Elevated serum uric acid (UA) levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum UA levels, the authors conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum UA levels fall in the following nine regions: SLC22A11, SLC22A12 (chromosome 11), SLC16A9 (chromosome 10), LRRC16A, SLC17A1 (chromosome 6), SLC2A9, ABCG2 (chromosome 4), GCKR (chromosome 2) and near PDZK1 (chromosome 1). Identified variants were analyzed for gender differences. The authors found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering UA levels in women and the minor allele of rs2231142 in ABCG2 elevates UA levels more strongly in men compared to women. To further characterize the identified variants, their association with a panel of metabolites was analyzed. The minor allele of rs12356193 within SLC16A9 was associated with DL-carnitine and propionyl-L-carnitine concentrations, which in turn were associated with serum UA levels, forming a triangle between SNP, metabolites and UA levels. Taken together, these associations highlight pathways that are important in the regulation of serum UA levels and point towards novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum UA levels.
Kolz M, Johnson T, Sanna S, Teumer A, Vitart V, Perola M, Mangino M, Albrecht E, Wallace Chr, Farrall M, Johansson A, Nyholt DR, Aulchenko Y, Beckmann JS, Bergmann S, Bochud M, Brown M, Campbell H, Connell J, Dominiczak A, Homuth G, Lamina C, McCarthy MI, Meitinger T, Mooser V, Munroe P, Nauck M, Peden J, Prokisch H, Salo P, Salomaa V, Samani N, Schlessinger D, Uda M, Völker U, Waeber G, Waterworth D, Wang-Sattler R, Wright AF, Adamski J, Whitfield JB, Gyllensten U, Wilson JF, Rudan I, Pramstaller P, Watkins H, Doering A, Wichmann HE, Spector TD, Peltonen L, Völzke H, Nagaraja R, Vollenweider P, Caulfield M, Illig T, Gieger Chr. Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci that Influence Uric Acid Concentrations. PLoS Genetics 2009.