According to an article published early online and in an upcoming edition of The Lancet, researchers have gained new insights into the genetic properties of gout. Dr Caroline Fox (National Heart Lung and Blood Institute, Bethesda, MD, USA) and colleagues demonstrate that three genes are linked to an increased risk of gout. Well before onset of clinical symptoms, doctors can analyze a genetic risk score based on these genes to find those at highest risk of the condition. This information can aid in developing early, targeted, and/or new treatments.

Gout is one of the most common forms of arthritis and is caused by a buildup of uric acid. When the bloodstream contains elevated concentrations of uric acid, monosodium urate (uric acid crystals) is deposited on the cartilage of joints, tendons, and surrounding tissues. The result is an inflammatory reaction in these tissues.

Dr Fox and colleagues studied the genetic factors behind gout by using data on 7,699 participants in the Framingham Heart Study and 4,148 participants in the Rotterdam Study. Researchers used genetic analysis to find out which genes were associated with a gout biomarker called serum uric acid. The results were then replicated in 11,024 white and 3,843 black participants who were part of the Atherosclerosis Risk in Communities (ARIC) study.

The gene SCLA29, involved in urate transport in the kidney, and the genes ABCG2 and SLC17A3 (also likely to be kidney urate transporters) were found to be associated with gout. Gout risk was determined using an additive genetic risk score of these high-risk alleles, and the analysis revealed graded associations with uric acid levels in all three cohorts. For example, a person with more at-risk alleles has higher uric acid levels and thus a higher risk of gout. About 2 to 13% in the Framingham cohort, 2 to 8% in the Rotterdam cohort, and 1 to 18% of white participants in the ARIC study had gout.

“Our genetic risk score was associated with up to 40-fold increased risk of developing gout, which is substantially higher than that for environmental risk factors, suggesting that knowledge of genotype could help to identify individuals at risk of developing gout long before onset of clinical features of the disease. This result underscores the value of a single assessment of the genetic risk score, whereas the measurement of uric acid concentration depends on measurement error and physiological variation over time,” write the researchers.

“In addition to risk prediction, knowledge of an individual’s genotype or risk score could be used to help guide clinical decisions, especially with respect to selection of drugs that are known to increase uric acid concentration and worsen gout. At present, prophylaxis for asymptomatic hyperuricaemia [increased levels of serum uric acid] is not recommended, but our genetic risk score could be used to identify individuals in which asymptomatic hyperuricaemia should be treated…The genes identified in our study could be useful for the ascertainment of novel proteins and molecular mechanisms that affect uric acid concentration, and for novel drug targets to improve treatment of gout,” they conclude.

Dr Martin Aringer and Dr Juergen Graessler (University Clinical Centre Carl Gustav Carus, Dresden, Germany) write in an accompanying comment that: “Enhanced understanding of pathophysiological mechanisms might lead to improved drugs, with reduced potential for side-effects compared with today’s uricosurics [drugs to treat increased serum levels of uric acid]…Even more exciting is the idea that responding to the defects of these transporter proteins might have further beneficial effects, because they could also transport other molecules besides urate.”

Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study
Abbas Dehghan, Anna Köttgen, Qiong Yang, Shih-Jen Hwang, W H Linda Kao, Fernando Rivadeneira, Eric Boerwinkle, Daniel Levy, Albert Hofman, Brad C Astor, Emelia J Benjamin, Cornelia M van Duijn, Jacqueline C Witteman, Josef Coresh, Caroline S Fox
The Lancet (2008).
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Written by: Peter M Crosta