Thursday 23 August 2018 3:49pm
There are dozens of regions in the human genome with signals of association with serum urate levels and gout, and kidney function. The new scientific challenge is converting these signals into functional insights. This information is critical to allow new medical interventions 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. Significantly, these associated regions could represent regulatory elements that control gene expression.
In our new manuscript published in Human Molecular Genetics, we have characterised a genetic variant that lies not inside, but just next to a gene called PDZK1. The 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.
We found that the genetic variant doesn’t affect the PDZK1 protein, but causes change in the amount of the PDZK1 gene produced. The genetic variant in human causes an increase of PDZK1 expression in the gut and kidney, and we confirmed this by studying the gene in zebrafish. 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.
Understanding how genetic variation contributes to someone’s risk of kidney disease or gout can, going forward, inform choice of drug and / or dietary regime for that person. This kind of scientific understanding of disease risk is bringing us into a new age of “precision medicine”.