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Gout is a common disease which results from hyperuricemia. We have reported that the dysfunction of urate exporter ABCG2 is the major cause of renal overload (ROL) hyperuricemia, but its involvement in renal underexcretion (RUE) hyperuricemia, the most prevalent subtype, is not clearly explained so far. In this study, the association analysis with 644 hyperuricemia patients and 1,623 controls in male Japanese revealed that ABCG2 dysfunction significantly increased the risk of RUE hyperuricemia as well as overall and ROL hyperuricemia, according to the severity of impairment. ABCG2 dysfunction caused renal urate underexcretion and induced hyperuricemia even if the renal urate overload was not remarkable. These results show that ABCG2 plays physiologically important roles in both renal and extra-renal urate excretion mechanisms. Our findings indicate the importance of ABCG2 as a promising therapeutic and screening target of hyperuricemia and gout.

Background Magnetic resonance imaging (MRI) cardiac gated phase contrast (PC) cine techniques have non-invasively shown the effect of the cardiac pulse on cerebrospinal fluid (CSF) movement. Echo planar imaging (EPI) has shown CSF movement as influenced by both cardiac pulsation and respiration. Previously, it has not been possible to visualize CSF movement in response to respiration non-invasively. The present study was undertaken to do so. Methods The effect of respiration on CSF movement was investigated using a non-contrast time-spatial labeling inversion pulse (Time-SLIP) with balanced steady-state free precession (bSSFP) readout. CSF movement was observed in the intracranial compartment in response to respirations in ten normal volunteers. To elucidate the respiration effect, the acquisition was triggered at the beginning of deep inhalation, deep exhalation and breath holding. Results By employing this respiration-induced spin labeling bSSFP cine method, we were able to visualize CSF movement induced by respiratory excursions. CSF moved cephalad (16.4 ± 7.7 mm) during deep inhalation and caudad (11.6 ± 3.0 mm) during deep exhalation in the prepontine cisternal area. Small but rapid cephalad (3.0 ± 0.4 mm) and caudad (3.0 ± 0.5 mm) movement was observed in the same region during breath holding and is thought to reflect cardiac pulsations. Conclusions The Time-SLIP bSSFP cine technique allows for non-invasive visualization of CSF movement associated with respiration to a degree not previously reported.

Dysfunctional missense variant of organic anion transporter 10 ( OAT10 / SLC22A13 ), rs117371763 (c.1129C>T; p.R377C), is associated with a lower susceptibility to gout. OAT10 is a urate transporter; however, its physiological role in urate handling remains unclear. We hypothesized that OAT10 could be a renal urate re-absorber that will be a new molecular target of urate-lowering therapy like urate transporter 1 (URAT1, a physiologically-important well-known renal urate re-absorber) and aimed to examine the effect of OAT10 dysfunction on renal urate handling. For this purpose, we conducted quantitative trait locus analyses of serum urate and fractional excretion of uric acid (FE UA ) using samples obtained from 4,521 Japanese males. Moreover, we performed immunohistochemical and functional analyses to assess the molecular properties of OAT10 as a renal urate transporter and evaluated its potential interaction with urate-lowering drugs. Clinico-genetic analyses revealed that carriers with the dysfunctional OAT10 variant exhibited significantly lower serum urate levels and higher FE UA values than the non-carriers, indicating that dysfunction of OAT10 increases renal urate excretion. Given the results of functional assays and immunohistochemical analysis demonstrating the expression of human OAT10 in the apical side of renal proximal tubular cells, our data indicate that OAT10 is involved in the renal urate reabsorption in renal proximal tubules from urine. Additionally, we found that renal OAT10 inhibition might be involved in the urate-lowering effect of losartan and lesinurad which exhibit uricosuric effects; indeed, losartan, an approved drug, inhibits OAT10 more strongly than URAT1. Accordingly, OAT10 can be a novel potential molecular target for urate-lowering therapy.

Gout is a common disease which mostly occurs after middle age, but more people nowadays develop it before the age of thirty. We investigated whether common dysfunction of ABCG2, a high-capacity urate transporter which regulates serum uric acid levels, causes early-onset gout. 705 Japanese male gout cases with onset age data and 1,887 male controls were genotyped and the ABCG2 functions which are estimated by its genotype combination were determined. The onset age was 6.5 years earlier with severe ABCG2 dysfunction than with normal ABCG2 function ( P = 6.14 × 10 −3 ). Patients with mild to severe ABCG2 dysfunction accounted for 88.2% of early-onset cases (twenties or younger). Severe ABCG2 dysfunction particularly increased the risk of early-onset gout (odds ratio 22.2, P = 4.66 × 10 −6 ). Our finding that common dysfunction of ABCG2 is a major cause of early-onset gout will serve to improve earlier prevention and therapy for high-risk individuals.

Purpose NPB-22 (quinolin-8-yl 1-pentyl-1 H -indazole-3-carboxylate), Adamantyl-THPINACA ( N -(1-adamantantyl)-1-[(tetrahydro-2 H -pyran-4-yl)methyl]-1 H -indazole-3-carboxamide), and CUMYL-4CN-B7AICA (1-(4-cyanobutyl)- N -(2-phenylpropan-2-yl)-1 H - pyrrolo[2,3-b]pyridine-3-carboxamide), synthetic cannabinoids were evaluated in terms of CB 1 (cannabinoid receptor type 1) and CB 2 (cannabinoid receptor type 2) activities, and their biological effects when inhaled similar to cigarettes were examined. Methods The half maximal effective concentration values of the aforementioned synthetic cannabinoids at the CB 1 and CB 2 were investigated using [ 35 S]guanosine-5’- O -(3-thio)-triphosphate binding assays. In addition, their biological effects were evaluated using the inhalation exposure test with mice. The smoke generated was recovered by organic solvents in the midget impingers, and the thermal degradation compounds of the smoke components were identified and quantified using a liquid chromatography–photo diode array detector. Results NPB-22 and Adamantyl-THPINACA had equivalent CB 1 activity in in vitro assays. Meanwhile, NPB-22 had a weaker biological effect on some items on the inhalation exposure test than Adamantyl-THPINACA. When analyzing organic solvents in the midget impingers, it was revealed that NPB-22 was degraded to 8-quinolinol and pentyl indazole 3-carboxylic acid by combustion. In addition, these degradation compounds did not have CB 1 activity. Conclusion It was estimated that the biological effects of NPB-22 on the inhalation exposure test weakened because it underwent thermal degradation by combustion, and the resultant degradation compounds did not have any CB 1 activity in vitro.

Urate transporter 1 ( URAT1/SLC22A12 ), a urate transporter gene, is a causative gene for renal hypouricemia type 1. Among several reported nonsynonymous URAT1 variants, R90H (rs121907896) and W258X (rs121907892) are frequent causative mutations for renal hypouricemia. However, no case-control study has evaluated the relationship between gout and these two variants. Additionally, the effect size of these two variants on serum uric acid (SUA) levels remains to be clarified. Here, 1,993 primary gout patients and 4,902 health examination participants (3,305 males and 1,597 females) were genotyped with R90H and W258X. These URAT1 variants were not observed in any gout cases, while 174 subjects had the URAT1 variant in 2,499 health examination participants, respectively ( P  = 8.3 × 10 −46 ). Moreover, in 4,902 health examination participants, the URAT1 nonfunctional variants significantly reduce the risk of hyperuricemia ( P  = 6.7 × 10 −19 ; risk ratio = 0.036 in males). Males, having 1 or 2 nonfunctional variants of URAT1 , show a marked decrease of 2.19 or 5.42 mg/dl SUA, respectively. Similarly, females, having 1 or 2 nonfunctional variants, also evidence a decrease of 1.08 or 3.89 mg/dl SUA, respectively. We show that URAT1 nonfunctional variants are protective genetic factors for gout/hyperuricemia and also demonstrated the sex-dependent effect size of these URAT1 variants on SUA ( P for interaction = 1.5 × 10 −12 ).

Gout/hyperuricemia is a common multifactorial disease having typical environmental risks. Recently, common dysfunctional variants of ABCG2 , a urate exporter gene also known as BCRP , are revealed to be a major cause of gout/hyperuricemia. Here, we compared the influence of ABCG2 dysfunction on serum uric acid (SUA) levels with other typical risk factors in a cohort of 5,005 Japanese participants. ABCG2 dysfunction was observed in 53.3% of the population investigated and its population-attributable risk percent (PAR%) for hyperuricemia was 29.2%, much higher than those of the other typical environmental risks, i.e. overweight/obesity (BMI ≥ 25.0; PAR% = 18.7%), heavy drinking (>196 g/week (male) or >98 g/week (female) of pure alcohol; PAR% = 15.4%) and aging (≥60 years old; PAR% = 5.74%). SUA significantly increased as the ABCG2 function decreased (P = 5.99 × 10 −19 ). A regression analysis revealed that ABCG2 dysfunction had a stronger effect than other factors; a 25% decrease in ABCG2 function was equivalent to “an increase of BMI by 1.97-point” or “552.1 g/week alcohol intake as pure ethanol” in terms of ability to increase SUA. Therefore, ABCG2 dysfunction originating from common genetic variants has a much stronger impact on the progression of hyperuricemia than other familiar risks. Our study provides a better understanding of common genetic factors for common diseases.

Gout is a common type of acute arthritis that results from elevated serum uric acid (SUA) levels. Recent genome-wide association studies (GWASs) have revealed several novel single nucleotide polymorphism (SNPs) associated with SUA levels. Of these, rs10821905 of A1CF and rs1178977 of BAZ1B showed the greatest and the second greatest significant effect size for increasing SUA level in the Japanese population, but their association with gout is not clear. We examined their association with gout using 1411 clinically-defined Japanese gout patients and 1285 controls, and meta-analyzed our previous gout GWAS data to investigate any association with gout. Replication studies revealed both SNPs to be significantly associated with gout (P = 0.0366, odds ratio [OR] with 95% confidence interval [CI]: 1.30 [1.02–1.68] for rs10821905 of A1CF, P = 6.49 × 10–3, OR with 95% CI: 1.29 [1.07–1.55] for rs1178977 of BAZ1B). Meta-analysis also revealed a significant association with gout in both SNPs (Pmeta = 3.16 × 10–4, OR with 95% CI: 1.39 [1.17–1.66] for rs10821905 of A1CF, Pmeta = 7.28 × 10–5, OR with 95% CI 1.32 [1.15–1.51] for rs1178977 of BAZ1B). This study shows the first known association between SNPs of A1CF, BAZ1B and clinically-defined gout cases in Japanese. Our results also suggest a shared physiological/pathophysiological background between several populations, including Japanese, for both SUA increase and gout susceptibility. Our findings will not only assist the elucidation of the pathophysiology of gout and hyperuricemia, but also suggest new molecular targets.