Novel Genetic Loci Identified for the Pathophysiology of Childhood Obesity in the Hispanic Population

Vanderbilt University, United States of America
PLoS ONE (Impact Factor: 3.23). 12/2012; 7(12):e51954. DOI: 10.1371/journal.pone.0051954
Source: PubMed

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.

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Available from: Anthony G Comuzzie, Sep 04, 2015
    • "Maternal BMI and child ' s birth weight were the only predictors of maternal perception of their child ' s weight Increased maternal BMI = higher child BMI and decreased maternal perception of child weight Comuzzie et al . ( 2012 ) 815 Hispanic Children Genetically map childhood obesity and associated biological processes in the Hispanic population Genetic factors increased the risk of childhood obesity"
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    ABSTRACT: The purpose of this integrative review was to identify factors associated with obesity in Hispanic preschool children. Integrative research review based on strategies described by Whittemore and Knafl. Thirty-five research reports using qualitative and/or quantitative methods and including a majority of participants (parents or preschool-aged children) of Hispanic ethnicity. Data were analyzed using the Matrix Method. Decreased physical activity of the child and increased maternal body mass index were found as contributors to obesity in the preschool, Hispanic population. The relationship between maternal feeding practices and beliefs, food choices and childhood obesity are widely studied with little consistency in findings across studies. Public health nurses can work with communities to promote physical activity and safe outdoor places for exercise. In addition, they can advocate for the availability of healthy food choices in neighborhood schools. Maternal feeding practices, acculturation, and the child's environment require further research. © 2015 Wiley Periodicals, Inc.
    Public Health Nursing 06/2015; DOI:10.1111/phn.12215 · 0.89 Impact Factor
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    • "This SNV is situated in the intron of the gene NOS1AP (also known as CAPON) [46], which encodes a cytosolic protein that binds to neuronal nitric oxide synthase, a signaling molecule. NOS1AP has been associated with cardiac phenotypes [47]–[51], and marginally associated with childhood hip circumference in a Hispanic population (p = 8.6·10−6 [52]). "
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    ABSTRACT: Many health outcomes are influenced by a person's body mass index, as well as by the trajectory of body mass index through a lifetime. Although previous research has established that body mass index related traits are influenced by genetics, the relationship between these traits and genetics has not been well characterized in people of South Asian ancestry. To begin to characterize this relationship, we analyzed the association between common genetic variation and five phenotypes related to body mass index in a population-based sample of 5,354 Bangladeshi adults. We discovered a significant association between SNV rs347313 (intron of NOS1AP) and change in body mass index in women over two years. In a linear mixed-model, the G allele was associated with an increase of 0.25 kg/m2 in body mass index over two years (p-value of 2.3·10-8). We also estimated the heritability of these phenotypes from our genotype data. We found significant estimates of heritability for all of the body mass index-related phenotypes. Our study evaluated the genetic determinants of body mass index related phenotypes for the first time in South Asians. The results suggest that these phenotypes are heritable and some of this heritability is driven by variation that differs from those previously reported. We also provide evidence that the genetic etiology of body mass index related traits may differ by ancestry, sex, and environment, and consequently that these factors should be considered when assessing the genetic determinants of the risk of body mass index-related disease.
    PLoS ONE 08/2014; 9(8):e105062. DOI:10.1371/journal.pone.0105062 · 3.23 Impact Factor
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    • "Therefore, it is crucial to investigate the genetic contribution to obesity and obesity-associated metabolic abnormalities, permitting screening and preventive treatment for obese children and adolescents. Many researchers have discovered multiple commonvariations that may give rise to genetic susceptibility of common childhood obesity, such as fat mass and obesity associated gene, melanocortin 4 receptor gene, glucosamine-6-phosphate deaminase 2 and so on [6-8]. Apolipoprotein A5 (APOA5) gene, located on chromosome 11 adjacent to APOA1/APOC3/APOA4 gene cluster with known functions in the metabolism of plasma lipids [9], also modulates the risk of obesity in a number of studies [10-12]. "
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    ABSTRACT: Background Although the association between the apolipoprotein A5 (APOA5) genetic variants and hypertriglyceridemia has been extensively studied, there have been few studies, particularly in children and adolescents, on the association between APOA5 genetic variants and obesity or non-high-density lipoprotein cholesterol (non-HDL-C) levels. The objective of this study was to examine whether APOA5 gene polymorphisms affect body mass index (BMI) or plasma non-HDL-C levels in Chinese child population. Methods This was a case–control study. Single nucleotide polymorphisms (SNPs) were genotyped using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry for an association study in 569 obese or overweight and 194 healthy Chinese children and adolescents. Results Genotype distributions for all polymorphisms in both cohorts were in accordance with the Hardy-Weinberg distribution. The frequencies of the risk alleles in rs662799 and rs651821 SNPs in APOA5 gene were all increased in obese or overweight patients compared to the controls. After adjusted for age and sex, C carriers in rs662799 had a 1.496-fold [95% confidence interval (CI): 1.074-2.084, P = 0.017] higher risk for developing obesity or overweight than subjects with TT genotype, while C carriers in rs651821 had a 1.515-fold higher risk than subjects with TT genotype (95% CI: 1.088-2.100, P = 0.014). Triglyceride (TG) and non-HDL-C concentrations were significantly different among rs662799 variants and both were higher in carriers of minor allele than in noncarriers for TG (1.64 ± 0.96 vs. 1.33 ± 0.67 mmol/L) (P < 0.001), and for non-HDL-C (3.23 ± 0.92 vs. 3.02 ± 0.80 mmol/L) (P = 0.005), respectively. There was also a trend towards increased TG and non-high-density lipoprotein cholesterol levels for rs651821 C carriers (P < 0.001 and P = 0.002, respectively). Furthermore, to confirm the independence of the associations between APOA5 gene and TG or non-HDL-C levels, multiple linear regression analysis was performed and the relationships were not eliminated by adjustment for age, sex and BMI. Conclusions These findings suggest the TG-raising genetic variants in the APOA5 gene may influence the susceptibility of the individual to obesity, which may also contribute to an increased risk of high non-HDL-C levels in Chinese obese children and adolescents.
    Lipids in Health and Disease 06/2014; 13(1):93. DOI:10.1186/1476-511X-13-93 · 2.31 Impact Factor
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