OBJECTIVE: Uric acid is the end product of purine metabolism in humans, and increased serum uric acid concentrations lead to gout. The objective of the current study was to identify factors that are independently associated with serum uric acid concentrations in a cohort of Czech control individuals. METHODS: The cohort consisted of 589 healthy subjects aged 18-65 years. We studied the associations between the serum uric acid concentration and the following: (i) demographic, anthropometric and other variables previously reported to be associated with serum uric acid concentrations; (ii) the presence of metabolic syndrome and the levels of metabolic syndrome components; and (iii) selected genetic variants of the MTHFR (c.665C>T, c.1286A>C), SLC2A9 (c.844G>A, c.881G>A) and ABCG2 genes (c.421C>A). A backward model selection procedure was used to build two multiple linear regression models; in the second model, the number of metabolic syndrome criteria that were met replaced the metabolic syndrome-related variables. RESULTS: The models had coefficients of determination of 0.59 and 0.53. The serum uric acid concentration strongly correlated with conventional determinants including male sex, and with metabolic syndrome-related variables. In the simplified second model, the serum uric acid concentration positively correlated with the number of metabolic syndrome criteria that were met, and this model retained the explanatory power of the first model. Moderate wine drinking did not increase serum uric acid concentrations, and the urate transporter ABCG2, unlike MTHFR, was a genetic determinant of serum uric acid concentrations. CONCLUSION: Metabolic syndrome, moderate wine drinking and the c.421C>A variant in the ABCG gene are independently associated with the serum uric acid concentration. Our model indicates that uric acid should be clinically monitored in persons with metabolic syndrome.

Institute of Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Prague Czech Republic

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Hayden MR, Tyagi SC (2004) Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: The urate redox shuttle. Nutr Metab (Lond) 1: 10. PubMed PMC

Heinig M, Johnson RJ (2006) Role of uric acid in hypertension, renal disease, and metabolic syndrome. Cleve Clin J Med 73: 1059–1064. PubMed

Onat A, Uyarel H, Hergenc G, Karabulut A, Albayrak S, et al. (2006) Serum uric acid is a determinant of metabolic syndrome in a population-based study. Am J Hypertens 19: 1055–1062. PubMed

Yang T, Chu CH, Bai CH, You SL, Chou YC, et al. (2012) Uric acid level as a risk marker for metabolic syndrome: a Chinese cohort study. Atherosclerosis 220: 525–531. PubMed

Houlihan LM, Wyatt ND, Harris SE, Hayward C, Gow AJ, et al. (2010) Variation in the uric acid transporter gene (SLC2A9) and memory performance. Hum Mol Genet 19: 2321–2330. PubMed

Davis JW, Grandinetti A, Waslien CI, Ross GW, White LR, et al. (1996) Observations on serum uric acid levels and the risk of idiopathic Parkinson's disease. Am J Epidemiol 144: 480–484. PubMed

De Vera M, Rahman MM, Rankin J, Kopec J, Gao X, et al. (2008) Gout and the risk of Parkinson's disease: a cohort study. Arthritis Rheum 59: 1549–1554. PubMed

Bengtsson C, Tibblin E (1974) Serum uric acid levels in women. An epidemiological survey with special reference to women with high serum uric acid values. Acta Med Scand 196: 93–102. PubMed

Wingrove CS, Walton C, Stevenson JC (1998) The effect of menopause on serum uric acid levels in non-obese healthy women. Metabolism 47: 435–438. PubMed

Rathmann W, Funkhouser E, Dyer AR, Roseman JM (1998) Relations of hyperuricemia with the various components of the insulin resistance syndrome in young black and white adults: the CARDIA study. Coronary Artery Risk Development in Young Adults. Ann Epidemiol 8: 250–261. PubMed

Meisinger C, Doring A, Stockl D, Thorand B, Kowall B, et al. (2012) Uric acid is more strongly associated with impaired glucose regulation in women than in men from the general population: the KORA F4-Study. PLoS One 7: e37180. PubMed PMC

Tang W, Miller MB, Rich SS, North KE, Pankow JS, et al. (2003) Linkage analysis of a composite factor for the multiple metabolic syndrome: the National Heart, Lung, and Blood Institute Family Heart Study. Diabetes 52: 2840–2847. PubMed

Wilk JB, Djousse L, Borecki I, Atwood LD, Hunt SC, et al. (2000) Segregation analysis of serum uric acid in the NHLBI Family Heart Study. Hum Genet 106: 355–359. PubMed

Nath SD, Voruganti VS, Arar NH, Thameem F, Lopez-Alvarenga JC, et al. (2007) Genome scan for determinants of serum uric acid variability. J Am Soc Nephrol 18: 3156–3163. PubMed

Yang Q, Guo CY, Cupples LA, Levy D, Wilson PW, et al. (2005) Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study. Metabolism 54: 1435–1441. PubMed

Faller J, Fox IH (1982) Ethanol-induced hyperuricemia: evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med 307: 1598–1602. PubMed

Puig JG, Fox IH (1984) Ethanol-induced activation of adenine nucleotide turnover. Evidence for a role of acetate. J Clin Invest 74: 936–941. PubMed PMC

Nakamura K, Sakurai M, Miura K, Morikawa Y, Yoshita K, et al. (2012) Alcohol intake and the risk of hyperuricaemia: a 6-year prospective study in Japanese men. Nutr Metab Cardiovasc Dis 22: 989–996. PubMed

Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, et al. (2002) Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 417: 447–452. PubMed

Stiburkova B, Sebesta I, Ichida K, Nakamura M, Hulkova H, et al. (2013) Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis. Eur J Hum Genet 21: 1067–1073. PubMed PMC

Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, et al. (2004) Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol 15: 164–173. PubMed

Doring A, Gieger C, Mehta D, Gohlke H, Prokisch H, et al. (2008) SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat Genet 40: 430–436. PubMed

Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, et al. (2008) SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 40: 437–442. PubMed

Caulfield MJ, Munroe PB, O'Neill D, Witkowska K, Charchar FJ, et al. (2008) SLC2A9 is a high-capacity urate transporter in humans. PLoS Med 5: e197. PubMed PMC

Matsuo H, Chiba T, Nagamori S, Nakayama A, Domoto H, et al. (2008) Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am J Hum Genet 83: 744–751. PubMed PMC

Stiburkova B, Ichida K, Sebesta I (2011) Novel homozygous insertion in SLC2A9 gene caused renal hypouricemia. Mol Genet Metab 102: 430–435. PubMed

Stiburkova B, Taylor J, Marinaki AM, Sebesta I (2012) Acute kidney injury in two children caused by renal hypouricaemia type 2. Pediatr Nephrol 27: 1411–1415. PubMed

Woodward OM, Kottgen A, Coresh J, Boerwinkle E, Guggino WB, et al. (2009) Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci U S A 106: 10338–10342. PubMed PMC

Golbahar J, Aminzadeh MA, Al-Shboul QM, Kassab S, Rezaian GR (2007) Association of methylenetetrahydrofolate reductase (C677T) polymorphism with hyperuricemia. Nutr Metab Cardiovasc Dis 17: 462–467. PubMed

Hong YS, Lee MJ, Kim KH, Lee SH, Lee YH, et al. (2004) The C677 mutation in methylene tetrahydrofolate reductase gene: correlation with uric acid and cardiovascular risk factors in elderly Korean men. J Korean Med Sci 19: 209–213. PubMed PMC

Itou S, Goto Y, Suzuki K, Kawai S, Naito M, et al. (2009) Significant association between methylenetetrahydrofolate reductase 677T allele and hyperuricemia among adult Japanese subjects. Nutr Res 29: 710–715. PubMed

Zuo M, Nishio H, Lee MJ, Maejima K, Mimura S, et al. (2000) The C677T mutation in the methylene tetrahydrofolate reductase gene increases serum uric acid in elderly men. J Hum Genet 45: 257–262. PubMed

Motti C, Gnasso A, Bernardini S, Massoud R, Pastore A, et al. (1998) Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine and other risk factors for vascular disease. Atherosclerosis 139: 377–383. PubMed

Janosikova B, Pavlikova M, Kocmanova D, Vitova A, Vesela K, et al. (2003) Genetic variants of homocysteine metabolizing enzymes and the risk of coronary artery disease. Mol Genet Metab 79: 167–175. PubMed

Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, et al. (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120: 1640–1645. PubMed

Alberti KG, Zimmet P, Shaw J (2006) Metabolic syndrome—a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 23: 469–480. PubMed

Choi HK, Curhan G (2004) Beer, liquor, and wine consumption and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 51: 1023–1029. PubMed

Kawamoto R, Kohara K, Tabara Y, Miki T, Doi T, et al. (2001) An association of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and common carotid atherosclerosis. J Hum Genet 46: 506–510. PubMed

Lwin H, Yokoyama T, Yoshiike N, Saito K, Yamamoto A, et al. (2006) Polymorphism of methylenetetrahydrofolate reductase gene (C677T MTHFR) is not a confounding factor of the relationship between serum uric acid level and the prevalence of hypertension in Japanese men. Circ J 70: 83–87. PubMed

Dehghan A, Kottgen A, Yang Q, Hwang SJ, Kao WL, et al. (2008) Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 372: 1953–1961. PubMed PMC

Hollis-Moffatt JE, Gow PJ, Harrison AA, Highton J, Jones PB, et al. (2011) The SLC2A9 nonsynonymous Arg265His variant and gout: evidence for a population-specific effect on severity. Arthritis Res Ther 13: R85. PubMed PMC

Tu HP, Chen CJ, Tovosia S, Ko AM, Lee CH, et al. (2010) Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese subjects and Solomon Islanders. Ann Rheum Dis 69: 887–890. PubMed

Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, et al. (2009) Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population. Sci Transl Med 1: 5ra11. PubMed

Yamagishi K, Tanigawa T, Kitamura A, Kottgen A, Folsom AR, et al. (2010) The rs2231142 variant of the ABCG2 gene is associated with uric acid levels and gout among Japanese people. Rheumatology (Oxford) 49: 1461–1465. PubMed

Phipps-Green AJ, Hollis-Moffatt JE, Dalbeth N, Merriman ME, Topless R, et al. (2010) A strong role for the ABCG2 gene in susceptibility to gout in New Zealand Pacific Island and Caucasian, but not Maori, case and control sample sets. Hum Mol Genet 19: 4813–4819. PubMed

Karns R, Zhang G, Sun G, Rao Indugula S, Cheng H, et al. (2012) Genome-wide association of serum uric acid concentration: replication of sequence variants in an island population of the Adriatic coast of Croatia. Ann Hum Genet 76: 121–127. PubMed PMC

Urano W, Taniguchi A, Anzai N, Inoue E, Sekita C, et al. (2010) Association between GLUT9 and gout in Japanese men. Ann Rheum Dis 69: 932–933. PubMed

Onat A, Can G, Ornek E, Altay S, Yuksel M, et al. (2013) Elevated serum uric acid in nondiabetic people mark pro-inflammatory state and HDL dysfunction and independently predicts coronary disease. Clin Rheumatol 32: 1767–1775. PubMed

Alderman M (1999) Uric acid in hypertension and cardiovascular disease. Can J Cardiol 15 Suppl F: 20F–22F. PubMed

Nakashima M, Uematsu T, Kosuge K, Kanamaru M (1992) Pilot study of the uricosuric effect of DuP-753, a new angiotensin II receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 42: 333–335. PubMed

Stiburkova B, Bleyer AJ (2012) Changes in serum urate and urate excretion with age. Adv Chronic Kidney Dis 19: 372–376. PubMed