Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children.

TitleResequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children.
Publication TypeJournal Article
Year of Publication2011
AuthorsButte, NF, V Voruganti, S, Cole, SA, Haack, K, Comuzzie, AG, Muzny, DM, Wheeler, DA, Chang, K, Hawes, A, Gibbs, RA
JournalPhysiol Genomics
Volume43
Issue18
Pagination1029-37
Date Published2011 Sep 22
ISSN1531-2267
KeywordsBayes Theorem, Child, Diabetes Mellitus, Fasting, Genetic Predisposition to Disease, Genotyping Techniques, Glucose, Hispanic Americans, Homeostasis, Humans, Insulin Receptor Substrate Proteins, Linkage Disequilibrium, Obesity, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Sequence Analysis, DNA
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.

DOI10.1152/physiolgenomics.00019.2011
Alternate JournalPhysiol. Genomics
PubMed ID21771880
PubMed Central IDPMC3180738
Grant ListC06 RR-013556 / RR / NCRR NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
DK-080457 / DK / NIDDK NIH HHS / United States
C06 RR-017515 / RR / NCRR NIH HHS / United States
R01 DK080457 / DK / NIDDK NIH HHS / United States