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-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.

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

“…For 16 loci ( ABCG2, B4GALT1, BCAS3, FGF5, BICC1, HFN4G, IGF1R, INHBB, NFAT5, PDZK1, QRICH2, SLC16A9, SLC17A1, TMEM171, TRIM46, UBE2Q2 ) the pattern of association was consistent between the East Asian and European GWAS suggesting strong similarity between the underlying haplotypic structure and casual variant(s) (Figure S5). The MAF locus contains two association signals in the East Asian population, one that is shared with the European population and one that is specific to the East Asian population (Figure S6) [12]. The lead SNP for the East Asian population is rs889472 ; this variant is common in both European (C-allele = 0.38) and East Asian (C-allele = 0.60) individuals from the 1000 Genomes Project yet there is no serum urate association signal in the European population.…”

“…Also, at SLC16A9 there was a second cis -eQTL over CCDC6 that was weakly associated with serum urate levels. Differential cis- and trans -eQTL signals are reminiscent of the situation at the serum urate-associated cis- and trans -eQTL signals at the MAFTRR locus [12].…”

“…There has, however, been little progress on understanding the molecular basis of the association for the various loci. Probable causal genes have been identified at only about one fifth of the 36 loci [10–12], with strong evidence for causality for variants identified at ABCG2 ( rs2231142 ; Q141K) and PDZK1 ( rs1967017 ) [11, 13–17].…”

GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background

“…Among the other top hits, five are close to transcription factors involved in kidney and liver development (HNF4G, HNF1A, HNF4A, HLF and MAF). These are not part of a globally enriched gene set, but recent functional work has shown that the associated missense variant in HNF4A results in differential regulation of the urate solute carrier ABCG2 [17], while the MAF association has been shown to regulate SLC5A8 [20]. Finally, two other loci show large signals: a missense variant in INHBC, a TGF-family hormone, and a variant in/near GCKR, a glucose-enzyme regulator.…”

Pleiotropic effect of ABCG2 in gout: involvement in serum urate levels and progression from hyperuricemia to gout

“…How rs10011796 (or more likely a variant in linkage disequilibrium) could synergise with rs2231142 to amplify the risk of gout is unclear. However it has previously been reported that a urate-associated variant at the MAF locus influences the expression of MAF via a long non-coding RNA (50). It is possible that in Western Polynesian people with HU, the combination of the 141K risk allele with the rs10011796 CC-genotype has an epistatic effect where an altered amount of 141K is internalized, disrupting important stoichiometric relationships and promoting gouty inflammation.…”