Investigating the Role of Interleukin 1 receptor antagonist (IL1RN) and Paraoxonase 1 (PON1) Susceptibility Factor with Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus is a chronic metabolic disorder that is associated with abnormal endocrine functioning and attributed to hyperglycaemia, defective insulin production and insulin resistance caused by many factors including genetic, environmental, lifestyle. Interleukin 1 receptor antagonist (IL1RN) protein, a member of the cytokine family encoded by the gene IL1RN located on the long arm of chromosome 2 expressed by the cells of immune system. It plays a key role in regulating uncontrolled inflammation by binding to the receptors of IL-1 and preventing it from activation. Inflammation is a crucial contributing factor of Type 2 Diabetes Mellitus (T2DM), Hence low levels of IL1RN or SNPs may lead to T2DM and its related complications. While Paraoxonase 1 enzyme encoded by PON1 gene, located on long arm of chromosome 7, perform metabolism of toxins as well as provide protection against oxidative stress and reactive oxygen species. Hence variation in PON1 leads to certain health conditions like T2DM and CVDs. Various abnormalities like SNPs in IL1RN and PON1 were found to be associated to T2DM in certain populations. This research study aimed to find out the missense pathogenic polymorphisms of IL1RN and PON1 using Insilico analysis and further invitro analysis of these polymorphisms were also performed. By using computational analysis, SNP rs201638660 (C94F), is reported as a high-risk non-synonymous SNP of IL-1RN because of its deleterious and disease associated nature and it causes loss interactions and destabilizes protein hence affecting protein function and five SNPs of PON1 (rs72552788 (L90P), rs138512790 (C42R), rs185623242 (S302L), rs368206333 (G344C), rs369422555 (W281C)) are shortlisted as deleterious, that will cause damage to protein structure and function. Association of rs854560 of PON1 and rs380092 of IL1RN is performed via HRM analysis which measures the change in fluorescence with gradual increase in temperature and detects variation. Using graph pad prism 10, p value comes out to be 0.0132 for rs380092 of IL1RN and 0.053 for rs854560 of PON1, and significant association is confirmed. Further invitro studies are required to validate the shortlisted pathogenic nsSNPs of PON1 and IL1RN sequencing is required to refine the data of these SNPs.