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Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.

ABSTRACT: 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 ?mol/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.

SUBMITTER: Yang Q

PROVIDER: S-EPMC3371395 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.

Yang Qiong Q Köttgen Anna A Dehghan Abbas A Smith Albert V AV Glazer Nicole L NL Chen Ming-Huei MH Chasman Daniel I DI Aspelund Thor T Eiriksdottir Gudny G Harris Tamara B TB Launer Lenore L Nalls Michael M Hernandez Dena D Arking Dan E DE Boerwinkle Eric E Grove Megan L ML Li Man M Linda Kao W H WH Chonchol Michel M Haritunians Talin T Li Guo G Lumley Thomas T Psaty Bruce M BM Shlipak Michael M Hwang Shih-Jen SJ Larson Martin G MG O'Donnell Christopher J CJ Upadhyay Ashish A van Duijn Cornelia M CM Hofman Albert A Rivadeneira Fernando F Stricker Bruno B Uitterlinden Andre G AG Paré Guillaume G Parker Alex N AN Ridker Paul M PM Siscovick David S DS Gudnason Vilmundur V Witteman Jacqueline C JC Fox Caroline S CS Coresh Josef J

Circulation. Cardiovascular genetics 20100930 6

<h4>Background</h4>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).<h4>Methods and results</h4>Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-ba ...[more]

PMID: 20884846

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Project description:BackgroundPrevious studies have noted significant variation in serum urate (sUA) levels, and it is unknown how this influences the accuracy of hyperuricemia classification based on single data points. Despite this known variability, hyperuricemic patients are often used as a control group in gout studies. Our objective was to determine the accuracy of hyperuricemia classifications based on single data points versus multiple data points given the degree of variability observed with serial measurements of sUA.MethodsData was analyzed from a cross-over clinical trial of urate-lowering therapy in young adults without a gout diagnosis. In the control phase, sUA levels used for this analysis were collected at 2-4 week intervals. Mean coefficient of variation for sUA was determined, as were rates of conversion between normouricemia (sUA ≤6.8 mg/dL) and hyperuricemia (sUA > 6.8 mg/dL).ResultsMean study participant (n = 85) age was 27.8 ± 7.0 years, with 39% female participants and 41% African-American participants. Mean sUA coefficient of variation was 8.5% ± 4.9% (1 to 23%). There was no significant difference in variation between men and women, or between participants initially normouricemic and those who were initially hyperuricemic. Among those initially normouricemic (n = 72), 21% converted to hyperuricemia during at least one subsequent measurement. The subgroup with initial sUA < 6.0 (n = 54) was much less likely to have future values in the range of hyperuricemia compared to the group with screening sUA values between 6.0-6.8 (n = 18) (7% vs 39%, p = 0.0037). Of the participants initially hyperuricemic (n = 13), 46% were later normouricemic during at least one measurement.ConclusionSingle sUA measurements were unreliable in hyperuricemia classification due to spontaneous variation. Knowing this, if a single measurement must be used in classification, it is worth noting that those with an sUA of < 6.0 mg/dL were less likely to demonstrate future hyperuricemic measurements and this could be considered a safer threshold to rule out intermittent hyperuricemia based on a single measurement point.Trial registrationData from parent study ClinicalTrials.gov Identifier: NCT02038179 .

Dataset Information

Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.

Publications

Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.

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