The Role of Obesity‐associated Loci Identified in Genome‐wide Association Studies in the Determination of Pediatric BMI

Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Obesity (Impact Factor: 3.73). 06/2009; 17(12):2254-7. DOI: 10.1038/oby.2009.159
Source: PubMed


The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Besides environmental factors, genetic factors are known to play an important role in the pathogenesis of obesity. A number of genetic determinants of adult BMI have already been established through genome-wide association (GWA) studies. In this study, we examined 25 single-nucleotide polymorphisms (SNPs) corresponding to 13 previously reported genomic loci in 6,078 children with measures of BMI. Fifteen of these SNPs yielded at least nominally significant association to BMI, representing nine different loci including INSIG2, FTO, MC4R, TMEM18, GNPDA2, NEGR1, BDNF, KCTD15, and 1q25. Other loci revealed no evidence for association, namely at MTCH2, SH2B1, 12q13, and 3q27. For the 15 associated variants, the genotype score explained 1.12% of the total variation for BMI z-score. We conclude that among 13 loci that have been reported to associate with adult BMI, at least nine also contribute to the determination of BMI in childhood as demonstrated by their associations in our pediatric cohort.

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    • "The FTO, INSIG2, CD36, and MC4R genes tested in our study are the main polymorphisms associated with body weight [15]. Substantial problems concerning obesity and T1DM include difficulty in distinguishing the types of disease in adolescents with features of insulin resistance, weight gain during intensive insulin therapy, the potential impact of obesity on long-term complications, and the relationship of body weight with metabolic control. "
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    ABSTRACT: The objective was to compare the impact of clinical and genetic factors on body mass index (BMI) in children with type 1 diabetes (T1DM) without severe obesity. A total of 1,119 children with T1DM (aged 4-18 years) were qualified to take part in the study. All children were genotyped for variants of FTO, MC4R, INSIG2, FASN, NPC1, PTER, SIRT1, MAF, IRT1, and CD36. Results. Variants of FTO showed significant association with BMI-SDS in the T1DM group. The main factors influencing BMI-SDS in children with T1DM included female gender (P = 0.0003), poor metabolic control (P = 0.0001), and carriage of the A allele of the FTO rs9939609 gene (P = 0.02). Conclusion. Our research indicates, when assessing, the risk of overweight and obesity carriage of the A allele in the rs9939609 site of the FTO gene adds to that of female gender and poor metabolic control. This trial is registered with (NCT01279161).
    International Journal of Endocrinology 08/2014; 2014:630712. DOI:10.1155/2014/630712 · 1.95 Impact Factor
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    • "Participants were recruited through the Children's Hospital of Philadelphia network between 2006 and 2010 (n=7225). All participants were of European ancestry, unrelated, and aged between 2 and 18 years old (3). Parental informed consent was given for each participant, and the Institutional Review Board of the Children's Hospital of Pennsylvania approved the study. "
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    ABSTRACT: Objective We aimed to determine if previously identified adult obesity susceptibility loci were associated uniformly with childhood BMI across the BMI distribution. Design and Methods Children were recruited through the Children's Hospital of Philadelphia (n=7225). Associations between the following loci and BMI were assessed using quantile regression: FTO (rs3751812), MC4R (rs12970134), TMEM18 (rs2867125), BDNF (rs6265), TNNI3K (rs1514175), NRXN3 (rs10146997), SEC16B (rs10913469), and GNPDA2 (rs13130484). BMI z-score (age and gender adjusted) was modeled as the dependent variable, and genotype risk score (sum of risk alleles carried at the 8 loci) was modeled as the independent variable. Results Each additional increase in genotype risk score was associated with an increase in BMI z-score at the 5th, 15th, 25th, 50th, 75th, 85th and 95th BMI z-score percentiles by 0.04 (±0.02, p=0.08), 0.07 (±0.01, p=9.58 × 10-7), 0.07 (±0.01, p=1.10 × 10-8), 0.09 (±0.01, p=3.13 × 10-22), 0.11 (±0.01, p=1.35 × 10-25), 0.11 (±0.01, p=1.98 × 10-20), and 0.06 (±0.01, p=2.44 × 10-6), respectively. Each additional increase in genotype risk score was associated with an increase in mean BMI z-score by 0.08 (±0.01, p=4.27 × 10-20). Conclusion Obesity risk alleles were more strongly associated with increases in BMI z-score at the upper tail compared to the lower tail of the distribution.
    Obesity 06/2013; 21(6). DOI:10.1002/oby.20319 · 3.73 Impact Factor
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    • "Adults who weighed nearly three Kg more compared to those who did not present the variant reported 6 . Identification of the variants found in the genomic scans has been verified by other studies, both in adults as in children 7 , 8 , revealing cumulative effects for the body-mass index (BMI) 7 ; some of these variants have been associated with anthropometric variables like the waist-hip ratio, but after adjusting for BMI these lose association 9 . This suggests that said loci are important in determining body fat gain in general, but not in its distribution. "
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    ABSTRACT: Increased prevalence of obesity in the world, especially accumulation of abnormal amounts of visceral fat predisposes to insulin resistance, which is the central role of metabolic syndrome (MS). Obesity can deregulate the intracellular signaling of insulin due to the production of inflammatory substances, chemoattractant proteins, adipokines and molecules that trigger hormonal mediator potentials for destabilization of signal transduction, leading to metabolic disorders such as hyperglycemia, hypertension, and dyslipidemia. The complexity of the MS and of the genetic mechanisms involved in its etiology derives from the combination of variants on genes involved and environmental factors that predispose it. The purpose of this paper is to review the effects of obesity in molecular and biochemical responses that trigger insulin resistance and its relation to some candidate genes and the ancestral component of the population.
    03/2013; 44(1):57-63.
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