Complex haplotypes of IRS2 gene are associated with severe obesity and reveal heterogeneity in the effect of Gly1057Asp mutation

Abstract

In order to understand the role of the insulin receptor substrate-2 (IRS2) gene (chromosome region: 13q34) in obesity, a complex disorder associated with insulin resistance and glucose intolerance, we determined single nucleotide polymorphims (SNPs) and complex haplotypes in women with morbid obesity and a body mass index (BMI) of 41±0.8 kg/m 2 (n=99) compared with controls having a BMI of 23.8±0.1 kg/m 2 (n=92). Sequencing of unphased DNA or digestion of polymerase chain reaction fragments revealed seven SNPs, including a new C/T(-769) replacement at the 5' untranslated region. Considering four or seven SNPs, we reconstructed with the PHASE program nine or 24 haplotypes, respectively, that were well correlated into the cladogram. Logistic regression analysis with nine haplotypes in the whole sample revealed that obesity was associated with haplotype H3, with P<0.025, an odds ratio (OR) of 1.9 and a 95% confidence interval (CI) of 1.1-3.4, or pairs 3/3 (P<0.005, OR=8.7, CI=1.9-40.1) and 3/4 (P<0.023, OR=2.5, CI=1.1-5.6), all containing the the Gly1057Asp allelic variant of IRS2, whereas controls were associated with H5 and H6 (P<0.02, OR=0.2, CI=0.01-0.81). Although obese H5 carriers (also containing Gly1057Asp mutation) were the most insulin resistant, haplotypes of IRS2 were poorly correlated (analysis of variance) with insulin resistance. By contrast, haplotypes H3, H4 and pairs 3/3 were consistently associated with increased 2-h glucose levels during an oral glucose tolerance test in obese individuals (P<0.0005, 0.025 and 0.027, respectively). These data indicate that IRS2 is an influential gene in severe obesity and glucose intolerance in this population, whereas gene-based haplotypes of IRS2 have revealed heterogeneity in the behaviour of the Gly1057Asp mutation in relation to insulin resistance.

Association between IRS1 Gene Polymorphism and Autism Spectrum Disorder: A Pilot Case-Control Study in Korean Males

“…The IGF pathway plays an important role in regulating cell proliferation, differentiation and apoptosis, and, thus, IGFs and their signaling regulators have been studied in growth-, weight gain- , and obesity-related diseases [20,28,33,34,35]. IRS1 and IRS2 are key mediators of the IGF pathway [20,21].…”

“…Binding of IGFs to IGF receptors phosphorylates IRSs and triggers downstream cascades such as MAPK and PI3K/AKT signaling, which finally leads to cell proliferation and differentiation [20,21]. Thus, IRS1 and IRS2 together with IGFs and IGFRs have been involved in obesity, birth weight, diabetes mellitus, insulin sensitivity and cancer, showing the genetic associations of their polymorphisms [28,29,30,31,33,34]. …”

“…Thus, they have been suggested as markers of an active IGF pathway within tumors [25,26], although they are involved in insulin signaling. Indeed, polymorphisms of IRS1 and/or IRS2 have shown the significant associations with diabetes, glucose levels [27], and obesity [28], as well as with cancers, along with IGF signaling regulator genes [29,30,31]. Herein, we investigated the association of the coding region single-nucleotide polymorphisms (cSNP) of IRS1 and IRS2 , active markers of the IGF pathway, with ASD in Korean males.…”

IRS-2 G1057D polymorphism in Turkish patients with colorectal cancer

“…The gene polymorphisms coding the IRS proteins were comprehensively studied by means of diseases such as polycystic ovary syndrome [19], obesity [20], type 2 diabetes [21], prostate cancer [22], breast cancer [8], gastric cancer [23], ovarian cancer [24] and colon cancer [14, 25, 26]. Tumour size, lymph nodes and metastasis are widely examined in cancer research studies; however, only specific genes that are known to play a role in tumour initiation, progression and metastasis are analysed to identify the relevance of tumour characteristics.…”

TheFOXO1Gene-Obesity Interaction Increases the Risk of Type 2 Diabetes Mellitus in a Chinese Han Population

“…1). Furthermore, according to literatures (222324), Gly1057Asp and −769C/T loci in IRS2 gene were selected to conduct the further detection.…”