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.

Voltage gated sodium channels (Nav) underlie the rapid upstroke of action potentials (AP) in excitable tissues. Binding of channel interactive proteins is essential for controlling fast and long term inactivation. In the structure of the complex of the carboxy-terminal portion of Nav1.5 (CTNav1.5) with Calmodulin (CaM)–Mg2+ reported here both CaM lobes interact with the CTNav1.5. Based on the differences between this structure and that of an inactivated complex, we propose that the structure reported here represents a non-inactivated state of the CTNav, i.e., the state that is poised for activation. Electrophysiological characterization of mutants further supports the importance of the interactions identified in the structure. Isothermal titration calorimetry experiments show that CaM binds to CTNav1.5 with high affinity. The results of this study provide unique insights into the physiological activation and the pathophysiology of Nav channels.

The pathophysiological nature of the common ABCG2 gout and hyperuricemia associated variant Q141K (rs2231142) remains undefined. Here, we use a human interventional cohort study (ACTRN12615001302549) to understand the physiological role of ABCG2 and find that participants with the Q141K ABCG2 variant display elevated serum urate, unaltered FEUA, and significant evidence of reduced extra-renal urate excretion. We explore mechanisms by generating a mouse model of the orthologous Q140K Abcg2 variant and find male mice have significant hyperuricemia and metabolic alterations, but only subtle alterations of renal urate excretion and ABCG2 abundance. By contrast, these mice display a severe defect in ABCG2 abundance and function in the intestinal tract. These results suggest a tissue specific pathobiology of the Q141K variant, support an important role for ABCG2 in urate excretion in both the human kidney and intestinal tract, and provide insight into the importance of intestinal urate excretion for serum urate homeostasis.

Hyperuricemia, or elevated serum urate, causes urate kidney stones and gout and also increases the incidence of many other conditions including renal disease, cardiovascular disease, and metabolic syndrome. As we gain mechanistic insight into how urate contributes to human disease, a clear sex difference has emerged in the physiological regulation of urate homeostasis. This review summarizes our current understanding of urate as a disease risk factor and how being of the female sex appears protective. Further, we review the mechanisms of renal handling of urate and the significant contributions from powerful genome-wide association studies of serum urate. We also explore the role of sex in the regulation of specific renal urate transporters and the power of new animal models of hyperuricemia to inform on the role of sex and hyperuricemia in disease pathogenesis. Finally, we advocate the use of sex differences in urate handling as a potent tool in gaining a further understanding of physiological regulation of urate homeostasis and for presenting new avenues for treating the constellation of urate related pathologies.

A primary function of the kidney is to maintain homeostasis. Recent studies have shown that specialized G‐protein coupled receptors, such as olfactory receptors (ORs), play essential roles in modulating kidney function. However, ORs are often orphan receptors with unknown ligands. In a recent RNA seq screen we identified 11 ORs as expressed in the renal cortex, including 5 ORs we had previously published as being expressed in the kidney, and 6 novel ORs. We have previously published the results of ligand screening for 4 of these ORs (Olfr31, Olfr78, Olfr1392, Olfr1393), but have not yet explored the ligands of the remaining 7 (Olfr56, Olfr90, Olfr461, Olfr558, Olfr1033, Olfr1034, Olfr1396). In order to better understand the physiological relevance of these ORs in the kidney, we cloned these 7 receptors from the kidney and attempted to determine ligands that activate these receptors to provide insight into physiological function. Ligand‐screening studies were performed using a cAMP dependent luciferase reporter assay, for which it is crucial that the ORs traffic to the cell surface. Because surface expression is often problematic for heterologously expressed ORs, we first performed immunofluorescence imaging utilizing an N‐terminal flag tag to determine the surface expression of each OR. Surface labeling for flag antibody in live, unpermeabilized cells revealed that 5 ORs (Olfr90, Olfr461, Olfr558, Olfr1034, Olfr1396) demonstrated robust surface trafficking, while 2 ORs (Olfr56 and Olfr1033) were very poorly trafficked to the cell surface. Thus, we screened the 5 ORs which trafficked to the cell surface using a ligand library of 85 compounds with diverse functional groups, divided into 3 categories: 1) compounds known to activate a large percentage of isolated olfactory sensory neurons, 2) sibling ligands, or compounds known to activate ORs within the same sub‐family as these uncharacterized ORs, particularly those known to be present in biofluids including blood and urine, and 3) other odorant and small molecules known to exist in the body produced either endogenously or by microorganisms. Olfr558 has previously reported ligands, and we were able to confirm activation by both butyric acid and nonanoic acid using our luciferase assay (p<0.05 vs control media); to date, none of the other chemicals screened have activated this receptor. Using this library of odorant compounds, we identified 10 novel ligands that activated Olfr90 (p<0.05 vs control media) in a dose dependent manner, none of which activated unrelated ORs or cells transfected with vector only (1‐octen‐3‐ol, 2‐methyl‐4‐propyl‐1,3‐oxathiane, 2‐pentylfuran, allyl benzene, amyl acetate, cinnamaldehyde, 2‐octanone, 3‐octanol, benzyl cyanide, linalool). Interestingly, 6 out of 10 of these ligands are known to be of fungal origin, strongly suggesting that this receptor senses fungal metabolites. To date, none of the compounds screened against Olfr461, Olfr1034, or Olfr1396 have resulted in OR activation. In sum, we have examined 7 ORs expressed in the renal c...