Unveiling Genetic Associations: Investigating CLDN16, GRID2, NRG3, and CACNG4 Gene Polymorphisms with Insulin Resistance Risk Among Normal BMI Individuals in the Indian Population

Abstract Studies estimate that India has about 65+ million diabetic patients with a substantial impending increase, making it the international ‘diabetes capital’. Diabetes Mellitus is a metabolic disorder which is signified by elevated blood sugar levels due to defects in insulin action, secretion or both. Insulin resistance (IR) or insulin resistance-linked obesity is also known to be a causing factor of Metabolic syndrome which is a combination of cardiovascular risk factors that include raised fasting plasma glucose, central obesity, hypertension, raised triglycerides, and reduced High-Density Lipoprotein (HDL) cholesterol. This study investigated the association between four single nucleotide polymorphisms (SNPs) in the selected genes - rs6801387 ( CLDN16 ), rs72872727 ( GRID2 ), rs1414756 ( NRG3 ), and rs8065294 ( CACNG4 ) and (IR) among a normal BMI Indian population. Through Chi-Square tests, we detected significant associations between SNP genotypes and (IR). Allele frequency analysis revealed higher frequencies of allele G (rs6801387) and T (rs72872727) among individuals with HOMA2-IR >2, while allele T (rs8065294) indicated decreased risk, emphasizing the relevance of genetic factors in metabolic disorders. The differences in clinical parameters such as fat mass, serum triglycerides and HbA1c between the cases and controls highlights the multifactorial nature of the condition. Inheritance model suggested the dominant inheritance for rs6801387 and rs72872727 and codominant inheritance for rs1414756 and rs806529, offering insights into genetic associations with IR. Despite the study’s moderate sample size,these genetic biomarkers exhibit strong susceptibility to the studied condition, showing the importance of exploring their functional significance and underlying biological mechanisms in future research endeavours.