Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

Abstract

Elevated serum urate levels cause gout, and correlate with cardio-metabolic diseases via poorly understood mechanisms. We performed a trans-ethnic genome-wide association study of serum urate among 457,690 individuals, identifying 183 loci (147 novel) that improve prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardio-metabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urateassociated loci and co-localization with gene expression in 47 tissues implicated kidney and liver as main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A trans-activated the promoter of the major urate transporter ABCG2 in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardio-metabolic traits.

High-Protein Diet Induces Hyperuricemia in a New Animal Model for Studying Human Gout

“…Hyperuricemia is the outcome of a combination of an endogenous purine metabolism disorder and an exogenous environmental disruption [37]. Recently, a trans-ancestry genome-wide association study, which included more than 450,000 individuals targeted at serum urate demonstrated that 183 loci were associated with gout [15]. However, few studies have focused on exogenous factors, such as dietary factors, that induce hyperuricemia or gout.…”

“…ABCG2 is also expressed in intestine, and many patients with hyperuricemia lost the expression of ABCG2 in intestines. The current researches based on genome-wide association study (GWAS) analysis almost focus on the comparison between patients and healthy people, and the results displayed the difference in these genes including ABCG2, SLC2A9, HNF1A, HNF4A, ALDH2, CNTN5, MIR302F and so on [15,16]. The mechanism of developing hyperuricemia and gout and the reasons for disruption or mutation in these genes remain unclear.…”

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 the ABCG2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout

“…The pathogenesis of gout is thought to require progression through three checkpoints: hyperuricaemia (HU), deposition of monosodium urate (MSU) crystals into articular and peri-articular structures, and an inflammatory response to these crystals [1]. Genome-wide association studies (GWAS) have emphasised the contribution to urate control of genetic variation in renal and gut urate transporters, including SLC2A9 and ABCG2 [2,3]. When combined, variants in these two genes explain 3-4% of variance in urate levels and have strong effects on the risk of gout [4,5].…”