LEPR Q223R Variant and Its Role in Type 2 Diabetes Susceptibility Among Iraqi Individuals

Abstract

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired β-cell function. Recent studies have highlighted the contribution of genetic polymorphisms, particularly in the leptin receptor (LEPR) gene, to T2DM susceptibility. The LEPR rs1137101 (A>G) polymorphism, which leads to a Q223R amino acid substitution, may influence leptin signaling and insulin sensitivity, thereby affecting T2DM pathogenesis. Methods: A case-control study included 300 participants (150 T2DM patients and 150 healthy controls) recruited from Najaf, Iraq. Genotyping of LEPR rs1137101 was performed using allele-specific PCR, while biochemical parameters, including fasting blood glucose (FBG), insulin, lipid profile, HOMA-IR, and serum leptin levels, were measured using standard methods. Data were analyzed under different genetic inheritance models with adjustment for age, sex, and BMI. Results: The LEPR rs1137101 G allele was significantly associated with an increased risk of T2DM. Individuals with the GG genotype had a 4.9-fold increased risk (p < 0.0001; OR = 4.96, 95% CI = 2.26–10.90), and AG carriers had a 3.7-fold increased risk (p < 0.0001; OR = 3.70, 95% CI = 2.19–6.26) compared to AA homozygotes. The G allele also showed a strong association in dominant (OR = 3.95), over-dominant (OR = 2.47), and recessive models (OR = 2.48), indicating its robust link to T2DM susceptibility. Furthermore, GG carriers exhibited significantly elevated insulin, HOMA-IR, and leptin levels, suggesting a relationship with increased insulin resistance and altered leptin signaling. However, no significant differences were observed in BMI, FBG, or lipid profile between genotypes. Conclusion: The LEPR rs1137101 (A>G) polymorphism is strongly associated with T2DM in the Iraqi population.