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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  MAF , respectively. Variants within SUA1 are expression quantitative trait loci (eQTL) for  LINC01229  and  MAFTRR , both co-expressed with  MAF . We have also identified that variants within SUA1 are  trans -eQTL for genes that are active in kidney- and serum urate-relevant pathways. Serum urate-associated variants  rs4077450  and  rs4077451  within SUA2 lie within an enhancer that recruits the transcription factor HNF4α and forms long range interactions with  LINC01229  and  MAFTRR . The urate-raising alleles of  rs4077450  and  rs4077451  increase enhancer activity and associate with increased expression of  LINC01229 . We show that the SUA2 enhancer region drives expression in the zebrafish pronephros, recapitulating endogenous  MAF  expression. Depletion of  MAFTRR  and  LINC01229  in HEK293 cells in turn lead to increased  MAF  expression. Collectively, our results are consistent with serum urate variants mediating long-range transcriptional regulation of the lincRNAs  LINC01229  and  MAFTRR  and urate relevant genes (e.g.,  SLC5A8  and  EHHADH ) in  trans .

Functional Urate-Associated Genetic Variants Influence Expression of lincRNAs LINC01229 and MAFTRR