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Is Gout Related To Genetics?

Gout is a common disease with a genetic predisposition.1 The last years, a number of studies were conducted in order to determine the genetic causes of gout. Several polymorphisms (the occurrence of more than one form or morph) were identified as associated with elevated serum urate levels and gout. The identification of these polymorphisms was done by genome-wide association studies which are a research technique to identify DNA polymorphisms distributed across different large populations. Using genome-wide association studies (GWAS) researchers managed to identify several DNA loci associated with serum urate concentration, and some of them linked to gout in several populations. The locus most strongly linked to gout corresponds to the glucose transporter 9 (GLUT9) or solute carrier 2A9 (SLC2A9). Some variants of SLC2A9 are linked to a reduced risk of gout.

In contrast to SLC2A9 some other loci are linked to an increased risk of gout. One of them corresponds to the gene encoding the urate transporter 1, URAT1 or SL22A12. An additional locus linked to increased risk of gout encodes the renal sodium phosphate transport protein 1 NPT1 or SL17A1, which is localized at the apical membrane of renal proximal tubules.

A more recent locus linked to gout corresponds to the ABCG2 gene, a transporter initially known for its involvement in resistance to chemotherapy.2In kidney cells, ABCG2 is crucial for getting uric acid out of the body. According to a recent study the ABCG2 126X and 141K alleles are linked to an increased risk of gout, whereas 12M has a protective effect on gout susceptibility in the Han Chinese population. This study concluded that ABCG2 dysfunction can be used to evaluate gout risk.3 While most gout can be controlled by dietary changes, about 10 percent of Caucasians get the disorder because their ABCG2 protein contains the Q141K mutation. The mutation Q141K is caused by an amino acid exchange for another. African-Americans get the disorder for 3% while it is 31% for Asians. 4 Another study conducted in Japan showed that any ABCG2 dysfunction causes early-onset gout. Researchers reported that dysfunctional ABCG2 accounts for about 9/10 of early-onset gout patients. They also claimed that this was the first report on a common genetic cause of an early-onset gout that occurs in the twenties or earlier.5 The common genetic variants identified in GWAS confer a modest risk of gout. However, an additive composite genetic urate score of high-risk alleles can confer up to a 41-fold increased risk for gout compared with individuals without any such alleles. 6

According to a previous mentioned study because early-onset gout is a disease of great duration, quality of life is a very important issue, but in order to provide it, high life-long medical costs are required. The ability of early screening for ABCG2 dysfunction and appropriate interventions will greatly benefit high-risk individuals. Methods such as genotyping of polymorphisms are reliable for gout risk evaluation and will reduce cost related to screening, promote public health and quality of life.5

References

  1. 1)Adv Chronic Kidney Dis. 2006 Apr;13(2):124-30. Genetic factors associated with gout and hyperuricemia. Bleyer AJ1, Hart TC.
  2. 2) F1000 Biol Rep. 2011;3:23. doi: 10.3410/B3-23. Epub 2011 Nov 1. Gout, genetics and ABC transporters. Basseville A1, Bates SE.
  3. 3) Int J Mol Sci. 2014 May 22;15(5):9149-59. doi: 10.3390/ijms15059149. Functional polymorphisms of the ABCG2 gene are associated with gout disease in the Chinese Han male population. Zhou D, Liu Y, Zhang X, Gu X, Wang H, Luo X, Zhang J, Zou H, Guan M
  4. 4) Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5223-8. doi: 10.1073/pnas.1214530110. Epub 2013 Mar 14. Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules. Woodward OM1, Tukaye DN, Cui J, Greenwell P, Constantoulakis LM, Parker BS, Rao A, Köttgen M, Maloney PC, Guggino WB.
  5. 5) Sci Rep. 2013;3:2014. doi: 10.1038/srep02014. Common dysfunctional variants in ABCG2 are a major cause of early-onset gout. Matsuo H1, Ichida K, Takada T, Nakayama A, Nakashima H, Nakamura T, Kawamura Y, Takada Y, Yamamoto K, Inoue H, Oikawa Y, Naito M, Hishida A, Wakai K, Okada C, Shimizu S, Sakiyama M, Chiba T, Ogata H, Niwa K, Hosoyamada M, Mori A, Hamajima N, Suzuki H, Kanai Y, Sakurai Y, Hosoya T, Shimizu T,
  6. 6) Circ Cardiovasc Genet. 2010 Dec;3(6):523-30. doi: 10.1161/CIRCGENETICS.109.934455. Epub 2010 Sep 30. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Yang Q1, Köttgen A, Dehghan A, Smith AV, Glazer NL, Chen MH, Chasman DI, Aspelund T, Eiriksdottir G, Harris TB, Launer L, Nalls M, Hernandez D, Arking DE, Boerwinkle E, Grove ML, Li M, Linda Kao WH, Chonchol M, Haritunians T, Li G, Lumley T, Psaty BM, Shlipak M, Hwang SJ, Larson MG, O'Donnell CJ, Upadhyay A, van Duijn CM, Hofman A, Rivadeneira F, Stricker B, Uitterlinden AG, Paré G, Parker AN, Ridker PM, Siscovick DS, Gudnason V, Witteman JC, Fox CS, Coresh
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