Dataset Information

Genetic variation in NOTCH1 is associated with overweight and obesity in Brazilian elderly.

ABSTRACT: Excessive weight (overweight and obesity) is a common disorder involving genetic and environmental factors, associated with cardiovascular diseases, type-2 diabetes, and others. NOTCH1 is critical for the maintenance of stem cells and adult tissues, being reported as a key player in metabolism and adipogenesis in animals. Thus, we test the hypothesis that NOTCH1 Single Nucleotide Polymorphisms (SNPs) are associated with excessive weight. Participants from the census-based cohort SABE (Saúde, Bem Estar e Envelhecimento-Health, Well-Being, and Aging), carried out in the city of São Paulo-Brazil, were stratified into cases and controls according to BMI. We filter the SNPs located at the start and end positions of NOTCH1 and 50 Kb on both sides. We selected SNPs with minor allelic frequency (MAF) greater than or equal to 0.01 and Hardy-Weinberg equilibrium (p > 0.05) and r² ≥ 0.8. We performed an association study with genotypes and haplotypes, as well as in silico functional analysis of the identified SNPs. We observed an association of the SNP rs9411207 with the risk of excessive weight, under log-additive model, and the genotype distribution showed an increased frequency of homozygous TT (OR 1.50, CI 1.20-1.88; p = 0.0002). The haplotype GAT constructed from this and other SNPs in high Linkage Disequilibrium was more frequent in excessive-weight individuals (p = 0.003). In silico analyses suggested that these SNPs are likely to affect the transcription of NOTCH1 and other genes involved in adipogenesis and metabolism. This is the first study reporting association between NOTCH1 SNPs and the risk of excessive weight. Considering the possibility of NOTCH1 modulation, additional population studies are important to replicate these data and confirm the usefulness of risk genotypes for management strategies of excessive weight.

SUBMITTER: Silva Barcelos EC

PROVIDER: S-EPMC11269636 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Genetic variation in NOTCH1 is associated with overweight and obesity in Brazilian elderly.

Silva Barcelos Estevão Carlos EC Naslavsky Michel Satya MS Fernandes Izadora Silveira IS Scliar Marilia Oliveira MO Yamamoto Guilherme Lopes GL Wang Jaqueline Yu Ting JYT Bride Laís L de Sousa Valdemir Pereira VP Pimassoni Lucia Helena Sagrillo LHS Sportoletti Paolo P de Paula Flavia F von Zeidler Sandra Ventorin SV Duarte Yeda Aparecida Oliveira YAO Passos-Bueno Maria Rita MR Zatz Mayana M Errera Flávia Imbroisi Valle FIV

Scientific reports 20240724 1

Excessive weight (overweight and obesity) is a common disorder involving genetic and environmental factors, associated with cardiovascular diseases, type-2 diabetes, and others. NOTCH1 is critical for the maintenance of stem cells and adult tissues, being reported as a key player in metabolism and adipogenesis in animals. Thus, we test the hypothesis that NOTCH1 Single Nucleotide Polymorphisms (SNPs) are associated with excessive weight. Participants from the census-based cohort SABE (Saúde, Bem ...[more]

PMID: 39048597

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Project description:Background and aims: Youth populations with overweight/obesity (OW/OB) exhibit heterogeneity in cardiometabolic health phenotypes (e.g. fasting glucose, serum triglycerides, etc.). The underling mechanisms for those differences are still unclear. This study aimed to analyze the whole blood transcriptome profile (RNA-seq) of children with metabolic healthy overweight/obesity (MHO) and metabolic unhealthy overweight/obesity (MUO) phenotypes. Methods: 27 children with OW/OB (10.14 ± 1.3 years, 59% boys) from the ActiveBrains project were included. MHO was defined as having none of the following criteria for metabolic syndrome: elevated fasting glucose, high serum triglycerides, low high-density lipoprotein cholesterol, and high systolic or diastolic blood pressure, while MUO was defined as presenting one or more of these criteria. Inflammatory markers interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), epidermal growth factor (EGF) and, vascular endothelial growth factor A (VEGF) were additionally determined. Total-blood RNA was analyzed by 5’-end RNA sequencing. Two different bioinformatics approaches were performed: 1) Differential gene expression analyses using Limma R/Bioconductor software package (analyses adjusted by sex and maturational status) and 2) weighted gene coexpression network analyses (WGCNA). Results: Children with MHO had lower values of pro-inflammatory cytokines TNF-α and IL-6 compared to MUO (p < 0.05). 40 genes were differentially expressed (FDR < 0.05) in children with MHO compared to MUO. WGCNA analysis identified 23 gene coexpression modules (i.e. clusters of genes) with low preservation (Zsummary < 2) in children with MHO compared to MUO. Differential and WGCNA gene expression patterns identified 32 genes linked to metabolism, mitochondrial and immune functions. Conclusions: Whole blood transcriptome analysis revealed a distinct pattern of gene expression in children with MHO compared to MUO children. The identified gene expression patterns related to metabolism, mitochondrial and immune functions can promote a better understanding of cardiovascular disease prognosis in individuals with MHO.

Dataset Information

Genetic variation in NOTCH1 is associated with overweight and obesity in Brazilian elderly.

Publications

Genetic variation in NOTCH1 is associated with overweight and obesity in Brazilian elderly.

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