ClinVar Genomic variation as it relates to human health

This variant, formerly titled INSULIN RESISTANCE, SUSCEPTIBILITY TO (with the INCLUDED title of Coronary Artery Disease, Susceptibility To) has been reclassified as a polymorphism based on a review of the gnomAD database. Hamosh (2024) identified the G972R variant in the gnomAD database (v4.1.0) in 99,672 of 1,613, 026 alleles, in 3,374 homozygotes, for an allele frequency of 6.2 x 10(-2). The most frequent IRS1 variant is gly972 to arg (G972R), and the arg972 variant is twice as prevalent in patients with type II diabetes (NIDDM; 125853) as in control subjects. Various data suggest that the single molecular defect in insulin signaling, involving the defective interaction between phosphatidylinositol 3-kinase (PI3K; see 171834) and IRS1, might result in both peripheral insulin resistance (see 125853) and impaired insulin secretion. Carriers of the arg972 variant show lower fasting insulin and C-peptide levels compared with noncarriers. For example, Clausen et al. (1995) described a young, healthy, lean male homozygous for the arg972 variant who had low fasting plasma insulin levels and a low acute insulin response. To investigate directly whether the polymorphism in codon 972 of the IRS1 gene impairs insulin secretion, Porzio et al. (1999) overexpressed both wildtype IRS1 and the arg972 IRS1 variant in cultured cells. The arg972 variant did not affect expression or function of endogenous IRS2 (600797). Cultured cells expressing the arg972 variant exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with wildtype cells. Porzio et al. (1999) suggested that the common arg972 IRS1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. (Almind et al. (1993) referred to the gly972-to-arg mutation as gly971 to arg.) Almind et al. (1996) examined insulin-stimulated processes in a cultured myeloid progenitor cell line stably overexpressing the insulin receptor when transfected with either wildtype human IRS1 or the gly972-to-arg common variant (numbering according to Nishiyama and Wands, 1992). They showed that the mutation in codon 972 of the IRS1 gene impairs insulin-stimulated signaling, especially along the PI3K pathway, and may contribute to insulin resistance in normal and diabetic populations. To determine the prevalence of variants in NIDDM candidate genes, 't Hart et al. (1999) studied random samples of subjects with NIDDM and controls from the Hoorn and Rotterdam population-based studies. A significant difference in the frequency of the G972R allele of the IRS1 gene was observed between control subjects from Hoorn and Rotterdam. Baroni et al. (1999) investigated the role of the G972R mutation in predisposition to coronary artery disease (CAD). They studied the DNA of 318 subjects with angiographically documented coronary atherosclerosis (greater than 50% stenosis) and 208 population control subjects. The frequency of the G972R mutation was 18.9% in CAD patients and 6.8% in controls (less than 0.001). After controlling for other coronary risk factors, the relative risk of CAD associated with the G972R mutation was 2.93 in the entire cohort. The risk was even higher in the subgroups of obese subjects and those with clinical features of insulin resistance syndrome. Hribal et al. (2000) overexpressed wildtype IRS1 and the arg972 IRS1 variant in L6 skeletal muscle cells and examined the functional consequences of the polymorphism on insulin metabolic signaling. Arg972 cells showed a decrease in insulin-stimulated IRS1-associated phosphatidylinositol 3-kinase (PI3 kinase) activity compared with wildtype cells as a consequence of decreased binding of the PI3 kinase p85 subunit (see 171833) to IRS1. Arg972 cells exhibited a decrease in both basal and insulin-stimulated glucose transport due to a reduction in the amount of glucose transporter-1 (GLUT1; 138140) and GLUT4 (138190) translocated to the plasma membrane. Both basal and insulin-stimulated AKT (see 164730) phosphorylations were decreased in arg972 cells compared with wildtype cells. Basal glycogen synthase kinase-3 (GSK3; see 605004) activity was increased in arg972 cells compared with wildtype cells, and insulin-induced inactivation of GSK3 was also reduced in arg972 cells. This change was associated with a significant decrease in insulin-stimulated glucose incorporation into glycogen and glycogen synthase activity in arg972 cells compared with wildtype cells. The authors concluded that the arg972 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI3 kinase/AKT/GSK3 signaling pathway. The data indicated that the G972R polymorphism may contribute to the in vivo insulin resistance observed in carriers of this variant. Marini et al. (2003) investigated the relationship between the common G972R IRS1 variant and the presence of cardiovascular risk factors in 153 glucose-tolerant, unrelated offspring of type II diabetic patients. Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of arg972. Carriers of arg972 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides, total/high density lipoprotein cholesterol ratio, free fatty acid levels, systolic blood pressure, microalbuminuria, and intima-media thickness. These results suggested that the arg972 IRS1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type II diabetes by producing a cluster of insulin resistance-related metabolic abnormalities. Abate et al. (2003) determined the frequency of the PC1 K121Q (173335.0006) and IRS1 G972R polymorphisms in Asian Indians and Caucasians and tested insulin responsiveness and glucose disposal in carriers of both polymorphisms compared to controls. (The authors referred to the IRS1 polymorphism as G972A.) The frequency of carrying at least 1 copy of the IRS1 972R variant in Asian Indians was similar to that in Caucasians (6% and 7%, respectively). IRS1 972R was not associated with any change in insulin sensitivity in the Asian Indian population studied. In insulin-stimulated human endothelial cells from carriers of the G972R variant, Federici et al. (2004) demonstrated reduced phosphatidylinositol 3-kinase (PIK3) activity, decreased AKT and eNOS (163729)-ser1177 phosphorylation, and increased eNOS-thr495 phosphorylation compared to wildtype cells. They concluded that genetic impairment of the IRS1/PIK3/PDPK1 (605213)/AKT insulin signaling cascade results in impaired insulin-stimulated NO release and suggested that this may be a mechanism through which the G972R polymorphism contributes to the genetic predisposition to develop endothelial dysfunction and cardiovascular disease. Perticone et al. (2004) found that human endothelial cells obtained from carriers of the arg972 IRS1 polymorphism exhibited reduced eNOS expression in response to chronic exposure to insulin. A reduction in eNOS expression would be expected to be associated with impaired endothelium-dependent vasodilation. To investigate a possible relationship between arg972 IRS1 polymorphism and endothelial dysfunction in vivo, they enrolled a cohort of 100 never-treated hypertensive subjects. Endothelium-dependent and endothelium-independent vasodilation were assessed by increasing doses of acetylcholine and sodium nitroprusside. Perticone et al. (2004) observed that acetylcholine-stimulated forearm blood flow was significantly (P less than 0.0001) lower in gly/arg heterozygous carriers than in gly/gly carriers. Sodium nitroprusside caused comparable increments in forearm blood flow in both groups. Perticone et al. (2004) concluded that, by inducing endothelial dysfunction, the arg972 IRS1 polymorphism may contribute to the genetic predisposition to develop cardiovascular disease. (less)