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

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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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Most cited references 51

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Variants in MTNR1B influence fasting glucose levels.

Inga Prokopenko, Claudia Langenberg, Jose C Florez … (2009)

To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.

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Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations.

David Meyre, Jérôme Delplanque, Jean-Claude Chèvre … (2009)

We analyzed genome-wide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls. Thirty-eight markers showing strong association were further evaluated in 14,186 European subjects. In addition to FTO and MC4R, we detected significant association of obesity with three new risk loci in NPC1 (endosomal/lysosomal Niemann-Pick C1 gene, P = 2.9 x 10(-7)), near MAF (encoding the transcription factor c-MAF, P = 3.8 x 10(-13)) and near PTER (phosphotriesterase-related gene, P = 2.1 x 10(-7)).

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An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.

L Pennacchio, M Olivier, J A Hubacek … (2001)

Comparison of genomic DNA sequences from human and mouse revealed a new apolipoprotein (APO) gene (APOAV) located proximal to the well-characterized APOAI/CIII/AIV gene cluster on human 11q23. Mice expressing a human APOAV transgene showed a decrease in plasma triglyceride concentrations to one-third of those in control mice; conversely, knockout mice lacking Apoav had four times as much plasma triglycerides as controls. In humans, single nucleotide polymorphisms (SNPs) across the APOAV locus were found to be significantly associated with plasma triglyceride levels in two independent studies. These findings indicate that APOAV is an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease.

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Author and article information

Contributors

Dana C. Crawford: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 14 December 2012

Volume: 7

Issue: 12

Electronic Location Identifier: e51954

Affiliations

[1 ]Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America

[2 ]Human Genome Sequencing Center, Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America

[3 ]USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America

Vanderbilt University, United States of America

Author notes

* E-mail: nbutte@ 123456bcm.edu

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: AGC SAC RAG NFB. Performed the experiments: SAC KH NFB. Analyzed the data: SLL VSV KH. Contributed reagents/materials/analysis tools: SAC KH. Wrote the paper: AGC SAC SLL VSV KH RAG NFB.

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Publisher ID: PONE-D-12-24984

DOI: 10.1371/journal.pone.0051954

PMC ID: 3522587

PubMed ID: 23251661

SO-VID: ce388d0a-2d64-4eeb-ac85-eba084b58377

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 15 August 2012

Date accepted : 7 November 2012

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Pages: 9

Funding

This work was supported by grants from the National Institutes of Health (NIH) (DK080457), and the USDA/ARS (Cooperative Agreement 6250-51000-053). Work performed at the Texas Biomedical Research Institute in San Antonio, Texas was conducted in facilities constructed with support from the Research Facilities Improvement Program of the National Center for Research Resources, NIH (C06 RR013556, C06 RR017515). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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

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Most cited references 51

Variants in MTNR1B influence fasting glucose levels.

Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations.

An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.

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