title: Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children.
abstract: Our objective was to resequence insulin receptor substrate 2 (IRS2) to identify variants associated with obesity- and diabetes-related traits in Hispanic children. Exonic and intronic segments, 5' and 3' flanking regions of IRS2 (∼14.5 kb), were bidirectionally sequenced for single nucleotide polymorphism (SNP) discovery in 934 Hispanic children using 3730XL DNA Sequencers. Additionally, 15 SNPs derived from Illumina HumanOmni1-Quad BeadChips were analyzed. Measured genotype analysis tested associations between SNPs and obesity and diabetes-related traits. Bayesian quantitative trait nucleotide analysis was used to statistically infer the most likely functional polymorphisms. A total of 140 SNPs were identified with minor allele frequencies (MAF) ranging from 0.001 to 0.47. Forty-two of the 70 coding SNPs result in nonsynonymous amino acid substitutions relative to the consensus sequence; 28 SNPs were detected in the promoter, 12 in introns, 28 in the 3'-UTR, and 2 in the 5'-UTR. Two insertion/deletions (indels) were detected. Ten independent rare SNPs (MAF = 0.001-0.009) were associated with obesity-related traits (P = 0.01-0.00002). SNP 10510452_139 in the promoter region was shown to have a high posterior probability (P = 0.77-0.86) of influencing BMI, fat mass, and waist circumference in Hispanic children. SNP 10510452_139 contributed between 2 and 4% of the population variance in body weight and composition. None of the SNPs or indels were associated with diabetes-related traits or accounted for a previously identified quantitative trait locus on chromosome 13 for fasting serum glucose. Rare but not common IRS2 variants may play a role in the regulation of body weight but not an essential role in fasting glucose homeostasis in Hispanic children.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, US Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Houston, TX, USA. nbutte@bcm.edu
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Butte
authors.forename: V Saroja
authors.initials: VS
authors.lastname: Voruganti
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
authors.forename: Karin
authors.initials: K
authors.lastname: Haack
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Comuzzie
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.forename: Kyle
authors.initials: K
authors.lastname: Chang
authors.forename: Alicia
authors.initials: A
authors.lastname: Hawes
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
mesh_terms: D001499:Bayes Theorem; D002648:Child; D003920:Diabetes Mellitus / Q000235:genetics; D005215:Fasting / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D005947:Glucose / Q000378:metabolism*; D006630:Hispanic or Latino / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D017422:Sequence Analysis, DNA
chemical_list: C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D005947:Glucose