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
Introduction TCF21 is a member of the basic helix-loop-helix (bHLH) transcriptor factor family, being critical for embryogenesis of the heart. It regulates epicardium-derived cells differentiation into smooth muscle (SMC) and fibroblast lineages. The biological roles of TCF21 in epicardial fate determination and the progression of atherosclerosis remains a controversial issue. Purpose Investigate the impact of the TCF21 rs12190287 G>C variant on the prognosis of a coronary artery disease (CAD) cohort. Methods A prospective study was performed with 1,713 CAD patients (mean age 53.3±7.8; 78.7% male) surveyed in terms of MACE occurrence in an extended follow-up of 5.0±4.3. TCF21 rs12190287 was genotyped and analysed using the dominant model (GC+CC) and, subsequently, compared with the wild-type GG to evaluate the survival probability by Kaplan-Meier. A Cox regression analysis with all the risk factors and genetic models was performed to assess the independent variables associated with the prognosis of CAD patients. Results GG wild genotype was present in 9.5% of the population, GC in 43.2% and the risk genotype CC accounted for 47.3% of the CAD patients. The dominant model GC+CC showed a worse survival throughout the follow-up period. After multivariate Cox regression analysis, this model remained in the equation as an independent risk factor for MACE occurrence with an HR of 1.41 (p=0.033) together with multivessel disease, physical inactivity, chronic kidney disease (CKD) and diabetes. Conclusion TCF21 rs12190287 is a risk factor for prognosis in our population. The role of this gene may influence fundamental SMC processes in response to vascular stress, accelerating atherosclerosis progression and may represent a target for future therapies. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM
Introduction Coronary artery calcium (CAC) score has emerged as the most predictive cardiovascular risk marker in asymptomatic individuals, capable of adding prognostic information beyond the traditional risk factors (TRF). Genetic risk score (GRS) significantly improves cardiovascular genetic risk assessment at the individual level providing a more personalized measure of disease risk. Purpose We intend to evaluate which tool, added to TRF, is more valuable in predicting and discriminating cardiovascular events and death (MACE) - GRS or CAC score? Methods We performed a prospective study with 1153 participants without CAD history at baseline (74.2% male, age 51.7±8.3 years) during a mean follow-up of 5.4±3.4 years. We selected 14 SNPs previously associated with CAD presenting a risk (HR) for cardiovascular events ≥1. A weighted GRS was calculated, as the sum of these 14 risk alleles weighted by the corresponding effect size in prognostic (HR), and subsequently, subdivided into tertiles. CAC (Agatson) score was calculated in all participants and categorized into: low CAC (0≤CAC<100 or P<50); moderate CAC (100≤CAC<400 or P50–75) and high or severe CAC (CAC≥400 or P>75). Two models were created with TRF baseline (hypertension, smoking, body mass index, dyslipidemia, diabetes, chronic kidney disease, physical inactivity): 1) plus wGRS and 2) plus CAC score categories. Cox Regression Analyses and C-statistic assessed the predictive and discriminative capacity of both models. Results For model 1, Cox regression presented an HR of 4.292 for TRF (p=0.007) and 2.713 for 3rd tertile of wGRS (0.036). A modest but statistically significant improvement in MACE discriminative capacity was verified by adding wGRS to TRF, increasing the C-statistic from 0.617 to 0.687 (ΔC=0.070; p=0.013). On the other hand, model 2 better discriminated MACE when the CAC score (C-statistic = 0.765) was added to TRF (ΔC=0.148; p=0.001). Cox regression displayed an HR of 4.42 for TRF (p=0.015) and an HR of 4.55 for high-risk CAC score (p=0.001). Conclusion Our results suggest that adding a polygenic risk score to conventional risk factors provides a modest improvement in the discrimination of first-onset MACE. However, the CAC score added to the traditional model allows better discrimination of MACE compared to wGRS. CAC score could be helpful for MACE prediction, at least in individuals belonging to the higher genetic risk group. However, further investigation is required before clinical implementation. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPERAM
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
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