Assessment of the Frequency and Clinical-pathogenetic Significance of the PDZK1 (PDZ Domain Containing 1) Gene and Its Polymorphism (rs3753581) in Patients with Gout: Sex-specific Analysis with Emphasis on Women

Abstract

Gout is a chronic multifactorial metabolic and inflammatory disease characterised by persistent hyperuricaemia, deposition of monosodium urate crystals in tissues and joints, recurrent inflammatory arthritis, and progressive renal and cardiovascular complications. Increasing attention has been directed towards the role of genetic factors in uric acid metabolism, particularly genes that regulate renal urate transport systems. Among these genes, PDZK1 has an important role because it regulates transporter proteins such as URAT1, GLUT9, ABCG2, and OAT4, which are involved in uric acid reabsorption and excretion. Functional disturbances and polymorphic variants of PDZK1 may impair urate homeostasis and contribute to hyperuricaemia and gout, especially in women, in whom hormonal changes also influence urate metabolism. This study aimed to evaluate the frequency of the PDZK1 (rs3753581) gene polymorphism in women with gout and determine its clinical and pathogenetic significance through comparison with male patients. The study included 102 women and 100 men diagnosed with gout according to established clinical criteria, 101 women with asymptomatic hyperuricaemia, and 20 apparently healthy women as the control group. All participants were examined in the clinics of Tashkent Medical Academy between 2021 and 2025. Molecular genetic analysis was performed using polymerase chain reaction (PCR)-based genotyping. DNA samples isolated from peripheral blood leucocytes were analysed to identify PDZK1 rs3753581 polymorphic variants and evaluate their associations with clinical manifestations and laboratory indicators. The results showed that the G/G genotype was significantly more common in women with gout and was associated with a more severe clinical phenotype, including higher serum uric acid levels, more frequent acute gout attacks, stronger pain syndrome, a greater number of tophi, and signs of nephropathy and impaired renal function. Correlation analysis revealed significant positive associations between the G/G genotype and the severity of hyperuricaemia, suggesting that this polymorphic variant may contribute to impaired uric acid excretion and enhanced inflammatory activity. In contrast, the A/A genotype was detected predominantly in healthy women and in patients with asymptomatic hyperuricaemia, suggesting a potential protective effect against progression to clinically manifest gout and severe metabolic complications. PDZK1 gene expression also showed statistically significant correlations with serum uric acid concentration, creatinine levels, glomerular filtration rate (GFR), and atherogenic index.