In a recent study, University of Otago researchers characterized a genetic variant that helps understand why some people are at risk of gout.
Gout is a painful and debilitating arthritic disease.
It is caused by persistently elevated levels of urate in the blood, which causes severe joint pain and swelling, especially in peoples’ toes, knees, elbows, wrists, and fingers.
Gout can be treated using drugs that lower urate levels. But if left untreated, it can cause serious damage to joints, kidneys, and quality of life.
Researchers have recently characterized the genetic variant that lies not inside, but just next to a gene called PDZK1.
This PDZK1 protein product helps excrete urate through the kidney and gut. In this way, PDZK1 controls the amount of serum urate which, when high, form crystals that cause gout.
In the study, the team found that the genetic variant doesn’t affect the PDZK1 protein, but causes a change in the amount of the PDZK1 gene produced.
Unexpectedly, the effect of the genetic variant in humans is in the gut as well as the kidney.
The team confirmed this by studying where the variant switches on gene expression in zebrafish embryos, which are ideal because their embryos are transparent.
The results identified a new molecular pathway for gout, enabling a new understanding of why there is gout risk in patients with this particular genetic variant.
The team explains there are dozens of regions in the human genome with signals that increase serum urate levels and risk of gout, and kidney function.
The new scientific challenge is converting these signals into functional insights. This information is critical to allow new medical intervention in gout and kidney disease.
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.
Understanding how genetic variation contributes to someone’s risk of gout or kidney disease can, going forward, inform the choice of treatment for that person.
The researchers suggest that this kind of scientific understanding of disease risk is bringing us into a new age of precision medicine.
The research is published in the journal Human Molecular Genetics. It was funded by the Health Research Council of New Zealand.
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