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

Abstract

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