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.
The dual-use risk of infectious disease research using enhanced potential pandemic pathogens (ePPP), particularly gain-of-function (GOF) research, has been debated since 2011. As of now, research is ...supported on the condition that the research plan is reviewed and the actual experiment is supervised. However, the kinds of research conducted and what benefits they have brought to our society have not been adequately verified. Nevertheless, due to the COVID-19 pandemic that began at the end of 2019 and caused numerous deaths and wide economic disruption, the importance of infectious disease control from an international perspective has been recognized. Although complete control of the pandemic is still far off, positive signs include generating epidemiological trends based on genome analysis, therapeutic drug and vaccine development, clinical patient management, and public health policy interventions. In this context, the time has come to reconsider the true significance of GOF research on ePPP and the state of research governance in the post-COVID-19 era. In particular, the risks of such research are clearer than before, whereas its benefits seem less apparent. In this paper, we summarize the history of discussions on such GOF research, its significance in the light of the current COVID-19 pandemic, and the direction we shall take in the future.
To clarify the physiological and pathophysiological roles of intestinal urate excretion via ABCG2 in humans, we genotyped ABCG2 dysfunctional common variants, Q126X (rs72552713) and Q141K ...(rs2231142), in end-stage renal disease (hemodialysis) and acute gastroenteritis patients, respectively. ABCG2 dysfunction markedly increased serum uric acid (SUA) levels in 106 hemodialysis patients (P = 1.1 × 10(-4)), which demonstrated the physiological role of ABCG2 for intestinal urate excretion because their urate excretion almost depends on intestinal excretion via ABCG2. Also, ABCG2 dysfunction significantly elevated SUA in 67 acute gastroenteritis patients (P = 6.3 × 10(-3)) regardless of the degree of dehydration, which demonstrated the pathophysiological role of ABCG2 in acute gastroenteritis. These findings for the first time show ABCG2-mediated intestinal urate excretion in humans, and indicates the physiological and pathophysiological importance of intestinal epithelium as an excretion pathway besides an absorption pathway. Furthermore, increased SUA could be a useful marker not only for dehydration but also epithelial impairment of intestine.
Hearing loss is one of the biggest health problems in the world and occupational noise-induced hearing loss is recognized as the most common work-related illness. However, many factors that result in ...hearing loss make it difficult to define the specific factor that induces noise-induced hearing loss. To access the exact effect of occupational noise exposure on hearing, we conducted a cross-sectional cohort study of the relationship between noise exposure and hearing impairment in 50-year-old male Japanese Self-Defense Force (JSDF) personnel who work in a noisy environment. This population is ideal for the detection of noise-induced hearing impairments due to the homogeneity of genetic and social backgrounds.
The data utilized in this study were collected from a “50-year-old milestone health examination” of the JSDF from July 2013 to October 2015. One thousand sixty-seven male personnel were enrolled in the study. Pure-tone audiometry was conducted with an audiometer. A survey questionnaire asked participants to self-report occupational noise exposure.
This cohort revealed that noise-exposed personnel had a higher hearing threshold and a higher odds ratio in 1) the average threshold of 4 frequencies (500 + 1000 + 2000 + 4000 Hz / 4), 2) the average threshold of higher 3 frequencies (2000 + 4000 + 8000 Hz / 3), and 3) the threshold of 4 kHz compared to no noise-exposed control personnel. The prevalence of tinnitus was also significantly higher in the noise-exposed group.
This study provides specific evidence for the relationship between noise exposure and noise-induced hearing impairments.
Dysfunctional missense variant of
(
/
), 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
) 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
variant exhibited significantly lower serum urate levels and higher FE
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.
Dysfunctional variants of ATP-binding cassette transporter subfamily G member 2 (ABCG2), a urate transporter in the kidney and intestine, are the major causes of hyperuricemia and gout. A recent ...study found that ABCG2 is a major transporter of uremic toxins; however, few studies have investigated the relationship between ABCG2 gene polymorphisms and mortality. This prospective cohort study of 1214 hemodialysis patients investigated the association between serum uric acid levels and ABCG2 genotype and mortality. Genotyping of dysfunctional ABCG2 variants, Q126X (rs72552713) and Q141K (rs2231142), was performed using the patients’ DNA. During the study period, 220 patients died. Lower serum uric acid levels were associated with higher mortality (hazard ratio HR 1.89, 95% confidence interval CI 1.14–3.10,
P
≤ 0.001). ABCG2 dysfunction, estimated by genetic variants, had a significant positive association with serum uric acid levels (full function: 7.4 ± 1.2 mg/dl, 3/4 function: 7.9 ± 1.3 mg/dl, 1/2 function: 8.2 ± 1.4 mg/dl, ≤ 1/4 function: 8.7 ± 1.3 mg/dl,
P
≤ 0.001). This association remained significant on multiple regression analysis. The Cox proportional hazard analysis indicated that the ABCG2 ≤ 1/4 function type was significantly associated with higher mortality (HR 6.66, 95% CI 2.49 to 17.8,
P
≤ 0.001) than the other function types. These results showed that ABCG2 plays a physiologically important role in uric acid excretion, and that ABCG2 dysfunction is a risk factor for mortality in hemodialysis patients.
Gout is a common disease resulting from hyperuricemia. Recently, a genome-wide association study identified an association between gout and a single nucleotide polymorphism (SNP) rs2188380, located ...on an intergenic region between MYL2 and CUX2 on chromosome 12. However, other genes around rs2188380 could possibly be gout susceptibility genes. Therefore, we performed a fine-mapping study of the MYL2-CUX2 region. From 8,595 SNPs in the MYL2-CUX2 region, 9 tag SNPs were selected, and genotyping of 1,048 male gout patients and 1,334 male controls was performed by TaqMan method. Eight SNPs showed significant associations with gout after Bonferroni correction. rs671 (Glu504Lys) of ALDH2 had the most significant association with gout (P = 1.7 × 10(-18), odds ratio = 0.53). After adjustment for rs671, the other 8 SNPs no longer showed a significant association with gout, while the significant association of rs671 remained. rs671 has been reportedly associated with alcohol drinking behavior, and it is well-known that alcohol drinking elevates serum uric acid levels. These data suggest that rs671, a common functional SNP of ALDH2, is a genuine gout-associated SNP in the MYL2-CUX2 locus and that "A" allele (Lys) of rs671 plays a protective role in the development of gout.
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.
The hepatocyte growth factor receptor c-Met is a receptor tyrosine kinase that plays an important role in tumor growth by activating mitogenic signaling pathways. The goal of this study was to ...evaluate the role of c-Met in the biology of ovarian cancer and to determine its potential as a therapeutic target. c-Met protein expression was detected by immunohistochemistry in 138 advanced-stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. Fifteen of 138 (11%) tissues had c-Met overexpression. Median survival for patients with high c-Met levels was 17 months versus 32 months (P = 0.001) for patients with low c-Met expression. Infection of SKOV-3ip1 cells with an adenovirus expressing a small interfering RNA (siRNA) against c-Met efficiently inhibited c-Met protein and mRNA expression as well as extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling. It also inhibited adhesion to different extracellular matrix components, human primary mesothelial cells, and full-thickness human peritoneum and, in vivo, to mouse peritoneum. This was paralleled by a significant reduction in alpha(5) and beta(1) integrin protein and mRNA expression as well as a reduction of urokinase and matrix metalloproteinase (MMP)-2/MMP-9 activity. In SKOV-3ip1 ovarian cancer xenografts, i.p. treatment with the c-Met siRNA significantly reduced tumor burden, ascites formation, protease activity, and the number of peritoneal implants but not tumor size or angiogenesis. These results suggest that c-Met overexpression is a prognostic factor in ovarian cancer and that targeting c-Met in vivo inhibits peritoneal dissemination and invasion through an alpha(5)beta(1) integrin-dependent mechanism. Therefore, c-Met should be explored further as a therapeutic target in ovarian cancer.
Local microbial infections induced by multiple-drug-resistant bacteria in the orthopedic field can be intractable, therefore development of new therapeutic modalities is needed. Photodynamic therapy ...(PDT) is a promising alternative modality to antibiotics for intractable microbial infections, and we recently reported that PDT has the potential to accumulate neutrophils into the infected site which leads to resolution of the infection. PDT for cancer has long been known to be able to stimulate the innate and adaptive arms of the immune system.
In the present study, a murine methicillin-resistant Staphylococcus aureus (MRSA) arthritis model using bioluminescent MRSA and polystyrene microparticles was established, and both the therapeutic (Th-PDT) and preventive (Pre-PDT) effects of PDT using methylene blue as photosensitizer were examined. Although Th-PDT could not demonstrate direct bacterial killing, neutrophils were accumulated into the infectious joint space after PDT and MRSA arthritis was reduced. With the preconditioning Pre-PDT regimen, neutrophils were quickly accumulated into the joint immediately after bacterial inoculation and bacterial growth was suppressed and the establishment of infection was inhibited.
This is the first demonstration of a protective innate immune response against a bacterial pathogen produced by PDT.
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