Functional Urate-Associated Genetic Variants Influence Expression of lincRNAs and .

Genetic variation in the genomic regulatory landscape likely plays a crucial role in the pathology of disease. Non-coding variants associated with disease can influence the expression of long intergenic non-coding RNAs (lincRNAs), which in turn function in the control of protein-coding gene expression. Here, we investigate the function of two independent serum urate-associated signals (SUA1 and SUA2) in close proximity to lincRNAs and an enhancer that reside ∼60 kb and ∼300 kb upstream of , respectively. Variants within SUA1 are expression quantitative trait loci (eQTL) for and , both co-expressed with . We have also identified that variants within SUA1 are -eQTL for genes that are active in kidney- and serum urate-relevant pathways. Serum urate-associated variants and within SUA2 lie within an enhancer that recruits the transcription factor HNF4α and forms long range interactions with and . The urate-raising alleles of and increase enhancer activity and associate with increased expression of . We show that the SUA2 enhancer region drives expression in the zebrafish pronephros, recapitulating endogenous expression. Depletion of and in HEK293 cells in turn lead to increased expression. Collectively, our results are consistent with serum urate variants mediating long-range transcriptional regulation of the lincRNAs and and urate relevant genes (e.g., and ) in .