Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The genetics of hyperuricaemia and gout

Abstract

Gout is a common and very painful inflammatory arthritis caused by hyperuricaemia. This Review provides an update on the genetics of hyperuricaemia and gout, including findings from genome-wide association studies. Most of the genes that associated with serum uric acid levels or gout are involved in the renal urate-transport system. For example, the urate transporter genes SLC2A9, ABCG2 and SLC22A12 modulate serum uric acid levels and gout risk. The net balance between renal urate absorption and secretion is a major determinant of serum uric acid concentration and loss-of-function mutations in SLC2A9 and SLC22A12 cause hereditary hypouricaemia due to reduced urate absorption and unopposed urate secretion. However, the variance in serum uric acid explained by genetic variants is small and their clinical utility for gout risk prediction seems limited because serum uric acid levels effectively predict gout risk. Urate-associated genes and genetically determined serum uric acid levels were largely unassociated with cardiovascular–metabolic outcomes, challenging the hypothesis of a causal role of serum uric acid in the development of cardiovascular disease. Strong pharmacogenetic associations between HLA-B*5801 alleles and severe allopurinol-hypersensitivity reactions were shown in Asian and European populations. Genetic testing for HLA-B*5801 alleles could be used to predict these potentially fatal adverse effects.

Key Points

  • The majority of the genes that associate with hyperuricaemia and gout in genome-wide association studies have been implicated in the renal urate-transport system

  • Genetic variation explains only a modest level of variance in serum uric acid levels (6%)

  • Serum uric acid levels are determined by the net balance between urate absorption and secretion, which is mediated by separate sets of transporters in the renal proximal tubule

  • The clinical utility of testing for urate-associated genes seems limited because serum urate levels themselves can effectively predict gout risk at a low cost

  • Urate-associated genes and genetically determined urate levels have been largely unassociated with cardiovascular or metabolic outcomes, suggesting that serum uric acid does not have a causal role in these outcomes

  • Strong pharmacogenetic associations between HLA-B*5801 alleles and severe allopurinol-hypersensitivity reactions have been shown in Asian and European populations, suggesting clinical utility of testing for these alleles

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Genetic variants implicated in the pathogenesis of hyperuricaemia or gout.
Figure 2: The uric acid transportasome.
Figure 3: The pathogenesis of hyperuricaemia and gout.

References

  1. 1

    Zhu, Y., Pandya, B. J. & Choi, H. K. Prevalence of gout and hyperuricaemia in the US general population: The National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum. 63, 3136–3141 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2

    Choi, H. K., Mount, D. B., Reginato, A. M., American College of Physicians & American Physiological Society. Pathogenesis of gout. Ann. Intern. Med. 143, 499–516 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. 3

    Wu, E. Q. et al. Disease-related and all-cause health care costs of elderly patients with gout. J. Manag. Care Pharm. 14, 164–175 (2008).

    PubMed  Google Scholar 

  4. 4

    Choi, H. K., Ford, E. S., Li, C. & Curhan, G. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 57, 109–115 (2007).

    Article  PubMed  Google Scholar 

  5. 5

    Abbott, R. D., Brand, F. N., Kannel, W. B. & Castelli, W. P. Gout and coronary heart disease: the Framingham Study. J. Clin. Epidemiol. 41, 237–242 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. 6

    Krishnan, E., Baker, J. F., Furst, D. E. & Schumacher, H. R. Gout and the risk of acute myocardial infarction. Arthritis Rheum. 54, 2688–2696 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. 7

    Choi, H. K. & Curhan, G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation 116, 894–900 (2007).

    Article  PubMed  Google Scholar 

  8. 8

    Choi, H. K., De Vera, M. A. & Krishnan, E. Gout and the risk of type 2 diabetes among men with a high cardiovascular risk profile. Rheumatology (Oxford) 47, 1567–1570 (2008).

    Article  CAS  Google Scholar 

  9. 9

    Syndenham, T. The Works of Thomas Sydndenham, MD on Acute and Chronic Diseases. A Treatise of the Gout and Dropsy. Vol II. (G. J. & J. Robinson, London, 1853).

    Google Scholar 

  10. 10

    Page, T. & Nyhan, W. L. The spectrum of HPRT deficiency: an update. Adv. Exp. Med. Biol. 253A, 129–133 (1989).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Mateos, E. A. & Puig, J. G. Purine metabolism in Lesch–Nyhan syndrome versus Kelley–Seegmiller syndrome. J. Inherit. Metab. Dis. 17, 138–142 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. 12

    Mineo, I. et al. Myogenic hyperuricaemia. A common pathophysiologic feature of glycogenosis types III, V, and VII. N. Engl. J. Med. 317, 75–80 (1987).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    Sulem, P. et al. Identification of low-frequency variants associated with gout and serum uric acid levels. Nat. Genet. 43, 1127–1130 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Vora, S., DiMauro, S., Spear, D., Harker, D. & Danon, M. J. Characterization of the enzymatic defect in late-onset muscle phosphofructokinase deficiency. New subtype of glycogen storage disease type VII. J. Clin. Invest. 80, 1479–1485 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Sabina, R. L. et al. Myoadenylate deaminase deficiency. Functional and metabolic abnormalities associated with disruption of the purine nucleotide cycle. J. Clin. Invest. 73, 720–730 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Davidson-Mundt, A., Luder, A. S. & Greene, C. L. Hyperuricaemia in medium-chain acyl-coenzyme A dehydrogenase deficiency. J. Pediatr. 120, 444–446 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Perheentupa, J. & Raivio, K. Fructose-induced hyperuricaemia. Lancet 2, 528–531 (1967).

    Article  CAS  PubMed  Google Scholar 

  18. 18

    Vyletal, P. et al. Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome. Kidney Int. 70, 1155–1169 (2006).

    Article  CAS  Google Scholar 

  19. 19

    Vyletal, P., Bleyer, A. J. & Kmoch, S. Uromodulin biology and pathophysiology—an update. Kidney Blood Press. Res. 33, 456–475 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Hart, T. C. et al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J. Med. Genet. 39, 882–892 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Kamatani, N. et al. Localization of a gene for familial juvenile hyperuricemic nephropathy causing underexcretion-type gout to 16p12 by genome-wide linkage analysis of a large family. Arthritis Rheum. 43, 925–929 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. 22

    Becker, M. A., Smith, P. R., Taylor, W., Mustafi, R. & Switzer, R. L. The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity. J. Clin. Invest. 96, 2133–2141 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Merriman, T. R. & Dalbeth, N. The genetic basis of hyperuricaemia and gout. Joint Bone Spine 78, 35–40 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. 24

    Reed, D. R. & Price, R. A. X-linkage does not account for the absence of father–son similarity in plasma uric acid concentrations. Am. J. Med. Genet. 92, 142–146 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. 25

    Emmerson, B. T., Nagel, S. L., Duffy, D. L. & Martin, N. G. Genetic control of the renal clearance of urate: a study of twins. Ann. Rheum. Dis. 51, 375–377 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Wilk, J. B. et al. Segregation analysis of serum uric acid in the NHLBI Family Heart Study. Hum. Genet. 106, 355–359 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Yang, Q. et al. Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study. Metabolism 54, 1435–1441 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. 28

    Choi, H. K., Zhu, Y. & Mount, D. B. Genetics of gout. Curr. Opin. Rheumatol. 22, 144–151 (2010).

    Article  PubMed  Google Scholar 

  29. 29

    Dalbeth, N. & Merriman, T. Crystal ball gazing: new therapeutic targets for hyperuricaemia and gout. Rheumatology (Oxford) 48, 222–226 (2009).

    Article  CAS  Google Scholar 

  30. 30

    Endou, H. & Anzai, N. Urate transport across the apical membrane of renal proximal tubules. Nucleosides Nucleotides Nucleic Acids 27, 578–584 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. 31

    Caulfield, M. J. et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 5, e197 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Kolz, M. et al. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet. 5, e1000504 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Yang, Q. et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ. Cardiovasc. Genet. 3, 523–530 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Vitart, V. et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat. Genet. 40, 437–442 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. 35

    Doring, A. et al. SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat. Genet. 40, 430–436 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. 36

    Wallace, C. et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am. J. Hum. Genet. 82, 139–149 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Dehghan, A. et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 372, 1953–1961 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Li, S. et al. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet. 3, e194 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Stark, K. et al. Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case–control study. PLoS ONE 3, e1948 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Matsuo, H. et al. Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricaemia. Am. J. Hum. Genet. 83, 744–751 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Anzai, N. et al. Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J. Biol. Chem. 283, 26834–26838 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. 42

    Hollis-Moffatt, J. E. et al. Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Maori, Pacific Island, and Caucasian case-control sample sets. Arthritis Rheum. 60, 3485–3492 (2009).

    Article  PubMed  Google Scholar 

  43. 43

    Brandstätter, A. et al. Sex-specific association of the putative fructose transporter SLC2A9 variants with uric acid levels is modified by BMI. Diabetes Care 31, 1662–1667 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Karns, R. et al. 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 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Mandal, A., Emerling, D. E., Serafini, T. A. & Mount, D. B. Tranilast inhibits urate transport mediated by URAT1 and GLUT9 [abstract]. Arthritis Rheum. 62 (Suppl. 10), 164 (2010).

    Google Scholar 

  46. 46

    Bibert, S. et al. Mouse GLUT9: evidences for a urate uniporter. Am. J. Physiol. Renal Physiol. 297, F612–F619 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Manolescu, A. R., Augustin, R., Moley, K. & Cheeseman, C. A highly conserved hydrophobic motif in the exofacial vestibule of fructose transporting SLC2A proteins acts as a critical determinant of their substrate selectivity. Mol. Membr. Biol. 24, 455–463 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Augustin, R. et al. Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking. J. Biol. Chem. 279, 16229–16236 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Richardson, S. et al. Molecular characterization and partial cDNA cloning of facilitative glucose transporters expressed in human articular chondrocytes; stimulation of 2-deoxyglucose uptake by IGF-I and elevated MMP-2 secretion by glucose deprivation. Osteoarthritis Cartilage 11, 92–101 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Phay, J. E., Hussain, H. B., Moley, J. F. Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9). Genomics 66, 217–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Charles, B. A. et al. A genome-wide association study of serum uric acid in African Americans. BMC Med. Genomics 4, 17 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    National Center for Biotechnology Information. dbSNP Short Genetic Variations. NCBI [online] (2012).

  53. 53

    Dinour, D. et al. Two novel homozygous SLC2A9 mutations cause renal hypouricaemia type 2. Nephrol. Dial. Transplant 27, 1035–1041 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Dinour, D. et al. Homozygous SLC2A9 mutations cause severe renal hypouricaemia. J. Am. Soc. Nephrol. 21, 64–72 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    McArdle, P. F. et al. Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order Amish. Arthritis Rheum. 58, 2874–2881 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Urano, W. et al. Association between GLUT9 and gout in Japanese men. Ann. Rheum. Dis. 69, 932–933 (2010).

    Article  PubMed  Google Scholar 

  57. 57

    Tu, H. P. et al. 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 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Hollis-Moffatt, J. E. et al. The SLC2A9 nonsynonymous Arg265His variant and gout; evidence for a population-specific effect on severity. Arthritis Res. Ther. 13, R85 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Yamagishi, K. et al. The rs2231142 variant of the ABCG2 gene is associated with uric acid levels and gout among Japanese people. Rheumatology (Oxford) 49, 1461–1465 (2010).

    Article  CAS  Google Scholar 

  60. 60

    Wang, B. et al. Genetic analysis of ABCG2 gene C421A polymorphism with gout disease in Chinese Han male population. Hum. Genet. 127, 245–246 (2010).

    Article  PubMed  Google Scholar 

  61. 61

    Phipps-Green, A. J. et al. 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 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    Woodward, O. M. et al. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc. Natl Acad. Sci. USA 106, 10338–10342 (2009).

    Article  PubMed  Google Scholar 

  63. 63

    Matsuo, H. et al. 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 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. 64

    Hosomi, A., Nakanishi, T., Fujita, T. & Tamai, I. Extra-renal elimination of uric acid via intestinal efflux transporter BCRP/ABCG2. PLoS ONE 7, e30456 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Rodrigues, A. C., Curi, R., Genvigir, F. D., Hirata, M. H. & Hirata, R. D. The expression of efflux and uptake transporters are regulated by statins in Caco-2 and HepG2 cells. Acta Pharmacol. Sin. 30, 956–964 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Enomoto, A. et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 417, 447–452 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. 67

    Shima, Y., Teruya, K. & Ohta, H. Association between intronic SNP in urate-anion exchanger gene, SLC22A12, and serum uric acid levels in Japanese. Life Sci. 79, 2234–2237 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Graessler, J. et al. Association of the human urate transporter 1 with reduced renal uric acid excretion and hyperuricaemia in a German Caucasian population. Arthritis Rheum. 54, 292–300 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Vázquez-Mellado, J. et al. Molecular analysis of the SLC22A12 (URAT1) gene in patients with primary gout. Rheumatology (Oxford) 46, 215–219 (2007).

    Article  PubMed  Google Scholar 

  70. 70

    Tu, H. P. et al. The SLC22A12 gene is associated with gout in Han Chinese and Solomon Islanders. Ann. Rheum. Dis. 69, 1252–1254 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Guan, M. et al. High-resolution melting analysis for the rapid detection of an intronic single nucleotide polymorphism in SLC22A12 in male patients with primary gout in China. Scand. J. Rheumatol. 38, 276–281 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Tin, A. et al. Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. Hum. Mol. Genet. 20, 4056–4068 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Li, C. et al. Multiple single nucleotide polymorphisms in the human urate transporter 1 (hURAT1) gene are associated with hyperuricaemia in Han Chinese. J. Med. Genet. 47, 204–210 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    Jang, W. C. et al. T6092C polymorphism of SLC22A12 gene is associated with serum uric acid concentrations in Korean male subjects. Clin. Chim. Acta 398, 140–144 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. 75

    van der Harst, P. et al. Replication of the five novel loci for uric acid concentrations and potential mediating mechanisms. Hum. Mol. Genet. 19, 387–395 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Iharada, M. et al. Type 1 sodium-dependent phosphate transporter (SLC17A1 protein) is a CI-dependent urate exporter. J. Biol. Chem. 285, 26107–26113 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Jutabha, P. et al. Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. J. Biol. Chem. 285, 35123–35132 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Wright, A. F., Rudan, I., Hastie, N. D. & Campbell, H. A 'complexity' of urate transporters. Kidney Int. 78, 446–452 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. 79

    Jutabha, P. et al. Functional analysis of human sodium-phosphate transporter 4 (NPT4/SLC17A3) polymorphisms. J. Pharmacol. Sci. 115, 249–253 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    Nabipour, I. et al. Serum uric acid is associated with bone health in older men: a cross-sectional population-based study. J. Bone Miner. Res. 26, 955–964 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. 81

    Anzai, N., Jutabha, P., Amonpatumrat-Takahashi, S. & Sakurai, H. Recent advances in renal urate transport: characterization of candidate transporters indicated by genome-wide association studies. Clin. Exp. Nephrol. 16, 89–95 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Yang, C. et al. Mammalian CARMIL inhibits actin filament capping by capping protein. Dev. Cell 9, 209–221 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Thiagalingam, A. et al. RREB-1, a novel zinc finger protein, is involved in the differentiation response to Ras in human medullary thyroid carcinomas. Mol. Cell. Biol. 16, 5335–5345 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Scmitt, J. et al. Structure, chromosomal localization, and expression analysis of the mouse inhibin/activin βC (Inhbc) gene. Genomics 32, 358–366 (1996).

    Article  Google Scholar 

  85. 85

    Yang Chou, J. & Mansfield, B. C. Molecular genetics of type 1 glycogen storage diseases. Trends Endocrinol. Metab. 10, 104–113 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Orho-Melander, M. et al. Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes 57, 3112–3121 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Morcillo, S. et al. Trp64Arg polymorphism of the ADRB3 gene predicts hyperuricaemia risk in a population from southern Spain. J. Rheumatol. 37, 417–421 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. 88

    Rho, Y. H., Choi, S. J., Lee, Y. H., Ji, J. D. & Song, G. G. The association between hyperuricaemia and the Trp64Arg polymorphism of the β-3 adrenergic receptor. Rheumatol. Int. 27, 835–839 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Hayashi, H. et al. Contribution of a missense mutation (Trp64Arg) in β3-adrenergic receptor gene to multiple risk factors in Japanese men with hyperuricaemia. Endocr. J. 45, 779–784 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. 90

    Zuo, M. et al. The C677T mutation in the methylene tetrahydrofolate reductase gene increases serum uric acid in elderly men. J. Hum. Genet. 45, 257–262 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Hong, Y. S. et al. 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 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Itou, S. et al. Significant association between methylenetetrahydrofolate reductase 677T allele and hyperuricaemia among adult Japanese subjects. Nutr. Res. 29, 710–715 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Kimi Uehara, S. & Rosa, G. Association of uricemia with biochemical and dietary factors in human adults with metabolic syndrome genotyped to C677T polymorphism in the methylenetetrahydrofolate reductase gene. Nutr. Hosp. 26, 298–303 (2011).

    CAS  PubMed  Google Scholar 

  94. 94

    Wang, B. et al. Positive correlation between β-3-adrenergic receptor (ADRB3) gene and gout in a Chinese male population. J. Rheumatol. 38, 738–740 (2011).

    Article  PubMed  Google Scholar 

  95. 95

    Strazzullo, P. et al. Relationship of the Trp64Arg polymorphism of the β3-adrenoceptor gene to central adiposity and high blood pressure: interaction with age. Cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study. J. Hypertens. 19, 399–406 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Chang, S. J. et al. The cyclic GMP-dependent protein kinase II gene associates with gout disease: identified by genome-wide analysis and case–control study. Ann. Rheum. Dis. 68, 1213–1219 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. 97

    Chang, S. J. et al. Associations between gout tophus and polymorphisms 869T/C and −509C/T in transforming growth factor β1 gene. Rheumatology (Oxford) 47, 617–621 (2008).

    Article  CAS  Google Scholar 

  98. 98

    Choi, H. K. & Curhan, G. Beer, liquor, wine, and serum uric acid level—The Third National Health and Nutrition Examination Survey. Arthritis Rheum. 51, 1023–1029 (2004).

    Article  PubMed  Google Scholar 

  99. 99

    Zhang, W. et al. EULAR evidence based recommendations for gout. Part I: Diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann. Rheum. Dis. 65, 1301–1311 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Neogi, T. Clinical practice. Gout. N. Engl. J. Med. 364, 443–452 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. 101

    Feig, D. I., Soletsky, B. & Johnson, R. J. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA 300, 924–932 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    McKeigue, P. M. et al. 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. Int. J. Epidemiol. 39, 907–918 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Parsa, A. et al. Genotype-based changes in serum uric acid affect blood pressure. Kidney Int. 81, 502–507 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. 104

    Stark, K. et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS ONE 4, e7729 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Terkeltaub, R. A. Clinical practice. Gout. N. Engl. J. Med. 349, 1647–1655 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. 106

    Kang, H. R. et al. Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans. Pharmacogenet. Genomics 21, 303–307 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. 107

    Jung, J. W. et al. HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency. Nephrol. Dial. Transplant. 26, 3567–3572 (2011).

    Article  CAS  PubMed  Google Scholar 

  108. 108

    Hung, S. I. et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc. Natl Acad. Sci. USA 102, 4134–4139 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. 109

    Kaniwa, N. et al. HLA-B locus in Japanese patients with antiepileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 9, 1617–1622 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. 110

    Tassaneeyakul, W. et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet. Genomics 19, 704–709 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. 111

    Lonjou, C. et al. A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet. Genomics 18, 99–107 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. 112

    Somkrua, R., Eickman, E. E., Saokaew, S., Lohitnavy, M. & Chaiyakunapruk, N. Association of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. BMC Med. Genet. 12, 118 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Tohkin, M. et al. A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Pharmacogenomics J. http://dx.doi.org/10.1038/tpj.2011.41.

  114. 114

    Choi, H. K. A prescription for lifestyle change in patients with hyperuricaemia and gout. Curr. Opin. Rheumatol. 22, 165–172 (2010).

    Article  PubMed  Google Scholar 

  115. 115

    Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    Bertorini, T. E., Shively, V., Taylor, B., Palmieri, G. M. & Fox, I. H. ATP degradation products after ischemic exercise: hereditary lack of phosphorylase or carnitine palmityltransferase. Neurology 35, 1355–1357 (1985).

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Urano, W. et al. Sodium-dependent phosphate cotransporter type 1 sequence polymorphisms in male patients with gout. Ann. Rheum. Dis. 69, 1232–1234 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. 118

    Golbahar, J., Aminzadeh, M. A., Al-Shboul, Q. M., Kassab, S. & Rezaian, G. R. Association of methylenetetrahydrofolate reductase (C677T) polymorphism with hyperuricaemia. Nutr. Metab. Cardiovasc. Dis. 17, 462–467 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partly supported by grants from the NIH (R01AR056291 and P60AR047785).

Author information

Affiliations

Authors

Contributions

All authors contributed equally to researching the data for the article, discussions of the content, writing the article and editing of the manuscript before submission.

Corresponding author

Correspondence to Hyon K. Choi.

Ethics declarations

Competing interests

A. M. Reginato is a consultant for URL and a member of the speakers bureau (honoraria) for Savient, Takeda and URL. D B. Mount has received grant or research support from Nuon and URL. H. K. Choi has received grant or research support from Takeda and URL. I. Yang declares no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Reginato, A., Mount, D., Yang, I. et al. The genetics of hyperuricaemia and gout. Nat Rev Rheumatol 8, 610–621 (2012). https://doi.org/10.1038/nrrheum.2012.144

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing