Decoding genetics to understand gout, kidney disease

Associate Professor Julia Horsfield and Professor Tony Merriman from the University of Otago, and Dr Justin O’Sullivan from the University of Auckland, and colleagues, have had their Health Research Council of New Zealand-funded research published in Human Molecular Genetics.

“Understanding how genetic variation contributes to someone’s risk of kidney disease or gout can, going forward, inform choice of drug for that person,” says Dr Horsfield. “This kind of scientific understanding of disease risk is bringing us into a new age of “precision medicine”.

Dr Horsfield and co-authors characterised a genetic variant that does not lie inside a gene. Rather, it lies externally to one, next to the ‘Na(+)/H(+) exchange regulatory cofactor NHE-RF3’ gene (PDZK1). The PDZK1 protein has a specific job – it helps the body to excrete urate, which when present in high levels forms 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,” says Dr Horsfield. “Unexpectedly, the effect of the genetic variant in human is in the gut as well as the kidney and we confirmed this by studying the how the variant controls gene expression 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.”

Reference:

Kathanathan S, Leask M, Boocock J, Phipps-Green AJ, Antony J, O’Sullivan JM, Merriman TR, Horsfield JA. A non-coding genetic variant maximally associated with serum urate levels is functionally linked to HNF4A-dependent PDZK1 expression. Human Molecular Genetics. 2018 Aug; ddy295, https://doi.org/10.1093/hmg/ddy295