Open AccessResequencing ofIRS2reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children
Author(s) -
Nancy F. Butte,
V. Saroja Voruganti,
Shelley A. Cole,
Karin Haack,
Anthony G. Comuzzie,
Donna M. Muzny,
David A. Wheeler,
Kyle Chang,
Alicia Hawes,
Richard A. Gibbs
Publication year - 2011
Publication title -
physiological genomics/physiological genomics (print)
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.078
H-Index - 112
eISSN - 1531-2267
pISSN - 1094-8341
DOI - 10.1152/physiolgenomics.00019.2011
Subject(s) - biology , glucose homeostasis , obesity , homeostasis , medicine , endocrinology , type 2 diabetes , impaired fasting glucose , genetics , diabetes mellitus , insulin resistance , impaired glucose tolerance
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.