented higher GRS, that remained an independent predictor of higher EAT volumes. The group with more EAT consistently presented higher polymorphic burden across numerous pathways. After adjustment, age, BMI, and mGRS of each functional axis emerged as independently related to higher EAT volumes. Amongst the 33 SNPs, MTHFR677 polymorphism emerged as the only significant and independent predictor of higher EAT volumes. Patients with higher polymorphism burden for atherosclerosis present higher EAT volumes. We present the first study in a Portuguese population, evaluating the genetic profile of EAT through GWAS and GRS, casting further insight into this complicated matter.
- Genetic information improves the prediction of major adverse cardiovascular events in the GENEMACOR populationPublication . Mendonca, Maria Isabel; Henriques, Eva; Borges, Sofia; Sousa, Ana Célia; Pereira, Andreia; Santos, Marina; Temtem, Margarida; Freitas, Sónia; Monteiro, Joel; Sousa, João Adriano; Rodrigues, Ricardo; Guerra, Graça; Palma Reis, RobertoThe inclusion of a genetic risk score (GRS) can modify the risk prediction of coronary artery disease (CAD), providing an advantage over the use of traditional models. The predictive value of the genetic information on the recurrence of major adverse cardiovascular events (MACE) remains controversial. A total of 33 genetic variants previously associated with CAD were genotyped in 1587 CAD patients from the GENEMACOR study. Of these, 18 variants presented an hazard ratio >1, so they were selected to construct a weighted GRS (wGRS). MACE discrimination and reclassification were evaluated by C-Statistic, Net Reclassification Index and Integrated Discrimination Improvement methodologies. After the addition of wGRS to traditional predictors, the C-index increased from 0.566 to 0.572 (p=0.0003). Subsequently, adding wGRS to traditional plus clinical risk factors, this model slightly improved from 0.620 to 0.622 but with statistical significance (p=0.004). NRI showed that 17.9% of the cohort was better reclassified when the primary model was associated with wGRS. The Kaplan-Meier estimator showed that, at 15-year follow-up, the group with a higher number of risk alleles had a significantly higher MACE occurrence (p=0.011). In CAD patients, wGRS improved MACE risk prediction, discrimination and reclassification over the conventional factors, providing better cost-effective therapeutic strategies.
- Genetic polymorphisms and coronary artery disease in the portuguese population: the GENEMACOR StudyPublication . Pereira MD PHDs, A; Mendonca, M; Neto, M; Rodrigues, R; Monteiro, Joel; Sousa, A C; Rodrigues, M; Guerra, G; Borges, S; Palma dos Reis, RMultiple studies have showed an association between genetic polymorphisms and the risk of coronary artery disease (CAD). Initially, studies focused mainly in variants acting in pathophysiological axis of CAD or its risk factors. Genome-Wide Association Studies (GWAS) revealed other genes that, besides having an unknown mechanism, are statistically significant. The importance of these in the development of CAD in the Portuguese population is unknown. Objective: Analyze the genetic polymorphisms associated with the development of CAD in a Portuguese population. Methods: We performed a case-control study with 1321 consecutive coronary patients (mean age 53.4 ± 8.1 years, 78.8% male) and 1148 controls (adjusted for age and sex) selected from GENEMACOR Study, an ongoing study designed to analyze the genetic profile of a Portuguese population. We evaluated, in both groups, 29 genetic variants previously associated with CAD: ACE I/D, AGT235 M/T, ATIR A/C, MTHFR C/T and 1298 A/C, PON192 Q/R and 55 L/M,LPA T/C, APO E, Locus 9p21.3 (rs1333049), CDKN2B (rs4977574), GJA4 C/T, PCSK9 A/G, TAS2R50 A/G, KIF6 C/T, IGF2BP2 G/T, ADAMTS7 A/G, MC4R T/C, PPARG Pro12 Ala, ZNF259 C/G, SMAD3 C/T, MIA3 C/A, MTHFD1L A/G, SLC30A8 C/T, TCF7L2 C/T, HNF4 C/G, FTO A/C and ADIPOQ C/G. Allele and genotypic frequencies of individuals with and without CAD were compared and the strength of association was expressed by the OR as well as by CI 95%. Results: The variants rs4340 (ACE I/D), rs266729 (ADIPOQ C/G), rs458560 (PON55 L/M), rs429358 (APOE2), LPA T/C, rs1333049 (locus 9p21.3) and rs4977574 (CDKN2B A/G) were significantly associated with CAD (p<0.05) (Table). Conclusions: In our population, the genetic polymorphisms significantly related to CAD were: ACE, associated with hypertension; ADIPOQ, associated with obesity; PON55, associated with oxidation; APOE and LPA, associated with dyslipidemia and finally the locus 9p21.3 with a unclear mechanism so far.
- 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.
- Genetic risk score and cardiovascular mortality in a southern european population with coronary artery diseasePublication . Pereira, Andreia; Mendonca, Maria Isabel; Sousa, Ana Célia; Borges, Sofia; Freitas, Sónia; Henriques, Eva; Rodrigues, Mariana; Freitas, Ana Isabel; Guerra, Graça; Ornelas, Ilídio; Pereira, Décio; Brehm, António; Palma dos Reis, RobertoSeveral 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. Objective: The objective of this study was to evaluate long- term cardiovascular mortality according to the genetic risk score in a Southern European population with CAD. Methods: A cohort of 1464 CAD patients with angiographic proven CAD were followed up prospectively for up to 58.3 (interquartile range: 25.8- 88.1) months. Genotyping of 32 single- nucleotide polymorphisms previously associated with CAD was performed using oligonucleotides probes marked with fluorescence for each allele. GRS was constructed according to the additive model assuming codominance and categorised using the median (=26). Cox Regression analysis was performed to determine independent multivariate predictors of cardiovascular mortality. Kaplan- Meier survival curves compared high vs low GRS using log- rank test. C- index was done for our population, as a measure of discrimination in survival analysis model. Results: During a mean follow- up of 58.3 months, 156 patients (10.7%) died, 107 (7.3%) of CV causes. High GRS (≥26) was associated with reduced cardiovascular survival. Survival analysis with Cox regression model adjusted for 8 variables showed that high GRS, dyslipidemia, diabetes and 3- vessel disease were independent risk factors for cardiovascular mortality (HR=1.53, P=.037; HR=3.64, P=.012; HR=1.75, P=.004; HR=2.97, P<.0001, respectively). At the end of follow- up, the estimated survival probability was 70.8% for high GRS and 80.8% for low GRS (Log- rank test 5.6; P=.018). C- Index of 0.71 was found when GRS was added to a multivariate survival model of diabetes, dyslipidemia, smoking, hypertension and 3 vessel disease, stable angina and dual antiplatelet therapy. Conclusions: Besides the classical risk factors management, this work highlights the relevance of the genetic profile in survival from CAD. It is expected that new therapies will be dirsected to gene targets with proven value in cardiovascular survival.
- A importância do polimorfismo da alfa aducina no risco de hipertensão arterial essencial nos individuos de baixa ingestão salinaPublication . Sousa, Ana Célia; Palma dos Reis, Roberto; Pereira, Andreia; Nascimento, Rafael; Góis, Teresa; Guerra, Graça; Rodrigues, Mariana; Henriques, Eva; Freitas, Carolina; Ornelas, Ilídio; Pereira, Décio; Mendonça, Maria IsabelIntrodução: A variante genética do gene da alfa aducina rs4961, ligado à gestão do sal a nível do rim, tem sido descrita como fator de risco para hipertensão arterial essencial (HTE) com resultados controversos. Vários estudos demonstraram que a ingestão de alto teor de sal se associa com a HTE, doença cardiovascular e renal. O contributo genético no desenvolvimento de HTE, em indivíduos com baixa ingestão salina, está ainda pouco definido. Objetivo: Pretendemos avaliar a importância da variante genética da alfa aducina (rs4961) no desenvolvimento de HTE em indivíduos com baixa ingestão salina. Métodos: Seleccionados para o estudo 1614 indivíduos, idade média 50,6±8,2 e divididos em dois grupos consoante tinham ou não HTE, um com 817 hipertensos e outro com 797 controlos. Todos colheram sangue para exames bioquímicos e para análises genéticas. Estudado o polimorfismo rs4961 da alfa aducina em ambos os grupos e avaliada, no grupo dos hipertensos, a excreção renal de sódio na urina de 24 horas, que de acordo com a bibliografia se associa com a ingestão de sódio. Os valores da excreção renal de sódio foram divididos em tercis. Comparada a frequência do genótipo Trp460Trp com a do Gly460Gly do 1º tercil (mais baixo valor de excreção sódio) com a frequência dos mesmos polimorfismos no grupo dos controlos. O mesmo procedimento em relação ao 3º tercil (mais alto valor de excreção sódio). Usado o teste de t de Student para variáveis contínuas e os odds ratio e intervalos de confiança da variante genética nos dois grupos. A análise dos dados foi feita pelo SPSS versão 19.0. Resultados: O genótipo Trp460Trp da alfa aducina foi mais frequente no grupo dos hipertensos com baixa excreção de sal (≤153mEq/24h) em relação aos controlos com significância estatística, odds ratio de 3,29 (IC a 95% 1,38 -7,84; p=0,004) e não influenciou o aparecimento de HTA nos indivíduos hipertensos com alta excreção de sal (≥181mEq/24h), odds ratio de 1,47 (IC a 95% 0,50-4,35; p=0,480). Conclusões: A variante rs4961 da alfa aducina é fator de risco de aparecimento de HTE nos indivíduos com baixa excreção de sal, mas não aumentou a susceptibilidade para HTE nos indivíduos com alta excreção salina. Com este estudo podemos comprovar que o contributo genético no desenvolvimento de HTE é mais importante nos indivíduos com baixa ingestão salina em relação aos com alta ingestão, já que nestes existe um fator ambiental que explica o aparecimento de HTE.
- «
- 1 (current)
- 2
- 3
- »