Genetic and computational analysis of AKR1C4 gene rs17134592 polymorphism in breast cancer among the Bangladeshi population.

Abstract

Breast cancer is characterized by the unchecked proliferation of breast cells. Variations in the metabolism of steroid hormones can influence the risk of this disease by modifying the concentration and the potency of these hormones. The enzyme AKR1C4, primarily found in the liver, is crucial for regulating these hormone levels in the bloodstream. This research examined the relationship between a polymorphic variant (rs17134592) of the AKR1C4 gene and the susceptibility to breast cancer among the Bangladeshi population. A case-control study was conducted with 310 breast cancer patients and 310 healthy individuals from Bangladesh. DNA was extracted using an organic process, followed by genotyping through the PCR-RFLP technique. To validate the accuracy of genotyping results, a subset of PCR products was randomly selected and confirmed using Sanger sequencing. Statistical assessments were conducted to analyze the association of polymorphism, while molecular dynamics simulation and diverse computational methods were employed to predict the structural and functional impacts of the SNP. The results indicate that rs17134592 in the AKR1C4 gene is linked with a heightened risk for breast cancer (p < 0.0001, OR = 3.39, 95% CI = 1.80 to 6.50 for the GG genotype in additive model 2). The recessive model (GG vs. CC + CG) also showed an enhanced risk of susceptibility to breast malignancy (p < 0.0001, OR = 3.25, 95% CI = 1.78 to 6.08). In the subgroup of post-menopausal women, the risk of developing breast cancer was significantly higher for carriers of the GG genotype, with relative risks of 4.02 and 3.92, in the additive model 2 and recessive model, respectively. However, no significant correlations were observed between these genotypes and tumor grade or size in breast cancer patients. Computational analysis suggested that the L311V mutation (rs17134592) could potentially reduce the stability of the protein. Additionally, molecular dynamics simulations indicated that the L311V mutation introduces notable conformational instability to the AKR1C4 enzyme, potentially impacting its biological functionality and catalytic efficiency. In conclusion, the genetic variant rs17134592 has been identified as significantly correlated with the prevalence of breast cancer in the Bangladeshi population. Computational studies suggest that the L311V mutation in the AKR1C4 gene, corresponding to rs17134592, results in marked conformational instability and changes in enzyme functionality.