Gout & genetic detective work

A new international study, in which an Oxford University researcher took part, has identified the role of a gene that had been previously implicated in the painful condition, gout.

The findings may offer a potential target for new drug development, but may be of more general interest because they highlight the value of new approaches that are increasingly being used to identify genes implicated in a variety of complex diseases.

Genome-wide association studies have led to an explosion in the number of genes implicated in conditions such as diabetes and heart disease. They have also led to the identification of genes that have an influence on height or body mass index, for example.

These recently developed, powerful techniques use a lot of data from genetic screens of large numbers of people. This amount of data is necessary to tease out the genetic influences on these diseases from all the other environmental and lifestyle factors that can have an effect.

But once you know the genes in which DNA sequence variations can influence susceptibility to disease, what then?

The hope is that the roles that the newly-identified genes play in the body can be studied and the biological processes they are involved in better understood. We should then be able to deduce some of the causes or molecular mechanisms of the disease and have new targets for drug development.

The new study, published in PLoS Medicine and led by Barts and The London School of Medicine and Dentistry in London, looked at a gene called SLC2A9 that two recent genome-wide association scans suggested was connected with gout and high levels of uric acid (urate) in the body.

Uric acid arises as a by-product of the breakdown of food and cellular molecules and is cleared by the kidney into our urine. High urate levels in the body are linked to a number of common disorders, including gout, diabetes, high blood pressure and heart disease.

The SLC2A9 gene was already known to be expressed in areas of the kidney and to transport the sugar glucose in and out of cells. The international team went back to look again at the function of SLC2A9 to try and explain its connection to urate levels and gout. They showed that the gene encodes a protein that transports urate across cell membranes in the kidney at a very high rate, much higher than it transports glucose.

‘It was a bit of a surprise,’ says Professor Martin Farrall of Oxford's Department of Cardiovascular Medicine, who was involved in the work. ‘Nobody knew there was this connection to urate transport.’

This is one of the first studies to determine the role of a gene identified in genome-wide associations scans and it all seems to fit neatly. The findings suggest that SLC2A9 plays an important role in the handling of urate in the kidney. It could also be a potential drug target for people suffering from gout.

Professor Farrall’s particular interest in the work was to see if there was any connection between the SLC2A9 gene and high blood pressure. No connection was found, but as he points out, the connection between urate levels and blood pressure is ‘fairly subtle’. A larger study might pull out a link, he adds, but this is not a high priority for further research. 

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