Preliminary insight into the potential role of Leptin Receptor Polymorphisms in Type 2 Diabetes Risk: case-control...

Type 2 diabetes mellitus (T2DM) develops primarily from obesity as leptin (LEP) functions as an essential adipokine that controls metabolic regulation, energy balance activities, and glucose maintenance. The T2DM and obesity susceptibility traits are believed to be affected by genetic variations in the leptin receptor gene (LEPR), disrupting LEP signaling mechanisms. This case-control study investigates the association of these variants with T2DM risk in a Southeastern Iranian population.

A case-control study was conducted involving 450 T2DM patients and 450 matched healthy controls from Zahedan. Genomic DNA for this study was isolated from peripheral blood samples, and genotyping for the specified LEPR rs1137100, rs1137101, and rs1805094 polymorphisms was conducted using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Computational analysis created a gene-gene interaction network, highlighting LEPR as a central hub gene and detailing its interactions with related genes.

Genetic models, such as codominant heterozygous (p-value = 0.009), dominant (p-value = 0.006), recessive (p-value = 0.008), and allelic (p-value = 0.011), all showed that the rs1137100 (A/G) polymorphism lowered the risk of T2DM. Several genetic models linked polymorphisms at the rs1137101 (G/A) and rs1805094 (G/C) loci to a higher risk of T2DM: The genetic models that were looked at were polymorphism rs1137101 (G/A) in codominant Homozygous (p-value = 0.031) and recessive (p-value = 0.028), as well as polymorphism rs1805094 (G/C) in codominant heterozygous (p-value = 0.009), dominant (p-value = 0.001), excess (p-value = 0.008), and allelic (p-value = 0.001). The research demonstrated a profound linkage disequilibrium (LD) among studied variants, especially in the LEPR haplotypes and across various blocks, with differing levels of association strength. The gene-gene interaction network for the LEPR gene highlights its strong associations with several key regulatory genes: LEP, PTPN11, STAT3, POMC, JAK2, IL6, and SOCS3.

We found a significant correlation between LEPR gene polymorphisms and the risk of T2DM, highlighting the prominent role of genetic factors in developing such a metabolic disorder. By elucidating the association between LEPR variations and susceptibility to T2DM, our findings enhance the understanding of molecular mechanisms involved in endocrine dysregulation and highlight the importance of including genetic profiling in clinical practice.