Ürat

Urate

Urate, also known as uric acid, is a chemical created when the body breaks down substances called purines. Purines are normally produced in the body and are also found in some foods and drinks. Most urate dissolves in the blood and travels to the kidneys. From there, it passes out of the body in urine. If your body produces too much urate or doesn’t eliminate enough, you can develop high levels of it in your blood. This condition is called hyperuricemia.

Hyperuricemia can lead to a number of health problems, including gout (a form of arthritis), kidney stones, and kidney failure. However, many people with hyperuricemia don’t have any symptoms.

Urate levels are influenced by a combination of genetic and environmental factors. Diet, alcohol consumption, obesity, and certain medications can all affect urate levels. Genetic factors also play a significant role, with several genetic variants having been associated with urate levels in genome-wide association studies (GWAS).

Genetic Factors Influencing Urate Levels

GWAS have identified numerous genetic loci associated with urate levels. These loci often contain genes involved in urate transport and metabolism. Some of the most well-established genetic variants include:

• SLC2A9: This gene encodes a urate transporter, and genetic variants in this gene have been consistently associated with urate levels and gout riskCITATION_0. For example, the SNP RSID_2in SLC2A9 has been shown to have a strong effect on serum urate levels. Individuals with the ‘C’ allele atRSID_2tend to have lower urate levels compared to those with the ‘T’ allele.
• ABCG2: This gene also encodes a urate transporter, and genetic variants in ABCG2 are associated with urate levels and gout riskCITATION_0. The SNP RSID_2in ABCG2 is a well-known example, with the ‘C’ allele being associated with increased urate levels.
• Other genes: Other genes that have been implicated in urate metabolism and transport includeSLC17A1, SLC22A12, and PDZK1. Genetic variants in these genes have also been associated with urate levels in GWASCITATION_0.

The genetic architecture of urate levels is complex and polygenic, with many common genetic variants each contributing a small effect. Rare genetic variants can also have a large effect on urate levels, but these are less common in the general population.

Clinical Significance

Understanding the genetic factors that influence urate levels can have several clinical implications:

• Risk prediction: Genetic testing for urate-associated variants could potentially be used to identify individuals at higher risk of developing hyperuricemia and gout.
• Personalized medicine: Genetic information could be used to tailor treatment strategies for individuals with hyperuricemia or gout. For example, individuals with certain genetic variants may respond differently to urate-lowering medications.
• Drug development: Identifying the genes and pathways involved in urate metabolism and transport can provide targets for the development of new drugs to treat hyperuricemia and gout.

Resources

• National Institute of Arthritis and Musculoskeletal and Skin Diseases:URL_1

References

[1] Li S, et al. “The GLUT9gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.” PLoS Genet, 2007.

[2] Carvalho BS, Louis TA, Irizarry RA. “Quantifying uncertainty in genotype calls.” Bioinformatics, 2010.

[3] 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. 2012.

[4] Aringer M, McKeigue PM, Ralston SH, Morris AD, Rudan P, Hastie ND, Campbell H, Wright AF. “SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.” Nat Genet. 2008.

[5] Dehghan A et al. “Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.” Lancet. 2008.

[6] Yang B et al. “A genome-wide association study identifies common variants influencing serum uric acid concentrations in a Chinese population.” BMC Med Genomics. 2014.

[7] Kolz M et al. “Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.” PLoS Genet. 2009.

[8] Li, WD. “A genome wide association study of plasma uric acid levels in obese cases and never-overweight controls.”Obesity (Silver Spring), 2013. PMID: 23703922.

[9] Wallace C, Newhouse SJ, Braund P, Zhang F, Tobin M, Falchi M, Ahmadi K, Dobson RJ, Marçano AC, Hajat C, Burton P, Deloukas P, Brown M, Connell JM, Dominiczak A, Lathrop GM, Webster J, Farrall M, Spector T, Samani NJ, Caulfield MJ, Munroe PB. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.” Am J Hum Genet. 2008.

[10] Wen, C. C., et al. “Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response.” Clin Pharmacol Ther, 2015.