Human Molecular Genetics Advance Access [Accepted Manuscript] published online on October 27, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp489
Replication of the 5 Novel Loci for Uric Acid Concentrations and Potential Mediating Mechanisms
1 The Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 2 The Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 3 The Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 4 The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ 5 The Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
* corresponding author: Dr. P. van der Harst, Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RB Groningen, The Netherlands, Phone: +31 (0)50 3612355; Fax: +31 (0)50 3614391; e-mail; p.van.der.harst{at}thorax.umcg.nl
Received July 29, 2009; Revised October 10, 2009; Accepted October 20, 2009
Uric acid 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 5 novel loci associated with serum uric acid levels. In our population based cohort of 7,795 subjects we replicated 4 of these 5 loci; PDZK1 (rs12129861 P=1.07x10–3), GCKR (rs780094 P=4.83x10–4), SLC16A9 (rs742132 P=0.047), and SLC22A11 (rs17300741 P=6.13x10–3), but not LRRC16A (rs742132 P=0.645). Serum uric acid concentration is a complex trait, closely associated to renal uric acid handling (fractional uric acid excretion; P< 1 x 10–300), renal function (serum creatinine; P< 1 x 10–300), and the metabolic syndrome (including fasting insulin; P=2.48x10–232, insulin resistance; P=2.51x10–258, 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 uric acid levels. Therefore, we sought to determine the potential contribution of these factors to the association of these novel loci with uric acid 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 uric acid excretion. We also observed the GCKR locus to be associated with total cholesterol (P= 7.52x10–6), triglycerides (P=2.65x10–9), fasting glucose (P=0.011), fractional uric acid excretion (P=3.36 x10–5), and high-sensitive CRP (P=1.18x10–3) also after adjusting for serum UA levels. We argue that GCKR locus affects serum UA levels through a factor that also affects triglycerides.