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Title: Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population

Author
item COMUZZIE, ANTHONY - Texas Biomedical Institute
item COLE, SHELLEY - Texas Biomedical Institute
item LASTON, SANDRA - Texas Biomedical Institute
item VORUGANTI, V - Texas Biomedical Institute
item HAACK, KARIN - Texas Biomedical Institute
item GIBBS, RICHARD - Baylor College Of Medicine
item BUTTE, NANCY - Children'S Nutrition Research Center (CNRC)

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/7/2012
Publication Date: 12/14/2012
Citation: Comuzzie, A.G., Cole, S.A., Laston, S.L., Voruganti, V.S., Haack, K., Gibbs, R.A., Butte, N.F. 2012. Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PLoS One. 7(12):e51954.

Interpretive Summary: A genome-wide association study (GWAS) was performed in the VIVA LA FAMILIA Study to identify genetic variants associated with childhood obesity in the Hispanic population. The GWAS involved genotyping 1.1 million single nucleotide polymorphisms (SNPs) in 815 Hispanic children. We identified several genetic variants at a genome-wide significance level. These variants 1) confirmed genes implicated in other studies; 2) localized novel genes in plausible biological pathways; and 3) revealed novel genes with unknown function in obesity pathogenesis. Particularly promising findings include a protein-coding variant for weight; another variant associated with fasting glucose; variants associated with triglycerides; and another protein-coding variant for an immune protein. The VIVA cohort successfully identified novel genetic loci associated with the development and pathophysiology of childhood obesity.

Technical 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.