Abstract
Genetic variants responsible for susceptibility to obesity and its comorbidities among Hispanic children have not been identified. The VIVA LA FAMILIA Study was designed to genetically map childhood obesity and associated biological processes in the Hispanic population. A genome-wide association study (GWAS) entailed genotyping 1.1 million single nucleotide polymorphisms (SNPs) using the Illumina Infinium technology in 815 children. Measured genotype analysis was performed between genetic markers and obesity-related traits i.e., anthropometry, body composition, growth, metabolites, hormones, inflammation, diet, energy expenditure, substrate utilization and physical activity. Identified genome-wide significant loci: 1) corroborated genes implicated in other studies (MTNR1B, ZNF259/APOA5, XPA/FOXE1 (TTF-2), DARC, CCR3, ABO); 2) localized novel genes in plausible biological pathways (PCSK2, ARHGAP11A, CHRNA3); and 3) revealed novel genes with unknown function in obesity pathogenesis (MATK, COL4A1). Salient findings include a nonsynonymous SNP (rs1056513) in INADL (p = 1.2E-07) for weight; an intronic variant in MTNR1B associated with fasting glucose (p = 3.7E-08); variants in the APOA5-ZNF259 region associated with triglycerides (p = 2.5-4.8E-08); an intronic variant in PCSK2 associated with total antioxidants (p = 7.6E-08); a block of 23 SNPs in XPA/FOXE1 (TTF-2) associated with serum TSH (p = 5.5E-08 to 1.0E-09); a nonsynonymous SNP (p = 1.3E-21), an intronic SNP (p = 3.6E-13) in DARC identified for MCP-1; an intronic variant in ARHGAP11A associated with sleep duration (p = 5.0E-08); and, after adjusting for body weight, variants in MATK for total energy expenditure (p = 2.7E-08) and in CHRNA3 for sleeping energy expenditure (p = 6.0E-08). Unprecedented phenotyping and high-density SNP genotyping enabled localization of novel genetic loci associated with the pathophysiology of childhood obesity.
Highlights
Obesity is a complex disease influenced by genetic and environmental factors and their interactions
Extensive phenotyping and high-density single nucleotide polymorphism (SNP) genotyping enabled localization of novel genetic loci associated with the pathophysiology of obesity in Hispanic children
Our unprecedented phenotypes represent adiposity, and biological processes underlying the development of childhood obesity
Summary
Obesity is a complex disease influenced by genetic and environmental factors and their interactions. The current surge in childhood obesity in the U.S is attributable to an interaction between a genetic predisposition toward efficient energy storage and a permissive environment of readily available food and sedentary behaviors [1]. The phenotypic description of the obese child usually has been limited to body mass index (BMI). Markers of biological processes underlying the development of obesity such as dietary intake, energy expenditure and nutrient partitioning may be more effectual in identifying causal genetic variants [2]. Childhood obesity has been shown to be genetically correlated with glucose intolerance, hypertension, dyslipidemia, insulin resistance, chronic inflammation, and risk for fatty liver disease [3,4]. Identification of genes underlying these distinct patterns of association may unravel important biological pathways involved in the pathophysiology of childhood obesity
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