Gene raises gout risk

“Gene ‘linked to higher gout risk’” reports BBC News. The article states that a new study of more than 12,000 people has found a gene variant that could raise the risk of gout. It adds that, one day, the gene variant might be targeted by "new gout drugs".

The study behind this story identified genetic variants more likely to occur in people with gout (or with features that suggest they have impaired uric acid processing). The results show that these variations are responsible for a small proportion of the variation in blood uric acid levels between individuals. However, quite persuasive evidence also links gout to weight, alcohol and red meat. These environmental factors clearly play a role in the origin and development of this complex disorder.

This is a well-conducted study and it increases our understanding of why only certain people get gout. However, new diagnostic techniques or drugs to treat the condition on the basis of these findings are a long way off.

Where did the story come from?

Dr Veronique Vitart and colleagues from the MRC Human Genetics Unit in Edinburgh and from other academic institutions in the UK, Croatia and Germany carried out the research. The study was funded by grants from the Medical Research Council, the Wellcome Trust, the Arthritis Research Campaign, Cancer Research UK, and the Republic of Croatia Ministry of Science, Education and Sports. The study was published in peer-reviewed medical journal Nature Genetics.

What kind of scientific study was this?

This genome-wide association study looked for particular genetic sequences (variants) that are associated with gout. Gout is a painful joint condition caused by too much uric acid (urate) in the blood. When this happens, tiny crystals can form and collect in the joints causing inflammation and pain. Uric acid is made from the breakdown of purines, which are always in the body, but are also found in alcohol and some foods. In most cases, the reason for the excess uric acid is unclear. The body may have made too much, or the kidneys may not have got rid of (excreted) enough. Current medical opinion is that unhealthy diet and lifestyle increases the risk of gout.

The researchers analysed the DNA for 317,503 variants known as single nucleotide polymorphisms (SNPs). These types of study often involve replication in different populations to confirm the initial results, so there were several parts to the study.

Firstly, the researchers enrolled 986 Croatians and assessed their levels of serum uric acid (the concentration of uric acid in the blood, which is a good indicator of whether the person has, or is at risk of developing, gout). They then determined whether there was an association between variations in DNA and this indicator of gout using complex statistical methods. The methods took into account that some of the participants were related to each other and were therefore more likely to have similar genes. To confirm the findings from this part of the experiment, it was also done in 706 people from the Scottish island of Orkney.

Next, the researchers recruited 349 German subjects whose excretion of uric acid was impaired (i.e. they had ‘low fractional excretion of uric acid’, another strong indicator of gout) and compared them with 255 controls who had normal uric acid excretion. In this part of the study, the researchers were particularly interested in determining the strength of the association with the gene variants they had identified in the first part of the experiment. A similar ‘case-control’ comparison was then performed in 484 Scottish people who had gout and 9,659 controls.

In the final part of their experiment, the researchers determined the entire DNA sequence of the gene they identified in the first part and examined how the protein encoded by the gene functions in unfertilised frog eggs. By doing this, they identified possible biological reasons for the link between the gene and impaired uric acid processing.

What were the results of the study?

In both the Croatian and UK population, the study revealed a strong association between serum uric acid levels and three SNPs all within a gene called SLC2A9. These variants accounted for 1.7% to 5.3% of the variation in serum uric acid concentrations seen in the Croatian sample. This pattern of association was confirmed in the UK sample.

In the German population, the researchers found that having these gene variants increased the odds of having diminished excretion of uric acid (a strong indicator of gout) by 53% to 67%. In the Scottish population, these variants increased the odds of having gout by 32% to 40%.

The researchers found that the protein encoded by the SLC2A9 gene was involved in transportation of both sugar (fructose) and uric acid. This may explain the known link between intake of fructose and increase in serum uric acid concentration.

What interpretations did the researchers draw from these results?

The researchers conclude that a region of DNA within the SLC2A9 gene contains variants associated with an increased risk of gout. They say that further investigation of the gene will help to clarify "the complex relationships between" genes and how gout manifests physically in humans.

The finding that SLC2A9 is involved in transporting uric acid could, they say, lead to new drugs to lower uric acid levels in a range of conditions.

What does the NHS Knowledge Service make of this study?

This was a well-conducted study using recognised methods in this field. The researchers checked their results in different groups of individuals and were able to show similar patterns of association between particular gene variants and gout or markers for gout across different populations.

The researchers established some biological basis for this association through further investigation of the function of the gene in which these variants occurred. These results strengthen their conclusion that they have found a real association between particular variants in the DNA and levels of uric acid. This finding is a first step, and although studies such as this offer hope for new diagnostic techniques and drugs to treat the condition, these are a long way off.

The study identified variants that accounted for only a small fraction of the difference in the serum acid concentrations between people (1.7% to 5.3%). This suggests that other factors (perhaps other genetic or environmental factors, such as alcohol or diet) account for a larger proportion of this. The evidence linking gout with diet and weight is limited, but it is quite persuasive and supports the contribution of these environmental factors to the disease.

Further studies are needed before these findings are translated into technologies that will further the diagnosis or treatment of gout. Until then, sufferers should continue to follow well-established medical advice and take any treatments they are prescribed.

Sir Muir Gray adds...

We will find that every chronic condition has both genetic and environmental causes.