Johns Hopkins scientists have found that a malfunctioning gene they helped uncover last year can lead to high concentrations of blood urate that forms crystals in joint tissue and causes inflammation and pain, the hallmark of gout.
The ABCG2 gene's discovery sprang from a survey of the genomes of 12,000 individuals, which was conducted to find a genetic cause for gout.
Using frog egg cells genetically engineered with human DNA, the researchers have now discovered that the gene makes a protein that normally transports urate out of the kidney and into urine before the waste product does any harm.
The new findings lend credence to suspicions that metabolic deficiencies, in addition to too much rich food and alcohol, are mostly to blame for this painful type of arthritis.
The researchers even believe that the gene may be responsible for some 10 per cent of gout in Caucasians.
"We were able to show for what we believe is the first time that the ABCG2 protein is vital for transporting urate out of cells," says Dr. Owen Woodward, a postdoctoral fellow in physiology in the Johns Hopkins University School of Medicine.
The study further showed that the ABCG2 protein is located in the kidney at a location where urate exretion takes place, and the researchers suggest that a lack of efficiency in removing urate from the blood leads to its increased concentration and crystallization.
In humans, these crystals get caught in joint tissues, leading to painful inflammation.
"As the first major gene identified to cause gout, we believe that ABCG2 also represents an attractive new drug target," says Dr. Michael Kottgen, a biological chemistry research associate in the Johns Hopkins University School of Medicine.
One strategy is to identify a drug that makes excretion faster and more efficient by activating the "urate transporter" protein.
"Instead of trying to limit urate production - the major current approach to gout treatment - newer treatments could focus on getting urate out of the bloodstream," Kottgen says. "We anticipate that activation of ABCG2 with a drug may help to promote excretion of urate."
"It's exciting that a finding from genome-wide association studies has been directly translated into better understanding physiology and perhaps will help us find better clinical therapies", says Anna Kottgen, M.D., M.P.H., an epidemiologist in the Johns Hopkins University Bloomberg School of Public Health.
A report on the study has been published in the online Early Edition PNAS.