Outline of the genetic architecture of primary hyperuricemia and gout


Authors: B. Stibůrková
Authors‘ workplace: Revmatologický ústav ;  Ústav dědičných metabolických poruch, 1. lékařská fakulta, Univerzita Karlova a Všeobecná fakultní nemocnice, Praha
Published in: Čes. Revmatol., 25, 2017, No. 3, p. 116-123.
Category: Review Article

Overview

Gout, arthritis urica, is a metabolic disorder caused by an inflammatory reaction to the deposition of urate crystals into joints and soft tissues. Chronic hyperuricaemia, the cause of the gout, results in an imbalance between endogenous production and excretion of uric acid. The most common mechanism leading to hyperuricaemia is decreased excretion of uric acid. Urate transport is a complex process involving a number of transmembrane proteins that provide reabsorption (mostly URAT1, GLUT9) and secretion (ABCG2) on the apical and basolateral side of the proximal tubules. ABCG2, with a significant proportion, provides transport in the gastrointestinal tract. New knowledge on uric acid excretion has allowed the development of a new strategy in the treatment of hyperuricaemia by blocking urate transporters. Knowledge of the genetic background of uricemia is essential for early identification of the aetiology of the disease, the choice of appropriate treatment, and also the monitoring of compliance by the patient. Detailed examination of purine metabolism and uric acid excretion in specialized laboratories is particularly useful for patients with early onset and / or familial outbreaks of the disease.

Keywords:
Hyperuricaemia, gout, purine metabolism, hypoxanthine-guanine phosphoribosyltransferase deficiency, urate transporters, SLC22A12, SLC2A9, ABCG2.


Sources

1. Zhu Y1, Pandya BJ, Choi HK, et al. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum. 2011 Oct; 63(10): 3136–41.

2. Winnard D, Wright C, Taylor WJ, et al. National prevalence of gout derived from administrative health data in Aotearoa New Zealand. Rheumatology (Oxford). 2012 May; 51(5): 901–9.

3. Rothenbacher D, Primatesta P, Ferreira A, et al. Frequency and risk factors of gout flares in a large population–based cohort of incident gout. Rheumatology (Oxford). 2011; 50(5): 973–81.

4. Kuo CF, Grainge MJ, Mallen C, et al. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Ann Rheum Dis. 2015; 74: 661–67.

5. Saag K, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther. 2006; 8(Suppl 1): S2.

6. Arromdee E, Michet CJ, Crowson CS, et al. Epidemiology of gout: is the incidence rising? J Rheumatol. 2002; 29: 2403–2406.

7. López López CO, Lugo EF, Alvarez–Hernández E, et al. Severe tophaceous gout and disability: changes in the past 15 years. Clin Rheumatol. 2017; 36(1): 199–204.

8. Johnson RJ, Segal MS, Sautin Y, et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr. 2007; 86(4): 899–906.

9. Kim KM, Henderson GN, Frye RF, et al. Simultaneous determination of uric acid metabolites allantoin, 6-aminouracil, and triuret in human urine using liquid chromatography–mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2009; 1; 877(1–2): 65–70.

10. Glantzounis GK, Tsimoyiannis EC, Kappas AM, et al. Uric acid and oxidative stress. Curr Pharm Des. 2005; 11(32): 4145–51.

11. Bickel C, Rupprecht HJ, Blankenberg S, et al. Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol. 2002; 89(1): 12–7.

12. Viazzi F, Parodi D, Leoncini G, et al. Serum uric acid and target organ damage in primary hypertension. Hypertension. 2005; 45(5): 991–6.

13. Palmer TM, Nordestgaard BG, Benn M, et al. Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts. BMJ. 2013; 347: f4262.

14. Fabbrini E, Serafini M, Colic Baric I, et al. Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects. Diabetes. 2014; 63(3): 976–81.

15. Mikami T, Kita K, Tomita S, et al. Is allantoin in serum and urine a useful indicator of exercise–induced oxidative stress in humans? Free Radic Res. 2000; 32(3): 235–44.

16. Waring WS, Convery A, Mishra V, et al. Uric acid reduces exercise–induced oxidative stress in healthy adults. Clin Sci (Lond). 2003; 105(4): 425–30.

17. Davis JW1, Grandinetti A, Waslien CI, et al. Observations on serum uric acid levels and the risk of idiopathic Parkinson’s disease. Am J Epidemiol. 1996; 144(5): 480–4.

18. Hooper DC1, Spitsin S, Kean RB, et al. Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci U S A. 1998; 95(2): 675–80.

19. Yao JK, Reddy R, van Kammen DP, et al. Reduced level of plasma antioxidant uric acid in schizophrenia. Psychiatry Res. 1998; 80(1): 29–39.

20. Hayden MR, Tyagi SC. 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). 2004; 1(1): 10.

21. Ebrahimpour P, Fakhrzadeh H, Heshmat R, et al. Serum uric acid levels and risk of metabolic syndrome in healthy adults. Endocr Pract. 2008; 14(3): 298–304.

22. Heinig M, Johnson RJ. Role of uric acid in hypertension, renal disease, and metabolic syndrome. Cleve Clin J Med. 2006; 73(12): 1059–64.

23. Sui X, Church TS, Meriwether RA, et al. Uric acid and the development of metabolic syndrome in women and men. Metabolism. 2008; 57(6): 845–52.

24. Tamba S, Nishizawa H, Funahashi T, et al. Relationship between the serum uric acid level, visceral fat accumulation and serum adiponectin concentration in Japanese men. Intern Med. 2008; 47(13): 1175–80.

25. Chen S, Du H, Wang Y, et al. The epidemiology study of hyperuricemia and gout in a community population of Huangpu District in Shanghai. Chin Med J (Engl).1998; 111(3): 228–30.

26. Kuntz D, Chretien JM, Ryckewaert A, et al. [Distribution and correlations of serum uric–acid in two French adult populations: 13,885 men and 6,861 women (author’s transl)]. Sem Hop. 1979; 55(5–6): 241–8.

27. Lin K, Lin HY, Chou P. Community based epidemiological study on hyperuricemia and gout in Kin–Hu, Kinmen. J Rheumatol. 2000; 27(4): 1045–50.

28. Chang HY, Pan WH, Yeh WT et al. Hyperuricemia and gout in Taiwan: results from the Nutritional and Health Survey in Taiwan (1993–96). J Rheumatol. 2001; 28(7): 1640–6.

29. Tang W, Miller MB, Rich SS, et al. Linkage analysis of a composite factor for the multiple metabolic syndrome: the National Heart, Lung, and Blood Institute Family Heart Study. Diabetes. 2003; 52(11): 2840–7.

30. Wilk JB, Djousse L, Borecki I, et al. Segregation analysis of serum uric acid in the NHLBI Family Heart Study. Hum Genet. 2000; 106(3): 355–9.

31. Nath SD, Voruganti VS, Arar NH, et al. Genome scan for determinants of serum uric acid variability. J Am Soc Nephrol. 2007; 18(12): 3156–63.

32. Yang Q, Guo CY, Cupples LA, et al. Genome–wide search for genes affecting serum uric acid levels: the Framingham Heart Study. Metabolism. 2005; 54(11): 1435–41.

33. Köttgen A, Albrecht E, Teumer A, et al. Genome–wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013; 45(2): 145–54.

34. Nakayama A, Nakaoka H, Yamamoto K, et al. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. Ann Rheum Dis. 2016; doi: 10.1136/annrheumdis–2016–209632. [Epub ahead of print]

35. Curto R, Voit EO, Sorribas A. Mathematical models of purine metabolism in man. Math Biosci. 1998; 151(1): 1–49.

36. Curto R, Voit EO, Cascante M. Analysis of abnormalities in purine metabolism leading to gout and to neurological dysfunctions in man. Biochem J. 1998; 329( Pt 3): 477–87.

37. Simmonds HA, Reiter S, Davies PM, et al. Orotidine accumulation in human erythrocytes during allopurinol therapy: association with high urinary oxypurinol-7-riboside concentrations in renal failure and in the Lesch-Nyhan syndrome. Clin Sci (Lond) 1991; 80: 191–7.

38. Duley JA, Christodoulou J, de Brouwer AP. The PRPP synthetase spectrum: what does it demonstrate about nucleotide syndromes? Nucleosides Nucleotides Nucleic Acids

2011; 30: 1129–39.

39. Kostalova E, Pavelka K, Vlaskova H, et al. Hyperuricemia and gout due to deficiency of hypoxanthine–guanine phosphoribosyltransferase in female carriers: New insight to differential diagnosis. Clin Chim Acta. 2015; 440: 214–7.

40. Dawson PA, Gordon RB, Keough DT, et al. Normal HPRT coding region in a male with gout due to HPRT deficiency. Mol Genet Metab. 2005; 85: 78–80.

41. Nguyen KV, Naviaux RK, Paik KK, et al. Lesch–Nyhan syndrome: mRNA expression of HPRT in patients with enzyme proven deficiency of HPRT and normal HPRT coding region of the DNA. Mol Genet Metab. 2012; 106: 498–501.

42. Rahul Mittal, 1 Kunal Patel, 1 Jeenu Mittal, et al. Association of PRPS1 Mutations with Disease Phenotypes. Dis Markers. 2015; 2015: 127013.

43. Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417(6887): 447–52.

44. Sugihara S, Hisatome I, Kuwabara M. Depletion of Uric Acid Due to SLC22A12 (URAT1) Loss–of–Function Mutation Causes Endothelial Dysfunction in Hypouricemia. Circ J. 2015; 79(5): 1125–32.

45. Ichida K, Hosoyamada M, Kamatani N, et al. Age and origin of the G774A mutation in SLC22A12 causing renal hypouricemia in Japanese. Clin Genet. 2008; 74(3): 243–51.

46. Stiburkova B, Gabrikova D, Čepek P, et al. Prevalence of URAT1 allelic variants in the Roma population. Nucleosides Nucleotides Nucleic Acids. 2016 Dec;35(10-12): 529–535.

47. Doring A, Gieger C, Mehta D, et al. SLC2A9 influences uric acid concentrations with pronounced sex–specific effects. Nat Genet. 2008; 40(4): 430–6.

48. Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet. 2008; 40(4): 437–42.

49. Hollis–Moffatt JE, Xu X, Dalbeth N, et al. Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Māori, Pacific Island, and Caucasian case–control sample sets. Arthritis Rheum. 2009; 60(11): 3485–92.

50. Hollis–Moffatt JE, Gow PJ, Harrison AA, et al. The SLC2A9 nonsynonymous Arg265His variant and gout: evidence for a population – specific effect on severity. Arthritis Res Ther. 2011; 13(3): R85.

51. Bhasin B, Stiburkova B, De Castro–Pretelt M, et al. Hereditary renal hypouricemia: a new role for allopurinol? Am J Med. 2014; 127(1): e3–4.

52. Ekaratanawong S, Anzai N, Jutabha P, et al. Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules. J Pharmacol Sci. 2004; 94(3): 297–304.

53. Bahn A, Hagos Y, Reuter S, et al. Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13). J Biol Chem. 2008; 283(24): 16332–41.

54. Allikmets R, Schriml LM, Hutchinson A, et al. A human placenta–specific ATP–binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res. 1998; 58(23): 5337–9.

55. Mao Q, Unadkat JD. Role of the breast cancer resistance protein (ABCG2) in drug transport. AAPS J. 2005; 7(1): 118–33.

56. Kolz M, Johnson T, Sanna S, et al. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet. 2009; 5(6): 1000504.

57. Matsuo H, Takada T, Ichida K, 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. 2009; 1(5): 5ra11.

58. Woodward OM, Köttgen A, Coresh J, et al. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci U S A. 2009; 106(25): 10338–42.

59. Ichida K, Matsuo H, Takada T, et al. Decreased extra–renal urate excretion is a common cause of hyperuricemia. Nat Commun. 2012; 3: 764.

60. Stibůrková B, Pavlíková M, Sokolová J, et al. Metabolic syndrome, alcohol consumption and genetic factors are associated with serum uric acid concentration. PLoS One. 2014; 9(5): e97646.

61. Jutabha P, Anzai N, Kitamura K, et al. Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. J Biol Chem. 2010; 285(45): 35123–32.

62. Russel FG, Koenderink JB, Masereeuw R. Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol Sci. 2008; 29(4): 200–7.

63. Hoque MT, Conseil G, Cole SP. Involvement of NHERF1 in apical membrane localization of MRP4 in polarized kidney cells. Biochem Biophys Res Commun. 2009; 379(1): 60–4.

64. Eraly SA, Vallon V, Rieg T, et al. Multiple organic anion transporters contribute to net renal excretion of uric acid. Physiol Genomics. 2008; 33(2): 180–92.

65. Chong SS, Kristjansson K, Zoghbi HY, et al. Molecular cloning of the cDNA encoding a human renal sodium phosphate transport protein and its assignment to chromosome 6p21.3–p23. Genomics. 1993; 18(2): 355–9.

66. Uchino H, Tamai I, Yamashita K, et al. p-aminohippuric acid transport at renal apical membrane mediated by human inorganic phosphate transporter NPT1. Biochem Biophys Res Commun. 2000; 270(1): 254–9.

67. Urano W, Taniguchi A, Anzai N, et al. Sodium–dependent phosphate cotransporter type 1 sequence polymorphisms in male patients with gout. Ann Rheum Dis. 2010; 69(6): 1232–4.

68. Sekine T, Watanabe N, Hosoyamada M, et al. Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem. 1997; 272(30): 18526–9.

69. Cha SH, Sekine T, Fukushima JI, et al. Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001; 59(5): 1277–86.

70. Xu G, Chen X, Wu D, et al. Development of high–specificity antibodies against renal urate transporters using genetic immunization. J Biochem Mol Biol. 2006; 39(6): 696–702.

71. Anzai N, Kanai Y, Endou H. New insights into renal transport of urate. Curr Opin Rheumatol. 2007; 19(2) 151–57.

72. Nakayama A, Matsuo H, Nakaoka H, et al. Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors. Scientific Reports. 2014; 4: 5227.

73. Roberts RL, Wallace MC, Phipps–Green AJ, et al. ABCG2 loss–of–function polymorphism predicts poor response to allopurinol in patients with gout. Pharmacogenomics J. 2017; 17(2): 201–203.

74. Petru L, Pavelcova K, Sebesta I, et al. Genetic background of uric acid metabolism in a patient with severe chronic tophaceous gout. Clin Chim Acta. 2016; 460: 46–9.

75. Perez–Ruiz F, Sundy JS, Miner JN, et al. Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol. Ann Rheum Dis. 2016; 75(6): 1074–80.

Labels
Dermatology & STDs Paediatric rheumatology Rheumatology
Login
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account