Resequencing ofIRS2reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children

Abstract

Butte NF, Voruganti VS, Cole SA, Haack K, Comuzzie AG, Muzny DM, Wheeler DA, Chang K, Hawes A, Gibbs RA. Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children. Physiol Genomics 43: 1029-1037, 2011. First published July 19, 2011 doi:10.1152/physiolgenomics.00019.2011Our 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 (ϳ14.5 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 ϭ 0.001-0.009) were associated with obesity-related traits (P ϭ 0.01-0.00002). SNP 10510452_139 in the promoter region was shown to have a high posterior probability (P ϭ 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. DNA resequencing; diabetes; body mass index; single nucleotide polymorphisms; indels; insulin receptor substrate 2 INSULIN RECEPTOR SUBSTRATE 2 (IRS2) is a compelling candidate gene for obesity, insulin resistance, and Type 2 diabetes given its role in insulin signal transduction and the manifestation of obesity, insulin resistance and ␤-cell failure in Irs2Ϫ/Ϫ mice (30), and yet human studies of common IRS2 variants have not demonstrated consistent effects (2)(3)(4)34). IRS2 is a cytoplasmic signaling protein that mediates effects of insulin, insulinlike growth factor-1, and cytokines by acting as a relay protein between diverse receptor tyrosine kinases and downstream effectors (35,36) and thereby accounting for the diverse actions of insulin (18). Structurally, IRS2 has many modified residues (phosphotyrosines, phosphoserines, and phosphothreonines) and a CpG island in the promoter region, which suggests high regulatory potential. Highly express...

Asparaginase treatment side-effects may be due to genes with homopolymeric Asn codons (Review-Hypothesis)

“…IRS2 encodes insulin receptor substrate-2, a labile ( 30 , 31 ) intracellular signal transducer that is a substrate for a number of membrane spanning receptor tyrosine kinases specific for extracellular cytokines that include insulin, insulin-like-growth-factor-1, erythropoietin, thrombopoetin, growth hormone, leukemia inhibitory factor, interleukin-4 (IL-4) and interferon-γ ( 32 – 37 ). Sequence polymorphisms in the human IRS2 locus have been associated with obesity ( 38 ), type 2-diabetes-mellitus (T2DM) ( 39 , 40 ) or its complications ( 41 , 42 ), aspects of schizophrenia ( 43 ) and IgE immune responses ( 44 ). In transgenic mice, IRS2 deletion causes compromised maintenance of β-cell mass and produces a diabetic state similar to T2DM ( 45 , 46 ).…”

Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer

“…Two in-frame insertion mutations in IRS-2, one germline (p.Ala701_Val702insAla) and the other tumor-associated (p.Asn28_His29insAsn), were identified in CRC cases. These genetic variants were not detected in the control subjects of this study and in previous mutational analyses (17,28–30) and are not described in public databases. Overall, nearly 17% of the CRC tested (cell lines and primary CRC cases) had unique missense or a deletion or insertion mutations in IRS-1 and/or IRS-2.…”

“…Table IV summarizes the frequencies of 6 allelic variants identified in IRS-2 (c.2169C>T, c.2448T>C, c.2487C>T, p.Gly879Ser, pGly882Ala and p.Gly1057Asp), that were also detected in the general population (17,28–30) and are described in public databases.…”

“…Tables VI and VII summarize the 18 distinct allelic variants identified in IRS-2. Some of the detected IRS-1 and IRS-2 variants are common polymorphisms also found in the general population (Table VII) (17,20–30) and are described in public databases.…”

A genomewide study of body mass index and its genetic correlation with thromboembolic risk

“…It is the insulin receptor substrate 2 gene (IRS2), which codes for a cytoplasmatic protein of the insulin-signalling pathway. Previous candidate gene studies in humans have associated IRS2 polymorphisms with childhood (52,53) and adult obesity (54)(55)(56) and with overweight in the pathogenesis of type 2 diabetes (55). The IRS2 gene may play a key role in central control of energy homeostasis (57)(58)(59), but the mechanism by which genetic heterogeneity in this gene may impact energy homeostasis and body weight regulation is unclear.…”