ObjectivesGenome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000–3000 years.MethodsTwo genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype.ResultsIn addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10–8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients’ gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout.ConclusionsOur findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

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Summary Vitamin C (VC) distribution in our body requires VC transporters. However, mammalian VC exporters are yet to be identified. Herein, to unravel this long-standing mystery, we focused on the pathways whereby VC moves from blood to the brain, which should require a VC entrance and exit system composed of an importer and a latent exporter. Via cell-based transport analyses of VC efflux and using knockout mice generated via the CRISPR-Cas9 system, we identified GLUT12/SLC2A12 as a physiologically important VC efflux protein expressed in the choroid plexus; Glut12/Slc2a12 knockout halved the cerebral VC levels, markedly increased VC accumulation in the choroid plexus, and reduced the cerebrospinal fluid VC levels. These findings facilitate our understanding of VC regulation and the physiological impact of VC in our body.

The ABCG2 gene is a well-established hyperuricemia/gout risk locus encoding a urate transporter that plays a crucial role in renal and intestinal urate excretion. Hitherto, p.Q141K—a common variant of ABCG2 exhibiting approximately one half the cellular function compared to the wild-type—has been reportedly associated with early-onset gout in some populations. However, compared with adult-onset gout, little clinical information is available regarding the association of other uricemia-associated genetic variations with early-onset gout; the latent involvement of ABCG2 in the development of this disease requires further evidence. We describe a representative case of familial pediatric-onset hyperuricemia and early-onset gout associated with a dysfunctional ABCG2, i.e., a clinical history of three generations of one Czech family with biochemical and molecular genetic findings. Hyperuricemia was defined as serum uric acid (SUA) concentrations 420 μmol/L for men or 360 μmol/L for women and children under 15 years on two measurements, performed at least four weeks apart. The proband was a 12-year-old girl of Roma ethnicity, whose SUA concentrations were 397–405 µmol/L. Sequencing analyses focusing on the coding region of ABCG2 identified two rare mutations—c.393G>T (p.M131I) and c.706C>T (p.R236X). Segregation analysis revealed a plausible link between these mutations and hyperuricemia and the gout phenotype in family relatives. Functional studies revealed that p.M131I and p.R236X were functionally deficient and null, respectively. Our findings illustrate why genetic factors affecting ABCG2 function should be routinely considered in clinical practice as part of a hyperuricemia/gout diagnosis, especially in pediatric-onset patients with a strong family history.

In the present study we examined the effects of neonatal orosensory deprivation on taste-elicited gustatory activity in the rat parabrachial nucleus (PBN) using the functional anatomical marker cFos. Animals in three groups (GG, GO and GM) received gastric cannula implantation surgery on postnatal day 9 (P9). Animals in the fourth group (MR) did not receive any surgery. GG rats were fed by infusion of artificial milk directly into the stomach. GO rats were fed by intraoral infusion of artificial milk. GM and MR rats were reared by their mother with free access to mother's milk, water and rat chow. Rats from all groups were similar in body weight and length by P21. On P21 rats in all groups were intraorally presented with 0.5 M sucrose solution and the brains were extracted and processed for c-Fos immunohistchemistry. Taste-elicited c-Fos expression in both the gustatory waist area, and the external lateral subnucleus of the PBN in rats in the GG group was significantly more robust than in the other three groups. These findings suggest a substantial alteration in orosensoryevoked neuronal response in this nucleus, due to sensory or motor deprivation during a critical developmental stage.