ABC | Volume 111, Nº1, July 2018

Original Article Genetic Risk Analysis of Coronary Artery Disease in a Population- based Study in Portugal, Using a Genetic Risk Score of 31 Variants Andreia Pereira, 1 Maria Isabel Mendonça, 1 Sofia Borges, 1 Sónia Freitas, 1 Eva Henriques, 1 Mariana Rodrigues, 1 Ana Isabel Freitas, 2 Ana Célia Sousa, 1 António Brehm, 2 Roberto Palma dos Reis 3 Unidade de Investigação, Hospital Dr. Nélio Mendonça, 1 Funchal – Portugal Laboratório de Genética Humana, Universidade da Madeira, 2 Funchal – Portugal Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 3 Lisboa – Portugal Mailing Address: Andreia Pereira • Avenida Luís de Camões, nº 57. Postal Code 9004-514, Funchal – Portugal E-mail: andreiapereira21@gmail.com Manuscript received June 14, 2017, revised manuscript October 12, 2017, accepted February 22, 2018 DOI: 10.5935/abc.20180107 Abstract 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. (Arq Bras Cardiol. 2018; 111(1):50-61) Keywords: Coronary Artery Disease / history; Coronary Artery Disease / morbidity; Mortality; Polymorphism, Genetic; Epidemiology; Risk Factors. Introduction Coronary artery disease (CAD) has become a major health problem worldwide, with increasing prevalence and high morbidity and mortality. Traditional risk factors (TRFs) are insufficient to identify asymptomatic high-risk individuals. Epidemiology and family studies have long documented that approximately 50% of the susceptibility for heart disease is genetic. 1 Knowledge of genetic predisposition to cardiac disease is crucial for its comprehensive prevention and treatment. Althoughmuch of the genetic basis of coronary disease remains to be discovered, some progress has been made using both candidate gene and genome-wide association studies (GWAS). 2 In fact, a number of genetic variants have been previously identified at several genomic regions associated with CAD. 2 Until now, the risk attributable to any individual variant has been modest. However, discovering and combining multiple loci with modest effects into a global genetic risk score (GRS) could improve the identification of high-risk populations and improve individual risk assessment. Therefore, the purpose of this work was to generate a multilocus GRS based on common variants previously shown to be associated with CAD, and evaluate whether it is independent of TRFs and improves the predictive ability of a model based only on TRFs. Methods Study Population Study population was enrolled fromGENEMACOR (GENEs in Madeira Island Population with CORonary artery disease), a population-based ongoing case-control registry of CAD with 2,888 participants, 1,566 cases (mean age 53.3 ± 8.0 years, 79.1% male) and 1322 controls (mean age 52.7 ± 7.8 years, 76.4% male). Cases were selected from patients discharged after being admitted for myocardial infarction/unstable angina diagnosed according to the previously described 50