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HNF4A Gene can be a genetic protector for Coronary Artery Disease
Session:
CO 04 - Doença coronária-genética-avaliação funcional
Speaker:
Margarida Temtem
Congress:
CPC 2021
Topic:
E. Coronary Artery Disease, Acute Coronary Syndromes, Acute Cardiac Care
Theme:
12. Coronary Artery Disease (Chronic)
Subtheme:
12.2 Coronary Artery Disease – Epidemiology, Prognosis, Outcome
Session Type:
Comunicações Orais
FP Number:
---
Authors:
Margarida Temtem; Marco Gomes Serrão; Isabel Mendonça; Marina Santos; Flávio Mendonça; Adriano Sousa; Ana Célia Sousa; Eva Henriques; Sónia Freitas; Mariana Rodrigues; Sofia Borges; Graça Guerra; António Drumond; Roberto Palma Dos Reis
Abstract
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="font-size:10pt">Background</span></strong><span style="font-size:10pt">: </span><span style="font-size:10pt">Hepatocyte nuclear factor4 A (</span><span style="font-size:10pt">HNF4A) gene was considered by GWAS associated with atherosclerosis and CAD susceptibility. <span style="color:black">Loss-of-function mutations in human hepatocyte nuclear factor 4α (HNF4α), a transcriptor factor</span> <span style="color:black">encoded by the HNF4A gene, are associated with maturity-onset diabetes of the young and lipid disorders</span><span style="color:#222222">.</span><span style="color:black"> However, the mechanisms underlying the lipid disorders are poorly understood.</span></span></span></span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="font-size:10pt">Aim</span></strong><span style="font-size:10pt">: We propose to identify </span><span style="font-size:10pt">Hepatocyte nuclear factor4 A</span><span style="font-size:10pt"> genetic predisposition to atherosclerosis progression and events occurrence or regression and better prognosis, through a cohort study from GENEMACOR population.</span></span></span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="font-size:10pt">Methods:</span></strong><span style="font-size:10pt"> We investigated a cohort of 1712 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, including HNF4A. We evaluated the best genetic model associated with CAD prognosis (events) with a 95% CI in bivariate analysis.</span><span style="font-size:10pt"><span style="color:black"><span style="background-color:white"> The hazard function was performed </span></span></span><span style="font-size:10pt"><span style="color:black"><span style="background-color:white">by a Cox</span></span></span> <span style="font-size:10pt"><span style="color:black"><span style="background-color:white">survival regression model</span></span></span><span style="font-size:10pt"><span style="color:black"><span style="background-color:white"> adjusted for age, sex, type 2 diabetes, hypertension, and hypercholesterolemia, to evaluate their</span></span></span><span style="font-size:10pt"><span style="color:black"><span style="background-color:white"> relationship with the event´s incidence. </span></span></span><span style="font-size:10pt"><span style="color:black"><span style="background-color:white">Finally, we constructed Kaplan–Meier cumulative-event curves for the significant genetic variants. </span></span></span></span></span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="font-size:10pt">Results:</span></strong><span style="font-size:10pt"> Our evaluation revealed, among the 33 SNPS, a SNP paradoxically associated with protection from atherosclerosis progression and events occurrence: </span><span style="font-size:10pt">rs1884613 C>G</span><span style="font-size:10pt"> in the HNF4α gene on chromosome 20 dominant</span><span style="font-size:10pt"> model [OR=0.653; 95% CI (0.522 – 0.817); p=0.0002]</span><span style="font-size:10pt">.<span style="color:black"><span style="background-color:white"> Cox</span></span></span> <span style="font-size:10pt"><span style="color:black"><span style="background-color:white">survival regression mode</span></span></span><span style="font-size:10pt"><span style="color:black"><span style="background-color:white">l showed a CAD protective effect of </span></span></span><span style="font-size:10pt">HNF4α</span> <span style="font-size:10pt">with a </span><span style="font-size:10pt"><span style="color:black"><span style="background-color:white">Hazard ratio (HR) of 0.771; p=0.007.</span></span></span> <span style="font-size:10pt">The Kaplan-Meier cumulative event analysis disclosed that the CG+GG vs CC genotype of </span><span style="font-size:10pt">rs1884613 </span><span style="font-size:10pt">HNF4α was associated with a better prognosis (Breslow test, p=0.004) at the end of the follow-up. </span></span></span></span></p> <p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="font-size:10pt">Conclusion</span></strong><span style="font-size:10pt">: We identified, in this study, one SNPs paradoxically associated with a better CAD prognosis </span><span style="font-size:10pt">rs1884613 in</span><span style="font-size:10pt"> HNF4α.</span><span style="font-size:10pt"> The HNF4</span><span style="font-size:10pt">α</span><span style="font-size:10pt"> gene variants could induce loss of HNF4</span><span style="font-size:10pt">α</span><span style="font-size:10pt"> function, modifying and modulating hepatic lipase and lipid metabolism conferring a beneficial effect on atherosclerosis progression and events occurrence.</span></span></span></span></p>
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