Insulin receptor substrate-1 G972R single nucleotide polymorphism in Egyptian patients with chronic hepatitis C virus infection and type 2 diabetes mellitus

Abstract

Background Insulin receptor substrate-1 (IRS1) plays a critical role in insulin signaling. IRS-1 gene polymorphism with glycine to arginine substitution (GGG ↔ AGG substitutions) in codon 972 (G972R) (rs1801278) is a common polymorphism of the IRS-1 gene, which may have a pathogenic role in the development of type 2 diabetes mellitus (type 2 DM) due to insulin resistance and impaired insulin secretion. In hepatitis C virus infection (HCV), the IRS proteins might be counter-regulated by degradation, differential expression, or modification by phosphorylation in cells expressing HCV core protein, which inhibits the interactions of IRS-1 with both the insulin receptor and the downstream effectors of IRS-1. The present retrospective case–control study aimed to evaluate IRS-1 G972R (rs 1801278) SNP in Egyptian patients with HCV and type 2 DM, two hundred and two subjects including 100 males and 102 females The present work is a retrospective case–control study aimed to detect IRS-1 G972R (rs 1801278) SNP in Egyptian patients with chronic HCV infection and DM. The subjects were divided into the control group (group I) which included 50 apparently healthy volunteers of comparable age, gender, and socioeconomic status to patients; group II included 50 type 2 diabetic patients without chronic hepatitis C infection; group III included 52 chronic HCV-infected patients without type 2 diabetes mellitus; and group IV included 50 chronic hepatitis C-infected patients with type 2 diabetes mellitus. IRS-1 G972R (rs 1801278) genotyping was done by using polymerase chain reaction (PCR-RFLP) technique with restriction enzymes BstNI. Results HOMA-IR and QUICKI index was significantly higher in the patient groups (groups II, III, and IV) than controls (P < 0.001, P = 0.019, and P < 0.001 respectively). There was a significant increase in minor allele (A) in groups II, III, and IV than controls (P = 0.007, P = 0.017, and P = 0.007 respectively). There was increased frequency of mutant allele (A) than wild allele (G) of IRS-1 G972R polymorphism in type 2 diabetic patients with BMI < 25 kg/m2. The DM patients without HCV infection (group II), HCV patients without DM (group III), and HCV patients with DM (group IV) showed a significant decrease in GG genotypes and a significant increase in AA genotypes than the controls (P = 0.017, P = 0.019, and P = 0.009 respectively). Body mass index and waist to hip ratio were significantly higher in DM patients without chronic hepatitis C infection (group II) and in HCV patients with type 2 diabetes (group IV) than controls, in hepatitis C patients with type 2 diabetes (group IV) than controls, and in group IV than group III (P < 0.001). Conclusion IRS-1 G972R (rs 1801278) polymorphism might be a contributing risk factor for the development of type 2 DM. The mutant allele (A) of IRS-1 suggests the role of this SNP as risk factors for type 2 diabetes mellitus even in subjects with normal body weight. The increase of body mass index may be an independent risk factor for the development of type 2 diabetes mellitus.

Current Studies on Molecular Mechanisms of Insulin Resistance

“…The prevalent polymorphism of IRS1 is a glycine to arginine substitution in codon 972 (Gly972Arg), which is located between two potential tyrosine phosphorylation sites involved in binding with p85. This polymorphism has been linked to the development of T2D in obese Caucasian children [64], Egyptian patients with chronic hepatitis C virus infection and T2D [65], Kurdish ethnic, and Saudi and Pakistani populations [66][67][68]. However, no such association with this genetic variant has been found in Sistan and Baluchistan population of Iran [69], Arab, or Berber and Asian Indian populations [70,71] with T2D (Table 3).…”

Genetic Polymorphisms and Their Interactions with the Risk Factors of Cardiovascular Diseases: Review Chapter

“…The Gly972Arg polymorphism occurs as a result of a substitution between glycine and arginine (GGG ↔ AGG substitutions) in codon 972 (G972R). It has been demonstrated that this mutation is involved in the development of type 2 diabetes mellitus (type 2 DM) [141]. This is due to the fact that it's been described to influence tyrosine phosphorylation at a specific site of IRS-1 which may lead to the development of insulin resistance (IR) and impair insulin secretion [142].…”

Association between insulin receptor substrate 1 gene polymorphism rs1801278 and gestational diabetes mellitus: an updated meta- analysis

“…It also encodes IRS-1 protein, which plays an important role in signal transmission between insulin receptor and Phosphoinositide 3-kinase (PI3K) [ 6 ]. Previous studies have also shown that dysregulation of IRS-1 expression and function can affect the insulin signaling pathway, leading to the occurrence of IR and DM [ 7 , 8 ]. Previously, several studies have suggested a significant association between IRS-1 gene single nucleotide polymorphisms (SNPs) and T2DM risk [ 9 , 10 ].…”