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: 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
• Journal: Physiological genomics (Physiol Genomics) Vol. 43 Issue 18 Pg. 1029-37 (Sep 22 2011) ISSN: 1531-2267 [Electronic] United States
• PMID: 21771880 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• IRS2 protein, human
• Insulin Receptor Substrate Proteins
• Glucose

Topics

• Bayes Theorem
• Child
• Diabetes Mellitus (genetics)
• Fasting (metabolism)
• Genetic Predisposition to Disease
• Genotyping Techniques
• Glucose (metabolism)
• Hispanic or Latino (genetics)
• Homeostasis (genetics)
• Humans
• Insulin Receptor Substrate Proteins (genetics)
• Linkage Disequilibrium (genetics)
• Obesity (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Quantitative Trait, Heritable
• Sequence Analysis, DNA