Unraveling the Genetic Underpinnings of Obesity: Insights from the Baependi Heart Study

• Grant number: 24/01967-7
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2024
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Agreement: CNPq
• Principal Investigator: José Eduardo Krieger
• Grantee: José Eduardo Krieger
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 14/50889-7 - National Institute of Science and Technology Medicine Assisted by Scientific Computing (INCT-MACC), AP.TEM
• Associated scholarship(s): 24/13026-2 - Unraveling the Genetic Underpinnings of Obesity: Insights from the Baependi Heart Study, BP.JD

Abstract

Obesity is a multifactorial disease with a high global impact, as its main characteristic is the increase in body fat, anthropometric data are generally used in clinical practice, as they are easy to obtain, such as BMI (body mass index) and WHR (Ratio Waist-hip), which are designed to diagnose and classify overweight/obese individuals. Although the main causes generally associated with this disease are related to daily lifestyle habits, such as type of diet and frequency of physical exercise (calorie intake/expenditure relationship), recent studies demonstrate the correlation of diseases such as obesity with hereditary genetic predispositions and/or intracellular processes triggered by the interaction of genetic variants with transcriptional factors. Currently, genetics plays a crucial role in exploring the development of this disease, many studies have focused on identifying genetic variants associated with the obesity phenotype. Genome-wide association studies (GWAS) have been used to find correlations between specific genetic variations, known as single nucleotide polymorphisms (SNPs), and physical characteristics, such as BMI and WHR. A pioneering GWAS study for obesity identified variants associated with the FTO gene, correlating them with BMI. Since then, more than 1,100 loci have been identified in relation to obesity. The findings in relation to Leptin (LEP) and Melanocortin (MC4R) stand out, generally attributed to monogenic obesity, but also involved in polygenic obesity, which are directly linked to eating behavior and feelings of satiety. Although GWAS is effective in finding these associations, it does not explain the underlying mechanisms. To overcome this limitation, we used samples from the family cohort of the Baependi Heart Study (1,097 individuals from Baependi - MG, Brazil) to identify SNPs associated with BMI and WHR located in regions of chromatin interaction, suggesting their direct effect on the control of gene expression . We identified four candidate genetic variants related to BMI (rs141766039 and rs149309426) and WHR (rs16851962 and rs78545836) in active enhancer regions in human adipocytes. We will now confirm the presence of these variants in all samples and perform a series of computational and functional analyzes to establish the potential to influence gene expression in target cells and which target genes are potentially influenced by these SNPs. This will include testing in human adipocytes and preadipocytes to assess the impact of these variants on the function of reporter genes. Furthermore, we will use bioinformatics techniques such as JASPAR to predict transcription factor binding sites and the electrophoretic mobility technique to test the interaction between transcription factors and variants. We will also employ the HI-c bioinformatics technique to identify genes influenced by these interactions, followed by siRNA experiments to explore the influence of the genes on the phenotype of interest. We hope to find genes linked to metabolism and adiposity mechanisms, or to cellular stress associated with obesity. This could pave the way for new approaches to treating and preventing this complex disease. (AU)