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 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-increasing 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.