Association of IRS1 (Gly972Arg) and IRS2 (Gly1057Asp) genes polymorphisms with OSA and NAFLD in Asian Indians

Abstract

Aim and objective The aim of the study was to investigate the relationships between insulin receptor substrate (IRS) 1 (Gly972Arg) and IRS2 (Gly1057Asp) genes with obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) in Asian Indians. Method A total of 410 overweight/obese subjects (130 with OSA with NAFLD, 100 with OSA without NAFLD, 95 without OSA and with NAFLD and 85 without OSA and without NAFLD) were recruited. Degree of NAFLD was based on liver ultrasound and of OSA on overnight polysomnography. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and confirmed by gene sequencing. Result Mean values of blood pressure, body fat markers, blood glucose, lipids, liver function, and markers of insulin resistance were significantly increased in OSA and NAFLD subjects (p<0.05). In addition, according to age (years) categories, blood pressure, blood glucose, lipids, obesity markers, and markers of insulin resistance were significantly higher in 45–60 years group as compared to 20–45 years group (p<0.05). In IRS1 gene, the genotype frequency (%) of Arg/Arg was significantly higher in NAFLD and OSA subjects. In addition, Gly/Arg genotype of IRS1 gene was associated with significantly higher body mass index, fat mass, %body fat, triglycerides, cholesterol, alkaline phosphate, aspartate transaminase, fasting insulin and HOMA-IR levels in OSA and NAFLD subjects. No significant difference in genotype frequencies of IRS2 was observed between four groups. Further we found that subjects carrying IRS1 Gly/Arg (OR 4.49, 95% C.I. 1.06–12.52, p = 0.002) genotype possess a much higher risk of OSA and NAFLD compared to IRS2 Gly/Asp (OR 1.01, 95% C.I. 0.8–2.56, p = 0.05). In sub group analysis of IRS1 Gly/Arg have significant differences between the mild, moderate and severe group (P<0.05). In addition, patients with the ‘Gly’ allele were inclined to develop more severe OSA. Conclusion We concluded that Asian Indian subject carrying the allele Gly972Arg polymorphism of IRS1 is predisposed to develop OSA and NAFLD.

The genetic interactions between non-alcoholic fatty liver disease and cardiovascular diseases

“…Studies have shown that the frequency of the Arg allele of the Gly972Arg polymorphism of IRS-1 gene was significantly increased in NAFLD. Gly972Arg carriers are at significantly higher risk of NAFLD ( Bhatt and Guleria, 2021 ). The association between IRS-1 gene polymorphism and incident type 2 diabetes has been demonstrated in both the Asian and Caucasian populations ( Dongiovanni et al, 2010 ; Li et al, 2016 ).…”

Exploring the role of genetic variations in NAFLD: implications for disease pathogenesis and precision medicine approaches

“…Thereby, malfunction of the IRS impairs insulin signaling and increases the risk of insulin resistance. The loss-of-function rs1801278 Gly927Arg polymorphism diminishes the IRS-1 activity and inhibits the insulin receptor autophosphorylation, causing a reduction in insulin signaling [ 86 ]. A recent Pakistani population study demonstrated a correlation between the Gly972Arg variant of IRS-1 and insulin resistance in T2DM [ 87 ].…”

Current Studies on Molecular Mechanisms of Insulin Resistance

“…The Gly1057Asp variation of the IRS2 gene has been widely documented, and it is thought to be linked to insulin resistance, T2D, and obesity. Gly1057Asp inside IRS2 has been linked to greater insulin resistance and T2D in obese Caucasian youngsters, Kurdish ethnics, Iranians, and Asian Indians [66,[76][77][78], while research in a Turkish women's population suggests that this genetic variation may be linked to GDM as well [79]. However, the genetic variant of IRS2 Gly1057Asp was significantly associated with risk of T2D only in female Bangladeshi population, not males, and the authors were unable to replicate the association of IRS2 Gly1057Asp with obesity [80], while no association with obesity has been found in obese Polish pregnant women [81], implying more appropriate controls for related confounding factors, and a larger sample size is required to confirm this finding.…”