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Polygenic risk score for atrial fibrillation: validation in the brazilian population, association with heart failure outcomes and association with Chronic Chagas Cardiomyopathy

Abstract

Atrial fibrillation (AF) is the most common tachyarrhythmia in adults worldwide with both environmental and genetic risk factors. Genome-wide association studies (GWAS) demonstrated that AF risk is determined to a significant extent by the overall effect of common genetic variants, especially single nucleotide polymorphisms (SNP). Polygenic risk scores (PRS) were created based on GWAS results for prediction of the individual genetic risk for AF. Roselli et al conducted a meta-analysis in 2021 with 181,446 AF cases and 1,468,899 controls, identifying 403 SNPs independently associated with AF. This meta-analysis developed a PRS for AF risk prediction (PRS - AF). However, in populations of ancestry composition that differs from the original cohort, PRS - AF applicability requires confirmation.Objectives. The main purpose of this research project is to validate the use of PRS - AF in a sample of Brazilian individuals. Furthermore, PRSs may be exploited to assess shared etiology between phenotypes, since several polygenic traits share loci. Therefore, this research project also aims to (i) evaluate the correlation between PRS - AF and prognosis in heart failure (HF), and (ii) evaluate the association of PRS - AF with electrocardiographic and laboratorial manifestations of Chagas disease. Methods. This project consists of three studies based on the PRS - AF developed by Roselli et al (2021). All analysis will be independently conducted using the information on the databases of projects Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil), Genetic and ElectroNic medIcal records to predict oUtcomeS in Heart Failure patients (GENIUS-HF) and São Paulo - Minas Gerais Tropical Medicine Research Center (SaMi-Trop). Study 1 will calculate the PRS - AF of each participant in the ELSA - Brasil cohort, which is representative of the Brazilian population, and evaluate the association of PRS - AF with AF prevalence in this sample (case-control design). In addition, Study 1 will test the hypothesis of association between PRS - AF and mortality (prospective design). Study 1 will include 13,260 individuals recruited between 2008 and 2010. Study 2 will calculate the PRS - AF of each participant in the GENIUS - HF cohort, which is composed of patients with left ventricular ejection fraction d 50%. Study 2 will test the hypothesis of (i) association between PRS - AF and AF prevalence in this sample (case-control design), and (ii) association between PRS - AF and clinical outcomes (global mortality, cardiovascular mortality, hospitalization and heart transplantation - prospective design). Study 2 will include 1,215 participants recruited between 2011 and 2020. Finally, Study 3 will calculate the PRS - AF of each participant in the SaMi - Trop cohort, which includes only participants with positive serology for Trypanosoma cruzi. Study 3 will test the hypothesis of (i) association between PRS - AF and AF prevalence in this sample (case-control design), (ii) association between PRS - AF and electrocardiographic abnormalities (case-control design), and (iii) correlation between PRS - AF and brain natriuretic peptide values (retrospective design). Study 3 sample will consist of 2,964 individuals recruited between 2011 and 2012. Conclusion. This research project aims to develop a tool for AF risk prediction by means of a genetic score applicable to the Brazilian population. Moreover, it aims to analyze the performance of this score as a risk marker in cardiomyopathies that share a physiopathological substrate with AF. (AU)

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