Additive Association of ABCG2 rs4148155 and SLC22A12 rs75786299 Polymorphisms with Hyperuricemia, Gout, and Nephrolithiasis: A Hospital-Based, Case-Control Study

Introduction: This study aimed to investigate the interaction between the ABCG2 rs4148155 and SLC22A12 rs75786299 variants and their association with incident gout and nephrolithiasis in the Taiwanese population to better understand the genetic loci regulating hyperuricemia and their contribution to nephrolithiasis development. Methods: This retrospective case-control study involved 35,280 adults from the Taiwan Precise Medicine Initiative database. We examined the prevalence of gout and ultrasound confirmed nephrolithiasis as the primary and secondary outcome. Logistic regression models were used to explore the associations between genetic variants, serum uric acid levels, incident gout, and nephrolithiasis. Results: The frequencies of the rs4148155 variant and the rs75786299 variant were 63.2% and 3.7%, respectively. Among participants, 7,056 were gout, and 4,110 had nephrolithiasis. Multivariable odds ratios (ORs) for gout were 1.67 and 1.96 among rs4148155 and rs75786299 carriers, respectively (p = 0.01 and p < 0.001). For nephrolithiasis, the multivariable ORs were 1.1 and 1.11 for rs4148155 and rs75786299 carriers, respectively (p = 0.004 and p = 0.32). Sex-stratified analysis revealed an additive risk of gout and nephrolithiasis among carriers of these genetic variants, regardless of gender. Independent risk factors for nephrolithiasis included higher age, male gender, and the presence of gout, hypertension, and hyperlipidemia. Conclusion: The study highlights a significant association between the rs4148155, rs75786299 variants and the development of gout and nephrolithiasis, indicating an additive risk among carriers. These findings support precision healthcare approaches for individuals with risk genetic variants to target hyperuricemia, gout, and systemic comorbidities, ultimately preventing nephrolithiasis.