Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.
Yang Q., Köttgen A., Dehghan A., Smith AV., Glazer NL., Chen M-H., Chasman DI., Aspelund T., Eiriksdottir G., Harris TB., Launer L., Nalls M., Hernandez D., Arking DE., Boerwinkle E., Grove ML., Li M., Linda Kao WH., Chonchol M., Haritunians T., Li G., Lumley T., Psaty BM., Shlipak M., Hwang S-J., Larson MG., O'Donnell CJ., Upadhyay A., van Duijn CM., Hofman A., Rivadeneira F., Stricker B., Uitterlinden AG., Paré G., Parker AN., Ridker PM., Siscovick DS., Gudnason V., Witteman JC., Fox CS., Coresh J.
BACKGROUND:Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD). METHODS AND RESULTS:Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study. CONCLUSIONS:The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.