Abstract
BACKGROUND: Genetic background affects serum urate concentration and gout risk, especially regarding these variants in the urate-transporter gene ABCG2. However, the role of epistasis between PKD2 and ABCG2 on the pathogenesis of gout is poorly understood. Here we assess this epistatic interaction in the progression from elevated serum urate to gout. RESULTS: We identified two epistatic interaction pairs (rs2728121: rs1481012 and rs2728121: rs2231137) were associated with urate levels in 4914 Chinese individuals (P(int) = 0.018 and 0.004, respectively). Using subgroup analysis for gender and BMI, we found the degree of associations was varied by gender and BMI. The SNP pair rs2728121:rs1481012 influenced urate levels in females and overweight subjects (P(int) = 0.006 and 0.022, respectively), but rs2728121:rs2231137 did in males, overweight and normal-weight subjects (P(int) = 0.017, 0.047 and 0.013, respectively). Consistent results were also observed in associations between these epistatic interactions with hyperuricemia. Next, the SNP pair rs2728121:rs2231137 was identified to influence the development of gout from both hyperuricemia and healthy (P(int) = 0.035 and 0.001, respectively), especially in males (P(int) = 0.030 and 0.001, respectively). Furthermore, we demonstrated that interacting regions were enriched by regulatory elements. Finally, we observed a strong gene co-expression pattern between PKD2 and ABCG2 (r = 0.743, P = 5.83E-06). CONCLUSION: Our findings indicate epistasis between PKD2 and ABCG2 influence serum urate concentrations, hyperuricemia and gout risk, thus providing insight into the pathogenesis of gout.