Insulin Resistance Risk in Normal BMI Individuals: Investigating the Role of Genetic Polymorphisms in RNF138, ABCA1, and ESRRG-GPATCH2 Genes - A Case-Control Study in the Indian Population

Abstract Background: India, characterised as the "diabetes capital" of the world, faces a rapidly increasing diabetes crisis with over 65 million cases diagnosed. Despite the growing prevalence, the genetic underpinnings of insulin resistance (IR) among Indians with normal BMI remain understudied. This research aims to fill the knowledge gap by investigating the association of specific gene variants (RNF138, ABCA1, and ESRRG-GPATCH2) with IR risk in this demographic. Methods: A total of 191 participants (90 men, 101 women) were recruited for this cross-sectional study. Participants were categorized into cases (HOMA2-IR > 2) and controls (HOMA2-IR < 2) based on Homeostasis Model Assessment Insulin Resistance values. Genotyping for rs4799327 (RNF138), rs2275543 (ABCA1), and rs1497828 (ESRRG-GPATCH2) was performed using the Illumina Infinium Global Screening Array. Statistical analyses, including odds ratios (ORs), 95% confidence intervals (CIs), and inheritance model analysis, were conducted to assess the association between genotypes and IR. Results: Significant associations were found between IR and genetic variants rs4799327 in RNF138 and rs1497828 in ESRRG-GPATCH2 (dominant inheritance model) and rs2275543 in ABCA1 (additive model). The study highlights a notable susceptibility to IR linked to these genetic markers among normal BMI individuals in the Indian population. Conclusions:This study underscores the importance of genetic factors in the risk of developing insulin resistance among Indians with normal BMI, suggesting a complex interplay of genetics beyond traditional risk factors. These findings necessitate further research into the functional significance of these associations and their potential implications for targeted interventions and preventive strategies in high-risk populations.