A study has shown that three genes are associated with increased risk of gout. A genetic risk score based on these genes could reveal those at highest risk of the condition — long before onset of clinical symptoms — and facilitate early, targeted, and/or new treatments. These are the conclusions of an Article published early Online and in an upcoming edition of The Lancet, written by Dr Caroline Fox, National Heart Lung and Blood Institute, Bethesda, MD, USA, and colleagues.
Gout is a disease created by a buildup of uric acid. In this condition, monosodium urate or uric acid crystals are deposited on the cartilage of joints, tendons, and surrounding tissues due to elevated concentrations of uric acid in the bloodstream. This provokes an inflammatory reaction of these tissues.
This genome-wide association study used data from participants in two cohorts: 7699 from the Framingham Heart Study, and 4148 from the Rotterdam Study. Both cohorts were genetically analysed to determine which genes were associated with serum uric acid, a biomarker of gout, and the results were further replicated in both white (11 024) and black participants (3 843) who took part in the study of Atherosclerosis Risk in Communities.
The research confirmed the association of gene SCLA29 — involved in urate transport in the kidney — with gout, and also revealed two more genes, ABCG2 and SLC17A3, which are likely to be kidney urate transporters. An additive genetic risk score of these high-risk alleles* showed graded associations with uric acid levels in all three cohorts, ie, the more at-risk alleles present, the higher someone's uric acid level and therefore the higher their risk of gout. Gout prevalence was found to be 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in ARIC study.
The authors say: "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.
"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** 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."
In an accompanying Comment, Dr Martin Aringer and Dr Juergen Graessler, University Clinical Centre Carl Gustav Carus, Dresden, Germany, say: "Enhanced understanding of pathophysiological mechanisms might lead to improved drugs, with reduced potential for side-effects compared with today's uricosurics.***
"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."
Dr Caroline Fox, National Heart Lung and Blood Institute, Bethesda, MD, USA T) +1 301 496-4236 E) NHLBI_news@nhlbi.nih.gov / foxca@nhlbi.nih.gov
Dr Martin Aringer, University Clinical Centre Carl Gustav Carus, Dresden, Germany E) martin.aringer@uniklinikum-dresden.de
Notes to editors: * An allele is one member of a pair or series of different forms of a gene
** hyperuricaemia – increased levels of serum uric acid
***uricosurics – drugs for treating increased levels of serum uric acid
Full Article and Comment: http://press.thelancet.com/goutfinal.pdf
Journal
The Lancet