Molecular Genetics of Hyperuricaemia and Gout


Gout results from an innate immune reaction to monosodium urate crystals deposited in the joints of individuals with elevated serum urate levels (hyperuricaemia). Urate, the primary cause of gout, is a metabolite with beneficial properties. The use of genome‐wide association scanning has identified 28 loci that control serum urate levels. Predominant among these are loci containing uric acid transporter genes involved in renal and gut excretion of uric acid. The SLC2A9 (GLUT9) and ABCG2 genes have particularly strong effects on serum urate and risk of gout. In contrast to serum urate, the genetic control of inflammatory gout is very poorly understood, largely because no genome‐wide association scan has been conducted using clinically ascertained gout cases. Similarly, the full‐scope of the beneficial (or harmful) properties of urate is currently unknown; a genetic technique called Mendelian randomisation is being employed to better understand the relationship between urate and other metabolic conditions.

Key Concepts:

  • Urate is evolutionarily beneficial.

  • Urate is under genetic control.

  • Genetic variants in genes involved in the excretion of uric acid have the strongest effect on serum urate.

  • A total of 28 loci have been associated with control of serum urate.

  • Not all genes associated with serum urate have been associated with gout.

  • There are no genes associated with inflammatory gout with robust statistical evidence.

Keywords: urate; gout; gene; association; single‐nucleotide polymorphism; genome‐wide association study; SLC2A9; ABCG2; mendelian randomisation

Figure 1.

Current knowledge of urate transporters within the apical membrane of the kidney proximal tubule. Transporters are labelled using their protein names, those mentioned in the text under their gene names are: SLC2A9 (two isoforms SLC2A9a (GLUT9L), SLC2A9b (GLUT9S)), SLC17A1 (NPT1), SLC22A11 (OAT4), SLC22A12 (URAT1) and SLC22A7 (OAT2).



Ames BN, Cathcart R, Schwiers E and Hochstein P (1981) Uric acid provides an antioxidant defense in humans against oxidant‐ and radical‐caused aging and cancer: a hypothesis. Proceedings of the National Academy of Sciences of the USA 78(11): 6858–6862.

Anzai N and Endou H (2011) Urate transporters: an evolving field. Seminars in Nephrology 31(5): 400–409.

Batt C, Phipps‐Green AJ, Black MA et al. (2013) Sugar‐sweetened beverage consumption: a risk factor for prevalent gout with slc2a9 genotype‐specific effects on serum urate and risk of gout. Annals of the Rheumatic Diseases (in press)

Campion EW, Glynn RJ and DeLabry LO (1987) Asymptomatic hyperuricemia. Risks and consequences in the normative aging study. American Journal of Medicine 82(3): 421–426.

Caulfield MJ, Munroe PB, O'Neill D et al. (2008) SLC2A9 is a high‐capacity urate transporter in humans. PLoS Medicine 5(10): e197.

Choi JW, Ford ES, Gao X and Choi HK (2008) Sugar‐sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis and Rheumatism 59(1): 109–116.

Dalbeth N, House ME, Gamble GD et al. (2013) Population‐specific influence of SLC2A9 genotype on the acute hyperuricaemic response to a fructose load. Annals of the Rheumatic Diseases. DOI: 10.1136/annrheumdis-2013-203767.

Doring A, Gieger C, Mehta D et al. (2008) SLC2A9 influences uric acid concentrations with pronounced sex‐specific effects. Nature Genetics 40(4): 430–436.

Emmerson BT, Nagel SL, Duffy DL and Martin NG (1992) Genetic control of the renal clearance of urate: a study of twins. Annals of the Rheumatic Diseases 51(3): 375–377.

Euser SM, Hofman A, Westendorp RG and Breteler MM (2009) Serum uric acid and cognitive function and dementia. Brain 132(Pt 2): 377–382.

Ghaemi‐Oskouie F and Shi Y (2011) The role of uric acid as an endogenous danger signal in immunity and inflammation. Current Rheumatology Reports 13(2): 160–166.

Ghiringhelli F, Apetoh L, Tesniere A et al. (2009) Activation of the NLRP3 inflammasome in dendritic cells induces IL‐1beta‐dependent adaptive immunity against tumors. Nature Medicine 15(10): 1170–1178.

Hagos Y, Stein D, Ugele B, Burckhardt G and Bahn A (2007) Human renal organic anion transporter 4 operates as an asymmetric urate transporter. Journal of the American Society of Nephrology 18(2): 430–439.

van der Harst P, Bakker SJ, de Boer RA et al. (2010) Replication of the five novel loci for uric acid concentrations and potential mediating mechanisms. Human Molecular Genetics 19(2): 387–395.

Hollis‐Moffatt JE, Phipps‐Green AJ, Chapman B et al. (2012) The renal urate transporter SLC17A1 locus: confirmation of association with gout. Arthritis Research and Therapy 14(2): R92.

Hollis‐Moffatt JE, Xu X, Dalbeth N et al. (2009) Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Maori, Pacific Island, and Caucasian case–control sample sets. Arthritis and Rheumatism 60(11): 3485–3492.

Hughes K, Flynn T, de Zoysa J et al. (2013) Use of Mendelian randomization associates increased uric acid caused by genetic variation in uric acid transporters with improved renal function. Kidney International (in press).

Ichida K, Matsuo H, Takada T et al. (2012) Decreased extra‐renal urate excretion is a common cause of hyperuricemia. Nature Communications 3: 764.

Johnson R, Lanaspa M and Gaucher E (2011) Uric acid: a danger signal from the RNA world that may have a role in the epidemic of obesity, metabolic syndrome, and cardiorenal disease: evolutionary considerations. Seminars in Nephrology 31(5): 394–399.

Kamatani Y, Matsuda K, Okada Y et al. (2010) Genome‐wide association study of hematological and biochemical traits in a Japanese population. Nature Genetics 42: 210–215.

Kolz M, Johnson T, Sanna S et al. (2009) Meta‐analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genetics 5(6): e1000504.

Köttgen A, Albrecht E, Teumer A et al. (2013) Genome‐wide association analyses identify 18 new loci associated with serum urate concentrations. Nature Genetics 45(2): 145–154.

Krishnan E, Lessov‐Schlaggar CN, Krasnow RE and Swan GE (2012) Nature versus nurture in gout: a twin study. American Journal of Medicine 125(5): 499–504.

Kuo C‐F, Grainge M, See L‐C et al. (2012) Familial Aggregation and heritability of gout in Taiwan: a nationwide population study. Arthritis and Rheumatism 64(S10): S355.

Lyngdoh T, Vuistiner P, Marques‐Vidal P et al. (2012) Serum uric acid and adiposity: deciphering causality using a bidirectional Mendelian randomization approach. PLoS One 7(6): e39321.

McAdams‐DeMarco MA, Maynard JW, Baer AN et al. (2013) A urate gene‐by‐diuretic interaction and gout risk in participants with hypertension: results from the ARIC study. Annals of the Rheumatic Diseases 72(5): 701–706.

McKeigue P, Campbell H, Wild S et al. (2010) Bayesian methods for instrumental variable analysis with genetic instruments (‘Mendelian randomization’): example with urate transporter SLC2A9 as an instrumental variable for effect of urate levels on metabolic syndrome. International Journal of Epidemiology 39(3): 907–918.

Merriman TR (2011) Population heterogeneity in the genetic control of serum urate. Seminars in Nephrology 31(5): 420–425.

Merriman TR and Dalbeth N (2011) The genetic basis of hyperuricaemia and gout. Joint Bone Spine 78(1): 35–40.

Oda M, Satta Y, Takenaka O and Takahata N (2002) Loss of urate oxidase activity in hominoids and its evolutionary implications. Molecular Biology of Evolution 19(5): 640–653.

Ohta Y and Nishikimi M (1999) Random nucleotide substitutions in primate nonfunctional gene for L‐gulono‐gamma‐lactone oxidase, the missing enzyme in L‐ascorbic acid biosynthesis. Biochimica et Biophysica Acta – General Subjects 1472(1–2): 408–411.

Parsa A, Brown E, Weir MR et al. (2012) Genotype‐based changes in serum uric acid affect blood pressure. Kidney International 81(5): 502–507.

Pfister R, Barnes D, Luben R et al. (2011) No evidence for a causal link between uric acid and type 2 diabetes: a Mendelian randomisation approach. Diabetologia 54: 2561–2569.

Pieper‐Furst U and Lammert F (2013) Low‐density lipoprotein receptors in liver: Old acquaintances and a newcomer. Biochimica et Biophysica Acta – Molecular and Cell Biology of Lipids 1831(7): 1191–1198.

Roessler B, Nosal J, Smith P et al. (1993) Human X‐linked phosphoribosylpyrophosphate synthetase superactivity is associated with distinct point mutations in the PRPS1 gene. Journal of Biological Chemistry 268(35): 26476–26481.

Sonestedt E, Overby N, Laaksonen D and Birgisdottir BE (2012) Does high sugar consumption exacerbate cardiometabolic risk factors and increase the risk of type 2 diabetes and cardiovascular disease? Food and Nutrition Research 56. DOI: 10.3402/fnr.v56i0.19104.

Stark K, Reinhard W, Grassl M et al. (2009) Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 4(11): e7729.

Sulem P, Gudbjartsson DF, Walters GB et al. (2011) Identification of low‐frequency variants associated with gout and serum uric acid levels. Nature Genetics 43(11): 1127–1130.

Takeuchi F, Yamamoto K, Isono M et al. (2013) Genetic impact on uric acid concentration and hyperuricemia in the Japanese population. Journal of Atherosclerosis and Thrombosis 20: 351–367.

Taniguchi A and Kamatani N (2008) Control of renal uric acid excretion and gout. Current Opinions in Rheumatology 20(2): 192–197.

Tu HP, Chen CJ, Tovosia S et al. (2010) Associations of a nonsynonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese and Solomon Islanders. Annals of the Rheumatic Diseases 69: 887–890.

Urano W, Taniguchi A, Anzai N et al. (2010a) Association between GLUT9 and gout in Japanese men. Annals of the Rheumatic Diseases 69: 932–933.

Urano W, Taniguchi A, Anzai N et al. (2010b) Sodium‐dependent phosphate cotransporter type 1 sequence polymorphisms in male patients with gout. Annals of the Rheumatic Diseases 69(6): 1232–1234.

Urano W, Taniguchi A, Inoue E et al. (2013) Effect of genetic polymorphisms on development of gout. Journal of Rheumatology 40(8): 1374–1378.

Vaxillaire M, Cavalcanti‐Proenca C, Dechaume A et al. (2008) The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population. Diabetes 57(8): 2253–2257.

Vitart V, Rudan I, Hayward C et al. (2008) SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nature Genetics 40(4): 437–442.

Wang J, Liu S, Wang B et al. (2012) Association between gout and polymorphisms in GCKR in male Han Chinese. Human Genetics 131: 1261–1265.

Witkowska K, Smith KM, Yao SYM et al. (2012) Human SLC2A9a and SLC2A9b isoforms mediate electrogenic transport of urate with different characteristics in the presence of hexoses. American Journal of Physiology – Renal Physiology 303(4): F527–F539.

Woodward OM, Köttgen A, Coresh J et al. (2009) Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proceedings of the National Academy of Sciences USA 106(25): 10338–10342.

Woodward OM, Tukaye DN, Cui J et al. (2013) Gout‐causing Q141K mutation in ABCG2 leads to instability of the nucleotide‐binding domain and can be corrected with small molecules. Proceedings of the National Academy of Sciences of the USA 110(13): 5223–5228.

Yamanaka H, Kamatani N, Hakoda M et al. (1994) Analysis of the genotypes for aldehyde dehydrogenase 2 in Japanese patients with primary gout. Advances in Experimental Medicine and Biology 370: 53–56.

Yang Q, Köttgen A, Dehghan A et al. (2010) Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circulation: Cardiovascular Genetics 3(6): 523–530.

Further reading

Anzai N, Jutabha P, Kimura T et al. (2011) Urate transport: regulators of serum urate levels in humans. Current Rheumatology Reviews 7(2): 123–131.

Bhattacharjee S (2009) A brief history of gout. International Journal of Rheumatic Diseases 12(1): 61–63.

Dalbeth N and Merriman TR (2013) Hyperuricemia and gout. In: Valle D (in‐Chief), Beaudet A, Vogelstein B, Kinzler K, Antonarakis S and Ballabio A (eds) The Online Metabolic and Molecular Bases of Inherited Disease.

Mackenbach JP (2006) The origins of human disease: a short story on “where diseases come from”. Journal of Epidemiology & Community Health 60(1): 81–86.

Maniolo TA, Collins FS, Cox NJ et al. (2009) Finding the missing heritability of complex diseases. Nature 461: 747–753.

Richette P and Bardin T (2010) Gout. Lancet 375: 318–328.

Roddy E, Zhang W and Donerty M (2007) The changing epidemiology of gout. Nature Clinical Practice in Rheumatology 3: 443–449.

Singh JA, Reddy SG and Kundukulam J (2011) Risk factors for gout and prevention: a systematic review of the literature. Current Opinion in Rheumatology 23: 192–202.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Merriman, Tony R, and Flynn, Tanya J(Oct 2013) Molecular Genetics of Hyperuricaemia and Gout. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025153]