ABC | Volume 111, Nº1, July 2018

Original Article Pereira et al. Genes and coronary artery disease risk Arq Bras Cardiol. 2018; 111(1):50-61 Figure 3 – ROC curves based on the baseline model (traditional risk factors, TRFs) and after adding the genetic risk score (GRS) (quartiles) in predicting the risk for coronary artery disease. The two curves are based on logistic regression models incorporating conventional risk factors (diabetes, dyslipidemia, smoking and hypertension) with and without the GRS. AUC indicates area under curve. The Delong test compares the difference between the two AUCs (p < 0.0001). 100 100 80 80 60 60 40 40 20 20 0 0 Sensitivity Delong test, p < 0.0001 AUC = 0.716 AUC = 0.738 TRF TRF+GRS (Quartiles) 100 – Specificity Table 4 – The category-free net reclassification index (cfNRI) after addition of the GRS quartiles Group n Higher risk n (%) Lower risk n (%) p (cfNRI) cfNRI (%) cfNRI (95% CI) CAD patients 1566 897 (57.3%) 669 (42.7%) < 0.0001 14.6% (9.7-19.5%) Healthy controls 1322 553 (41.8%) 769 (58.2%) < 0.0001 16.4% (11.2-21.8%) Total 2888 --- --- < 0.0001 31% (23.8-38.3%) GRS: genetic Risk Score; CAD: coronary Artery Disease; CI: confidence Interval; cfNRI: category-free net reclassification index. This analysis uses the function “improveProb” from R software package “Hmisc”. After the development of high capacity arrays in 2008, 15 GWAS examined millions of polymorphisms simultaneously in several ethnical subpopulations with a case-control design. The standardized minimum significance level set at 1x10 -5 added reliability to cardiovascular genetics and put it into perspective. 16 In 2007, Samani et al. 17 first identified chromosomal loci that were strongly associated with CAD in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1,926 case subjects with CAD and 2938 controls) and looked for replication in the German MI (Myocardial Infarction) Family Study. 17 In the following years, a surprisingly large number of gene variants were consistently reported to be associated with CAD. The 9p21 variant was the most frequently gene variant reported across populations. The huge consortium of Wellcome Trust and three other European research groups joined for the CARDIOGRAM project that confirmed, in a very large sample (> 22,000 cases) of individuals of European ancestry, a 29% increase in risk for MI per copy of the rs1333049 9p21 variant (p = 2×10 - ² 0 ). 18 Our research group replicated this 9p21 variant analysis in the Portuguese population and found a CC genotype prevalence of 35.7% in CAD patients, with an adjusted OR of 1.34, p = 0.010. The adjusted OR for TRF of CC genotype was 1.7 (p = 0.018) and CG genotype of OR = 1.5, p = 0.048. The authors concluded that although the mechanism underlying the risk is still unknown, the robustness of this risk allele in risk stratification for CAD has been consistent, even in very different populations. The presence of the CC or CG genotype may thus prove to be useful for predicting the risk of developing CAD in the Portuguese population. 19 The most recent meta-analysis of GWAS for (CAD) identified 46 genome-wide loci with significant association and 104 genome-wide loci potentially associated with increased risk. 20,21 56