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- 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.
- 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.
- Reclassification of the intermediate group classified according to heartscore taking in considertaion individual genetic predisposition to coronary artery diseasePublication . Mendonça, M.; Pereira, A.; Rodrigues, R.; Neto, M.; Sousa, A.C.; Freitas, S.; Freitas, C.; Freitas, A.I.; Borges, S.; Palma dos Reis, R.Introduction: Cardiovascular risk stratification has included traditional cardiovascular risk factors (TRF) including tobacco, cholesterol and blood pressure adjusted to age and sex. The utility of genetic risk scores (GRS) as predictors of cardiovascular risk remains inconclusive. Objective: We intended to evaluate the ability of a multilocus GRS within the intermediate risk subgroup, defined by the European Heart score, to add predictive power for the association with coronary artery arterial disease (CAD). Methods: After applying European SCORE (ES) stratification to a total population of 2703 Portuguese individuals, 639 individuals with 59.0 ± 4.3 years were considered to be at intermediate risk subgroup (2 Results: GRS was an independent predictor for CAD (OR=2.411; p<0.0001). Diabetes mellitus (OR=3.196;p<0.0001), arterial hypertension (OR=2.201; p=0.003) and smoking (OR=3.148; p<0.0001) were also significantly associated with CAD. AUC increased from 0.694 to 0.734 after adding GRS to TRF. When discriminated by tertiles of GRS, the AUC for TRF was maximum for the 2nd tertile GRS [AUC (TRF)=0.734] and lower for the 1st and 3rd tertiles (AUC =0.673 and AUC =0.671, respectively). NRI showed better increase in the intermediate risk subgroup with a 35.2% interpreted as the roportion of patients reclassified to a more appropriate risk category, and 29.4% on the lower risk. Conclusion: In our population, the GRS increased the predictive value of TRF in the subgroup of patients at intermediate risk by the European Score. The predictive value of TRF is lower in patients with higher GRS. In this subgroup, the inclusion of genotyping may be considered for better stratification of cardiovascular risk.
- Score genético, história familiar de DC precoce e factores de risco cardiovascularPublication . Pereira, Andreia; Palma dos Reis, Roberto; Rodrigues Neto, Micaela; Rodrigues, Ricardo; Monteiro, Joel ponte; Freitas, Sónia; Rodrigues, Mariana; Freitas, Ana Isabel; Ornelas, Ilídio; Borges, Sofia; Pereira, Décio; Mendonça, Maria IsabelEstima-se que 50% da etiopatogénese da DC possa ser explicada por factores genéticos. A história familiar de Doença Coronária precoce tem sido utilizada como marcador equivalente de predisposição genética para DC. Pretende-se avaliar se a associação da HF de DC precoce, aos FRCV e ao Score de Risco Genético aumenta o poder preditor basal. Métodos: Em 2888 participantes no estudo GENEMACOR foi investigada a HF. Os FRCV foram determinados de acordo com os standards Internacionais. O SGM individual foi determinado pelo produto dos OR das 33 variantes genéticas estudadas associadas com a DC. Foram desenhadas as curvas ROC (Receiver Operating Curves) e calculadas as AUC (Areas Under Curve). A percentagem de doentes reclassificados foi calculada com recurso ao NET RECLASSIFICATION INDEX. A comparação das curvas AUC foi feita com recurso ao teste de DeLong. Resultados: A AUC para a HF foi de 0,556, para os FRCV foi de 0,738 e para o SGM foi de 0,606. A associação do SGM com FRCV demonstrou incremento preditivo com elevação da AUC para 0,758; p<0,0001. A associação da HF com SRG e com FRCV demonstrou aumentar o poder preditivo basal obtendo uma AUC=0,764; p<0,0001. A comparação entre a HF e o SGM ao associarmos cada um deles aos FRCV mostra que o poder preditivo do score genético é mais relevante do que ao adicionar a HF. A curva juntando os FRCV e a HF é AUC=0,749 e juntando o SGM com os FRCV é AUC=0,758 e o teste de DeLong revelou significância (p=0,034). CONCLUSÕES: A utilização da informação dada pelos doentes sobre HF não parece ser um bom substituto da informação genética individual. O SRG aumenta de forma significativa o grau de predição para DC conferido pelos factores de risco cardiovascular habituais.