Location: Children's Nutrition Research CenterTitle: Resequencing IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children Author
Submitted to: Physiological Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/13/2011
Publication Date: 9/1/2011
Citation: Butte, N.F., Voruganti, V.S., Cole, S.A., Haack, K., Comuzzie, A.G., Muzny, D.M., Wheeler, D.A., Chang, K., Hawes, A., Gibbs, R.A. 2011. Resequencing IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children. Physiological Genomics. 43(18):1029-1037. Interpretive Summary: In this study, we resequenced a gene called insulin receptor substrate 2 (IRS2) to identify variants that may have an effect on obesity or diabetes risk in Hispanic children. IRS2 is very important in the regulation of insulin signaling. We found a total of 140 variants, some of which were common and others rare in Hispanic children. One rare variant in particular was related to body mass index, fat mass, and waist circumference in Hispanic children. We concluded that rare but not common IRS2 variants may play a role in the regulation of body weight in Hispanic children. Understanding the genetics underlying obesity or diabetes is of great interest to the biomedical community.
Technical 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 (approx. 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.