Replication of the five novel loci for uric acid concentrations and potential mediating mechanisms

Uric acid (UA) is the final catabolic product of purine metabolism and elevated levels are associated with diabetes and cardiovascular disease. A recent meta-analysis of genome-wide association studies totalling 28 141 participants identified five novel loci associated with serum UA levels. In our population-based cohort of 7795 subjects, we replicated four of these five loci; PDZK1 (rs12129861, P = 1.07 x 10(-3)), glucokinase regulator protein (GCKR) (rs780094, P = 4.83 x 10(-4)), SLC16A9 (rs742132, P = 0.047) and SLC22A11 (rs17300741, P = 6.13 x 10(-3)), but not LRRC16A (rs742132, P = 0.645). Serum UA concentration is a complex trait, closely associated to renal UA handling (fractional UA excretion, P < 1 x 10(-300)), renal function (serum creatinine, P < 1 x 10(-300)) and the metabolic syndrome (including fasting insulin, P = 2.48 x 10(-232); insulin resistance, P = 2.51 x 10(-258); waist circumference, P < 1 x 10(-300)) and systolic blood pressure (P = 1.93 x 10(-219)). Together these factors explain 67% of the variance in UA levels. Therefore, we sought to determine the potential contribution of these factors to the association of these novel loci with UA levels, by including them as additional explanatory variables in our analyses, and by considering them as alternative response variables. The association with the GCKR locus is attenuated by serum triglycerides and fractional UA excretion. We also observed the GCKR locus to be associated with total cholesterol (P = 7.52 x 10(-6)), triglycerides (P = 2.65 x 10(-9)), fasting glucose (P = 0.011), fractional UA excretion (P = 3.36 x 10(-5)) and high-sensitive CRP (P = 1.18 x 10(-3)) also after adjusting for serum UA levels. We argue that GCKR locus affects serum UA levels through a factor that also affects triglycerides.