Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

Abstract

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

Genomics and metabolomics of muscular mass in a community-based sample of UK females

“…38 Strong association of serum urate concentrations with SLC2A9 was reported in previous studies and is in good agreement with our present findings. 19,34,39 It should be mentioned that although the last two studies used also twin's sample, we compared our results with the estimates obtained in the independent KORA sample also reported in these two papers. Finally, we found that mannose was significantly associated with protein coding GCKR (glucokinase (hexokinase 4) regulator) gene, which is also in a good agreement with previously published work.…”

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

“…Importantly, our study validated an association of chromosome 12q24.12. This locus was reported to be associated with CAD, 5 intracranial aneurysm, 14 ischemic stroke, 15 blood pressure, 16 kidney function, 17 type 1 diabetes, 18 serum urate 19 and lipid concentration, 20 and drinking behavior, 21 suggesting that this locus is an important genetic component of cardiovascular diseases and their risk factors. Because top associated SNP (rs3782886:A4G) is closely linked to two functional variants in this region (rs671:A4G in ALDH2 and rs11066001:C4T in BRAP), 22 we confirmed that the risk haplotype, which contains several functional variants, will affect the susceptibility of cardiovascular disease and its risk factors.…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…Therefore, rs12356193 is suggested to have an indirect effect on urate excretion through aberrant carnitine levels 50. A contribution of the missense variant rs2242206 (close to the previously identified intronic variant) to the risk of gout could be found only for renal overload gout in Japanese individuals, in contrast to renal underexcretion gout54 or all gout susceptibility in Europeans,51 indicating impaired intestinal urate excretion. The functional mechanisms and the clinical relevance of MCT9 and its contribution to the variability of SUA and the susceptibility to resulting diseases, especially gout, are, therefore, not fully clarified and need further investigations.…”

“…In a meta‐analysis of 14 genomewide association studies50 as well as in replication studies51, 52 a single‐nucleotide polymorphism (SNP; rs12356193) within the SLC16A9 gene was identified as a factor contributing to the variability of SUA levels. The variant correlated also to DL‐carnitine and propionyl‐L‐carnitine levels, which, in turn, were strongly associated with SUA.…”