Introduction Coronary artery disease (CAD) is a dynamic inflammatory disease caused by atherosclerosis. GWAS showed that ZNF259 rs964184 encoding zinc finger protein (ZPR1) was associated with dyslipidemia and CAD. Recent research found that ZPR1 transcription is up-regulated in the brain of mice fed a high-fat diet, influencing the cell cycle, apoptosis, and RNA metabolism in neurons. This process at the heart vessels may increase oxidative stress and CAD. Purpose Study the association between the ZNF259 rs964184 C>G polymorphism with dyslipidemia and CAD susceptibility in a Portuguese population. Methods A case-control study was performed with 3,160 individuals, namely 1,723 CAD patients (mean age 53.3±7.9; 78.7% male) and 1,437 controls (mean age 52.8±7.8; 76.3% male). Participants were stratified into two age groups (<45 and >55 years). ZNF259 rs964184 C>G was genotyped and analysed using the dominant model (CG+GG vs CC). Multivariate logistic regression was performed in both age groups to investigate whether rs964184 polymorphism was associated with dyslipidemia and CAD susceptibility. Results The dominant model of ZNF259 was associated with dyslipidemia (OR=1.85; 95% CI: 1.22–2.79; p=0.003) and CAD (OR=1.46; 95% CI: 1.02–2.09; p=0.036) in the younger population under 45 years. In the >55 years group, this model was associated with dyslipidemia (OR 1.46; 95% CI: 1.06–2.01; p=0.020) but not with CAD. After multivariate logistic regression, the CG+GG remained an independent risk factor for CAD susceptibility only in the population <45 years (OR=1.60; 95% CI: 1.03–2.50; p=0.037). Conclusion ZNF259 rs964184 is a risk factor for dyslipidemia in the whole population. Dyslipidemia may up-regulate ZPR1 transcription, enhancing the vulnerability of coronary endothelial cells to both oxidative stress and inflammatory response, increasing CAD susceptibility. This mechanism seems more relevant at the cellular level in young patients representing a possible prophylactic and therapeutic target, especially in this age group. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

The 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.

Background Hepatocyte nuclear factor4 A (HNF4A) gene was considered by GWAS associated with atherosclerosis and CAD susceptibility. Loss-of-function mutations in human hepatocyte nuclear factor 4α (HNF4α), a transcriptor factor encoded by the HNF4A gene, are associated with maturity-onset diabetes of the young and lipid disorders. However, the mechanisms underlying the lipid disorders are poorly understood. Aim We propose identifying the genetic predisposition to atherosclerosis progression and events occurrence or regression and better prognosis, through a cohort study from GENEMACOR population. Methods We investigated a cohort of 1,712 patients who underwent coronary angiography with more than 70% stenosis of at least one main coronary vessel. 33 SNPs associated with the risk of CAD in previous GWAS were genotyped by TaqMan assays methodology. We evaluated the best genetic model associated with CAD prognosis (events) with a 95% CI in bivariate analysis. The hazard function was performed by a Cox survival regression model adjusted for age, sex, type 2 diabetes, hypertension, and hypercholesterolemia, to evaluate their relationship with the event's incidence. Finally, we constructed Kaplan–Meier cumulative-event curves for the significant genetic variants. Results Our evaluation revealed a SNP paradoxically associated with protection from atherosclerosis progression and events occurrence: rs1884613 C>G in the HNF4A gene on chromosome 20 dominant model [OR=0.653; 95% CI (0.522–0.817); p=0.0002]. Cox survival regression model showed a CAD protective effect of HNF4A with a Hazard ratio (HR) of 0.771; p=0.007. The Kaplan-Meier cumulative event analysis disclosed that the CG+GG vs CC genotype of rs1884613 HNF4α was associated with a better prognosis (Breslow test, p=0.004) at the end of the follow-up. Conclusion We identified, in this study, one SNPs paradoxically associated with a better CAD prognosis rs1884613 in HNF4A. The HNF4A gene variants could induce loss of HNF4α function, modifying and modulating hepatic lipase and lipid metabolism conferring a beneficial effect on atherosclerosis progression and events occurrence. FUNDunding Acknowledgement Type of funding sources: None.

Introduction The European Systematic Coronary Risk Evaluation (SCORE) has predicted a 10-year risk of CVD since 1986. It included only fatal CVD outcomes, underestimating the total CVD burden, especially for younger people. To counteract this issue, a new score was created (SCORE2) to estimate 10-year fatal and non-fatal CVD risk in Europeans without previous CVD or diabetes aged 40–69 years. Purpose Establish a comparison between SCORE and SCORE2 in terms of CV outcomes in a moderate-risk population. Methods A population of 1,178 individuals without CVD (mean age 53.3±6.9 years; 73.9 male) was stratified into three risk categories for SCORE and SCORE2: low, moderate and high-risk. Using t-test and Chi-square, we compared the two scores in terms of means and risk categories. Kaplan-Meier estimator evaluated MACE occurrence for each category of the two scores during an extended follow-up (mean of 5.2±3.4 years). MACE discriminative capacity of SCORE and SCORE2 was evaluated through C-index methodology. Results The means of the two scores were significantly different (p<0.0001): 2.1±2.4 for SCORE and 6.0±3.3 for SCORE2. 51% of the individuals with high-risk SCORE2 presented the lowest value of SCORE (0–5%). Kaplan-Meier curves showed that the highest category had a worst survival for each score. SCORE2 showed a better discriminative capacity for MACE (C-index 0.678) relatively to SCORE (C-index 0.591), with statistical significance (p<0.0001). Conclusion SCORE2 enhanced the identification of individuals at higher risk of developing CVD and better discriminated MACE occurrence relatively to SCORE. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM

Genome-wide association studies have identified several loci linked to coronary artery disease, and coronary atherosclerosis progression. However, the impact of the genetic contribution to MACE occurrence in sub-clinical atherosclerosis is unknown. Purpose This study intended to assess the relationship between a set of single nucleotide popymorphism (SNP) associated with CAD by GWAS and the MACE occurrence in an asymptomatic population. After that evaluate whether a wGRS englobing these variants is useful to estimate the prognostic. Methods Prospective study performed in an asymptomatic cohort from GENEMACOR population-based sample of 1114 subjects aged 51.7±8.3, 74.2 male, without prior coronary artery disease. Coronary Artery Calcium (CAC) score was assessed by coronary computed tomography (Agatston method), and two categories were considered 1–99 and >100. 33 SNP were evaluate to assess the significantly associated with prognostic. A weighted (wGRS) was constructed as the sum of the risk alleles weighted by the corresponding effect size (HR). Cox regression analysis adjusted for the main risk factors, calcium score (CAC) and wGRS to assess the risk of MACE during follow-up. Kaplan Meier assessed the survival. Results Of the studied 33 SNPs previously associated with CAD (GWAS), only 4 presented the significant association with MACE occurrence: CDKN2B-AS1 rs4977574, HNF4A rs1884613, APOE rs7412/rs429358A and GJA4A rs 618675. After Cox regression analysis the wGRS remained in the equation (HR=2.834); p=0.012, together with CAC score (HR 3.35); p=0.012; diabetes (HR=2.398); p=0.032 and age (HR=1.056; p=0.049. WGRS above the median presented a worst survival rate (p=0.006). Conclusion The wGRS englobing: CDKN2B-AS1 rs4977574, HNF4A rs1884613, APOE rs7412/rs429358A and GJA4A rs 618675 is independently associated with cardiovascular events in an asymptomatic population. CDKN2B-AS1 rs4977574 gene expression modulates the progression and severity of vascular calcification in vascular smooth muscle cells (VSMCs), HNF1α-AS1 is an important regulatory molecule in cancer biology and cardiovascular disease (its expression may regulate VSMCs, and high expression promotes atheroprotection). More research is crucial for understand prognosis in asymptomatic population. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPE