Poster Annual Conference of the Genetics Society of Australasia with the NZ Society for Biochemistry & Molecular Biology

functional analysis of a gout-associated noncoding snp variant (706)

Sarada Ketharnathan 1 , Megan Leask 1 , Tony Merriman 1 , Julia Horsfield 1
  1. University of Otago, Dunedin, OTAGO, New Zealand

Gout is a type of chronic arthritis characterized by high levels of uric acid in the blood, and has an unusually high incidence in Maori and Pacific peoples. Genome-wide association studies identified about 30 genetic loci that increase the risk of high serum urate levels and/or gout.

Here, we functionally characterized a gout-associated single nucleotide polymorphism, rs1967017 located upstream of the PDZK1 gene, in a region that is highly enriched in gene regulatory features. We found that this variant region showed enhancer activity in the kidney cell line, HEK293 using a luciferase-based reporter system. Enhancer assays in zebrafish further revealed that the enhancer activity is highly specific to the pro-nephric ducts, which is also the site of expression of the pdzk1 gene in zebrafish. Interestingly, rs1967017 disrupts the binding site of the transcription factor HNF4A, which is crucial for kidney and liver development.

We propose that rs1967017 may lead to disrupted serum urate levels by aberrant regulation of PDZK1 gene expression, assisted by altered binding of the HNF4A transcription factor. This might impair the function of PDZK1 as a scaffolder that holds various urate transporters together.