%0 Journal Article %J Physiol Genomics %D 2011 %T Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children. %A Butte, Nancy F %A Voruganti, V Saroja %A Cole, Shelley A %A Haack, Karin %A Comuzzie, Anthony G %A Donna M Muzny %A David A Wheeler %A Chang, Kyle %A Hawes, Alicia %A Richard A Gibbs %K Bayes Theorem %K Child %K Diabetes Mellitus %K Fasting %K Genetic Predisposition to Disease %K Genotyping Techniques %K Glucose %K Hispanic Americans %K Homeostasis %K Humans %K Insulin Receptor Substrate Proteins %K Linkage Disequilibrium %K Obesity %K Polymorphism, Single Nucleotide %K Quantitative Trait, Heritable %K Sequence Analysis, DNA %X

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.

%B Physiol Genomics %V 43 %P 1029-37 %8 2011 Sep 22 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/21771880?dopt=Abstract %R 10.1152/physiolgenomics.00019.2011