There are over three million cases of gout, a painful arthritic condition; it happens when uric acid builds up and crystalizes in the joints. Researchers at the University of Otago have identified a small change in a gene that has opened up a new understanding of the disease. The work has been reported in Human Molecular Genetics.
When purines, which are naturally made by the body and are present in some foods, are broken down by the body, it creates uric acid. High levels of uric acid in the blood leads to painful swelling in the joints, particularly in fingers, wrists, elbows, toes, and knees. Therapeutics can be used to lower uric acid levels, or else joints can suffer serious damage.
A research team including graduate student Sarada Ketharnathan, Associate Professor Julia Horsfield of the Department of Pathology and Professor Tony Merriman of the Department of Biochemistry located the small change next to the PDZK1 gene that they linked to gout.
PDZK1 produces the PDZK1 protein, which helps the body excrete uric acid or urate through the gut and kidney. That keeps serum levels low and prevents the crystallization that leads to gout.
"We found that the genetic variant doesn't affect the PDZK1 protein, but causes [a] change in the amount of the PDZK1 gene produced," said Associate Professor Horsfield. "Unexpectedly, the effect of the genetic variant in humans is in the gut as well as the kidney. We confirmed this by studying where the variant switches on gene expression in zebrafish embryos, which are ideal because their embryos are transparent. Our results have identified a new molecular pathway for gout, enabling new understanding of why there is gout risk in patients with this particular genetic variant,” she added.
Many places in our genome contain signals that raise serum urate levels, and thereby increase the risk of gout, explained Horsfield. Next, we have to learn more about those signals. They pose an interesting challenge to researchers because often, they are not within the portions of the genome that code for protein.
"Since many of the regions lie outside of genes, it is not known how they could control urate levels and risk of gout or kidney disease. These associated regions probably represent regulatory elements that control gene expression," she continued.
For individual patients, genetic variation likely plays a major part in determining their risk for many diseases, like gout. It will be important to learn more about how those small changes in genes result in big changes in health risk.
"This kind of scientific understanding of disease risk is bringing us into a new age of 'precision medicine’,” added Horsfield.