Evidence points epicardial adipose tissue (EAT) as an emerging cardiovascular risk marker. Whether genetic polymorphisms linked with atherosclerosis are associated with higher EAT is still unknown. We aim to assess the role of genetic burden of atherosclerosis and its association to EAT in a cohort of asymptomatic individuals without coronary disease. A total of 996 participants were prospectively enrolled in a single Portuguese center. EAT volume was measured by Cardiac Computed Tomography and participants were distributed into 2 groups, above and below median EAT. SNPs were genotyped and linked to their respective pathophysiological axes. A multiplicative genetic risk score (mGRS) was constructed, representing the genetic burden of the studied SNPs. To evaluate the association between genetics and EAT, we compared both groups by global mGRS, mGRS by functional axes, and SNPs individually. Individuals above-median EAT were older, had a higher body mass index (BMI) and higher prevalence of hypertension, metabolic syndrome, diabetes, and dyslipidemia. They presented higher GRS, that remained an independent predictor of higher EAT volumes. The group with more EAT consistently presented higher polymorphic burden across numerous pathways. After adjustment, age, BMI, and mGRS of each functional axis emerged as independently related to higher EAT volumes. Amongst the 33 SNPs, MTHFR677 polymorphism emerged as the only significant and independent predictor of higher EAT volumes. Patients with higher polymorphism burden for atherosclerosis present higher EAT volumes. We present the first study in a Portuguese population, evaluating the genetic profile of EAT through GWAS and GRS, casting further insight into this complicated matter.
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 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.
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