Impact of the Genetic Background as a Risk Factor for Atherosclerotic Cardiovascular Disease in the Brazilian Population

Overview

The main objective of this project is to evaluate the genomic information previously associated with cardiovascular diseases (CVD) and its importance as an independent risk predictor (expressed in Odds Ratio) when adjusted for traditional risk factors (smoking, diabetes, arterial hypertension, obesity , anxiety and depression, inadequate diet, physical inactivity, alcohol consumption and apolipoprotein B/A1 ratio (ApoB/ApoA1). An unpaired case-control study of individuals over 18 years of age will be carried out. Cases (N = 1867) will be enrolled right after the occurrence of the first atherosclerotic cardiovascular event (Acute Myocardial Infarction, Stroke and Peripheral Artery Thrombotic-Ischemic Events). The ratio between cases and controls will be 1:1. The controls (N = 1867) will be adult individuals over 18 years of age who sought medical care at the same locations for other clinical reasons (no CVD) or individuals without any overt disease. The genetic evaluation will be performed through the association of Low-covering Whole Genome Sequencing (coverage 0.5-5x) and Whole Exome Sequencing (average coverage 30x).

The study will be carried out in about 50 centers, comprising the five Brazilian regions. The study will be conducted from July 2022 to December 2023. Data collection will be performed at each center consecutively, for cases and controls, through electronic Case Report Form (CRF). Cases (N = 1867) will be selected by the occurrence of the first atherosclerotic cardiovascular event (Acute Myocardial Infarction, Stroke and Peripheral Arterial Thrombotic-Ischemic Events) during the hospitalization phase for the management of the acute atherothrombotic event. The ratio between cases and controls will be 1:1. Controls (N = 1867) will be adult individuals over 18 years of age who sought medical care at the same locations for other clinical reasons (no CVD) or individuals without any overt disease. The definitions of acute atherothrombotic events follow classic clinical and complementary exam criteria and are based on national and international guidelines. The complete project was submitted to the local Institutional Review Board (IRB)/National Research Ethics Commission (CONEP) system and has ethical approval (CAAE: 56482922.2.1001.0070). All cases and controls will be invited to participate and, if they agree, an Informed Consent Form will be obtained. Investigators will assess exposures to traditional risk factors in combination with genomic data (polygenic risk score) in both cases and controls, and these exposures will be expressed as odds ratios. Multiple logistic regression models will be built to adjust and determine the strengths of association between demographic variables, traditional risk factors and genetic data: gender, age, ethnicity, weight, body mass index, smoking, diabetes, hypertension, obesity, anxiety and depression, inadequate diet, physical inactivity, alcohol consumption and apolipoprotein B/A1 ratio (ApoB/ApoA1). For each association variable with a greater chance of cardiovascular disease (significant OR), an attributable risk will be calculated to estimate the fraction of risk attributable to the genetic component (Polygenic Risk Score) and to other clinical and demographic variables. The polygenic risk score will be calculated through a hybrid approach by taking into account the following features: effect size of each Single Nucleotide Polymorphism (SNP), number of effect alleles observed, sample ploidy, total number of SNPs included in the Polygenic Risk Score, and the number of nonmissing SNPs in the sample. Each risk allele will be given points in the risk score, and the total score will range between 0 (absence of risk alleles) and the maximum value (yet to be defined), based on the distribution of risk alleles that will be identified in the population included in the study. The scale will be interpreted in a direct (positive) association, i.e., the higher the score, the higher the number of alleles and respective weighted effect sizes. Finally, the polygenic risk score will be adjusted to previously reported traditional risk factors for atherosclerotic cardiovascular disease to determine the attributable risk fraction associated with the genomic profile.