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Objective: The development of acquired middle ear cholesteatoma is associated with a single nucleotide polymorphism, 538G>A, in the human adenosine triphosphate‐binding cassette transporter C11 (ABCC11) gene, which is a determinant of the earwax morphotype, such as wet‐ and dry‐type earwax; however, the mechanism underlying this association is unclear. We focused on the earwax pH and aimed to elucidate the mechanism between ABCC11 genotypes and acquired middle ear cholesteatoma. Study Design: Prospective observational study. Setting: Single‐center, academic hospital. Methods: We recruited 40 patients with acquired middle ear cholesteatoma who underwent surgery and 115 controls with no history of middle ear cholesteatoma. We assessed the earwax pH and ABCC11 genotypes in all participants. Clinical information was collected from the patients with cholesteatoma. Results: The earwax pH was significantly less acidic in patients with cholesteatoma and those carrying wet earwax genotypes (ABCC11 538G/G or 538G/A) than in the controls and those carrying the dry earwax genotype (ABCC11 538A/A), respectively. Furthermore, earwax pH was significantly positively correlated with high preoperative cholesteatoma stages in the patients with cholesteatoma. Conclusion: Our results show that the less acidic earwax pH was significantly related to the development and progression of acquired middle ear cholesteatoma. The less acidic earwax pH may play an important role in the mechanism underlying the association between acquired middle ear cholesteatoma and the ABCC11 gene at site 538. [ABSTRACT FROM AUTHOR]

Uric acid is the final purine metabolite in humans. Serum urate levels are regulated by a balance between urate production, mainly in the liver, and its excretion via the kidneys and small intestine. Given that uric acid exists as a urate anion at physiological pH 7.4, membrane transporters are required to regulate urate homeostasis. In the kidney, urate transporter 1, glucose transporter 9, and organic anion transporter 10 contribute to urate reabsorption, whereas sodium-dependent phosphate transport protein 1 would be involved in urate excretion. Other transporters have been suggested to be involved in urate handling in the kidney; however, further evidence is required in humans. ATP-binding cassette transporter G2 (ABCG2) is another urate transporter, and its physiological role as a urate exporter is highly demonstrated in the intestine. In addition to urate, ABCG2 regulates the behavior of endogenous substances and drugs; therefore, the functional inhibition of ABCG2 has physiological and pharmacological effects. Although these transporters explain a large part of the urate regulation system, they are not sufficient for understanding the whole picture of urate homeostasis. Therefore, numerous studies have been conducted to find novel urate transporters. This review provides the latest evidence of urate transporters from pathophysiological and clinical pharmacological perspectives. [ABSTRACT FROM AUTHOR]

Objective: The effects of coffee consumption on serum uric acid (SUA) levels and gout risk are controversial. There have hitherto been no reports based on Mendelian randomization (MR) analysis of its effects that consider pleiotropy. Here, we evaluated the effects of coffee consumption across ancestry populations, taking pleiotropy into account. Methods: We performed the first MR analyses for coffee consumption on SUA levels and gout, considering pleiotropy. We used the following summary statistics of genome‐wide association studies from a Japanese population: habitual coffee consumption (152,634 subjects), gout (3053 cases and 4554 controls), and SUA levels (121,745 subjects). In addition to fixed‐effect inverse variance weighted (IVW) meta‐analysis, we performed a robust evaluation of heterogeneity and removed several instruments for reasons of possible pleiotropy. Previous European datasets were also reevaluated while heterogeneity was considered. Results: Habitual coffee consumption was significantly and inversely associated with gout (odds ratio [OR] = 0.29, 95% confidence interval [95% CI]: 0.16‐0.51, P = 1.9 × 10−5) in random‐effect IVW (Phet = 5.5 × 10−19). Excluding pleiotropic instruments, the protective effect on gout was confirmed in fixed‐effect IVW analysis (OR = 0.75, 95% CI: 0.58‐0.97, P = 0.026) without heterogeneity (Phet = 0.39). However, we observed no significance in the previous European datasets when heterogeneity was considered. Associations were not observed between coffee consumption and SUA levels in either ancestry in MR analyses that considered pleiotropy. Multivariable MR analysis showed that increased coffee consumption significantly reduced gout risk, even after adjusting for SUA levels (OR = 0.50, 95% CI: 0.31‐0.81, P = 0.0046). Conclusion: With pleiotropy taken into account, our MR analyses revealed that coffee consumption can causally reduce gout risk, and that it may reduce gout risk independently of SUA levels. [ABSTRACT FROM AUTHOR]

The article discusses research which investigated the heritability estimates of gout, including its subtypes, in Japanese populations via genome-wide association study (GWS) meta-analyses. Cited are the findings of the investigation on single nucleotidepolymorphism (SNP)-based heritability of three major subtypes of gout, the estimated polygenetic contributions to the heritability of gout, and results indicating that genetic factors are contributors to individual variability in gout.

Objectives Up to 0.3% of Japanese have hypouricaemia. Most cases appear to result from a hereditary disease, renal hypouricaemia (RHUC), which causes exercise-induced acute kidney injury and urolithiasis. However, to what extent RHUC accounts for hypouricaemia is not known. We therefore investigated its frequency and evaluated its risks by genotyping a general Japanese population. Methods A cohort of 4993 Japanese was examined by genotyping the non-functional variants R90H (rs121907896) and W258X (rs121907892) of URAT1/SLC22A12 , the two most common causative variants of RHUC in Japanese. Results Participants' fractional excretion of uric acid and risk allele frequencies markedly increased at lower serum uric acid (SUA) levels. Ten participants (0.200%) had an SUA level ≤2.0 mg/dl and nine had R90H or W258X and were likely to have RHUC. Logistic regression analysis revealed these URAT1 variants to be significantly and independently associated with the risk of hypouricaemia and mild hypouricaemia (SUA ≤3.0 mg/dl) as well as sex, age and BMI, but these URAT1 variants were the only risks in the hypouricaemia population (SUA ≤2.0 mg/dl). W258X was only a risk in males with SUA ≤3.0 mg/dl. Conclusion Our study accurately reveals the prevalence of RHUC and provides genetic evidence for its definition (SUA ≤2.0 mg/dl). We also show that individuals with SUA ≤3.0 mg/dl, especially males, are prone to RHUC. Our findings will help to promote a better epidemiological understanding of RHUC as well as more accurate diagnosis, especially in males with mild hypouricaemia. [ABSTRACT FROM AUTHOR]

Objective: A single-nucleotide polymorphism 538G>A in the human ABCC11 gene is a determinant of the earwax morphotype. ABCC11 538GG and GA correspond to wet earwax and 538AA to dry earwax. Despite a putative positive correlation between the frequency of the 538G allele and the prevalence of cholesteatoma, minimal clinical information is currently available. We aimed to evaluate this association between the ABCC11 genotypes and acquired middle ear cholesteatoma. Study Design: Case-control study. Setting: Single-center academic hospital. Methods: We recruited 67 Japanese patients with acquired middle ear cholesteatoma (cholesteatoma group) and 100 Japanese controls with no history of middle ear cholesteatoma. We assessed the ABCC11 genotypes for all participants. Clinical information was collected from the cholesteatoma group. The genotype data of 104 Japanese people from the 1000 Genomes Project who represent the general population were used. Results: The proportion of participants with ABCC11 538GG or GA was significantly higher in the cholesteatoma group than in the control group or general Japanese population (P <.001). The ABCC11 538G allele frequency was also significantly higher in the cholesteatoma group than in the control group or general Japanese population (P <.001). Multivariate logistic regression analyses revealed a significant association between the ABCC11 genotype and acquired middle ear cholesteatoma (odds ratio, 5.49; 95% CI, 2.61-11.5; P <.001). Conclusion: Our results suggest that the ABCC11 genotypes could be associated with the development of acquired middle ear cholesteatoma among Japanese people. [ABSTRACT FROM AUTHOR]