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• Genome-wide association studies for pelvic organ prolapse in the Japanese population

  Matsunami, M; Imamura, M; Ashikari, A; Liu, XX; Tomizuka, K; Hikino, K; Miwa, K; Kadekawa, K; Suda, T; Matsuda, K; Miyazato, M; Terao, C; Maeda, S

  COMMUNICATIONS BIOLOGY ( Nature Research )  7 ( 1 ) 1188 - 9   2024.09

  Type of publication: Research paper (scientific journal)

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  Pelvic organ prolapse (POP) affects approximately 40% of elderly women, characterized by thedescent of the pelvic organs into the vaginal cavity. Here we present the results of a genome-wideassociation study (GWAS) for susceptibility to POP comprising 771 cases and 76,625 controls in theJapanese population. We identified a significant association of WT1 locus with POP in the Japanesepopulation; rs10742277; odds ratio (OR) = 1.48, 95% confidence interval (CI), 1.29–1.68,P = 6.72 × 10−9. Subsequent cross-ancestry GWAS meta-analysis combining the Japanese data andpreviously reported European data, including 28,857 cases and 622,916 controls, identified FGFR2locus as a novel susceptibility locus to POP (rs7072877; OR = 1.06, 95% CI, 1.04–1.08,P = 4.11 × 10−8). We also observed consistent directions of the effects for 21 out of 24 European GWASderived loci (binomial test P = 2.8 × 10−4), indicating that most of susceptibility loci for POP are sharedacross the Japanese and European populations.

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• Gut microbiota-based prediction for the transition from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) in a remote island cohort study

  Uema, T; Tsukita, M; Okamoto, S; Uehara, M; Honma, KI; Nakayama, Y; Tamaki, A; Miyazato, M; Ashikari, A; Maeda, S; Imamura, M; Matsushita, M; Nakamura, K; Masuzaki, H

  DIABETES RESEARCH AND CLINICAL PRACTICE ( ELSEVIER )  213   111747 - 8   2024.07

  Type of publication: Research paper (scientific journal)

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  Aim: The present cohort study explored whether specific gut microbiota (GM) profile would predict the development of impaired glucose tolerance (IGT) in individuals with normal glucose tolerance (NGT). Methods: A total of 114 study subjects with NGT in Kumejima island, Japan participated in the present study and underwent 75 g oral glucose tolerance tests at baseline and one year later. We compared the profile of GM at baseline between individuals who consistently maintained NGT (NRN, n = 108) and those who transitioned from NGT to IGT (NTI, n = 6). Results: Within-individual bacterial richness and evenness as well as inter-individual bacterial composition showed no significant differences between NRN and NTI. Of note, however, partial least squares discriminant analyses revealed distinct compositions of GM between groups, with no overlap in their 95 % confidence interval ellipses. Multi-factor analyses at the genus level demonstrated that the proportions of CF231, Corynebacterium, Succinivibrio, and Geobacillus were significantly elevated in NTI compared to NRN (p < 0.005, FDR < 0.1, respectively) after adjusting for age, sex, HbA1c level, and BMI. Conclusions: Our data suggest that increased proportion of specific GM is linked to the future deterioration of glucose tolerance, thereby serving as a promising predictive marker for type 2 diabetes mellitus.

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• Effect of a mobile digital intervention to enhance physical activity in individuals with metabolic disorders on voiding patterns measured by 24-h voided volume monitoring system: Kumejima Digital Health Project (KDHP)

  Miyazato, M; Ashikari, A; Nakamura, K; Nakamura, T; Yamashiro, K; Uema, T; Uehara, M; Masuzaki, H; Saito, S; Maeda, S; Ishida, H; Matsushita, M

  INTERNATIONAL UROLOGY AND NEPHROLOGY ( International Urology and Nephrology )  53 ( 8 ) 1497 - 1505   2021.08 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  PURPOSE: To evaluate the effect of a mobile digital intervention on voiding patterns, we performed 24-h voided volume monitoring in individuals with metabolic disorders. METHODS: Participants with metabolic disorders were grouped into either the intervention group (n = 17), who had access to a smartphone app (CARADA), or the non-intervention group (n = 11), who did not. Urine monitoring was conducted for 24 h using a novel digital self-health monitoring system for urine excretion (s-HMSU). Body weight, abdominal circumference, blood pressure, and biomarkers were measured. RESULTS: Physical findings and blood test results at baseline and 6 months indicated no significant between-group differences. Night-time frequency did not change between baseline and 6 months in the intervention group but significantly worsened at 6 months in the non-intervention group, as compared to baseline (1.0 ± 0.7 vs. 1.5 ± 0.5, p < 0.05). The change in night-time frequency over 6 months did not differ between the intervention and non-intervention groups. Furthermore, the change in hours of undisturbed sleep over 6 months did not differ between the two groups. However, compared with baseline, nocturnal polyuria index tended to worsen at 6 months in the non-intervention group. CONCLUSION: Our study results suggest that mobile digital intervention might be useful for behavioral therapy to improve night-time frequency and urine production and that s-HMSU might be beneficial for confirming the prevention of progress in individuals with metabolic disorders, which can aid in modifying lifestyle.

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• Collagen type 1A1, type 3A1, and LOXL1/4 polymorphisms as risk factors of pelvic organ prolapse

  Ashikari, A; Suda, T; Miyazato, M

  BMC RESEARCH NOTES ( BMC Research Notes )  14 ( 1 ) 15 - 15   2021.01 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  OBJECTIVE: Collagen and elastin are the main components of the female pelvic tissue. We investigated whether single nucleotide polymorphisms (SNPs) of collagen type 1 alpha 1 (COL1A1), collagen type 3 alpha 1 (COL3A1), and lysyl oxidase-like (LOXL) 1 and 4 were associated with the onset of pelvic organ prolapse (POP) in Japanese women. Fifty-two women with POP and 28 women without POP were included. SNPs were identified using the TaqMan® SNP genotyping assay. RESULTS: Age, parity, and lower urinary tract symptoms were significantly higher in the POP group than in the control group. The prevalence of genotypes with rs2862296 polymorphism of LOXL4, an enzyme essential for extracellular matrix remodeling, was different between the POP (26.9% for GG, 51.9% for AG) and control groups (14.8% for GG, 33.3% for AG). However, polymorphisms of COL1A1, COL3A1, and LOXL1 were not related to the onset of POP. In the multivariate logistic regression analysis, age was significantly associated with the occurrence of POP. In the univariate analysis, LOXL4 polymorphism was associated with the onset of POP in Japanese women. The knowledge of acquired risk factors and polymorphisms in the genomic background of patients with POP may help prevent POP via early conservative interventions.

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• Changes in urethral smooth muscle and external urethral sphincter function with age in rats

  Oshiro, T; Kimura, R; Izumi, K; Ashikari, A; Saito, S; Miyazato, M

  PHYSIOLOGICAL REPORTS ( Physiological Reports )  8 ( 24 ) e14643   2021.01 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  To confirm changes in urethral activity with age, both intravesical pressure and urethral perfusion pressure (UPP) were recorded and external urethral sphincter electromyography (EUS-EMG) was performed. A total of 33 female Sprague Dawley rats aged 3 months (young rats), 12 months (middle-aged rats), and 24 months (aged rats) were used. Bladder activity was evaluated using continuous cystometry. Urethral activity was evaluated by simultaneously recording intravesical pressure and UPP in isovolumetric conditions under urethane anesthesia in each group. Additionally, EUS-EMG activity was monitored under the same conditions. In continuous cystometry, the amplitude of bladder contractions was not different among the three groups; nevertheless, residual urine volume was significantly increased in middle-aged and aged rats, as compared in young rats. With respect to UPP, the change in UPP was significantly smaller in aged rats (60%) and middle-aged rats (64%) than in young rats. Furthermore, the mean amplitude of high-frequency oscillations of the EUS was significantly lower in aged (61%) and middle-aged rats (70%) than in young rats. EUS-EMG revealed EUS bursting activity during voiding with clear active and silent phases in young rats but unclear active and silent phases in aged rats. Masson's trichrome staining of the urethra showed EUS atrophy in aged rats compared to young and middle-aged rats. The results indicate that aging induces two urethral dysfunctions in the urethral smooth muscle and EUS, which may lead to dyscoordination between the urinary bladder and urethra.

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• Grant-in-Aid for Scientific Research(C)

  Project Year: 2020.04  -  2023.03 

  Direct: 3,000,000 (YEN)  Overheads: 3,900,000 (YEN)  Total: 900,000 (YEN)

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2020.04  -  2023.03 

  Direct: 3,000,000 (YEN)  Overheads: 3,900,000 (YEN)  Total: 900,000 (YEN)

• Grant-in-Aid for Young Scientists(B)

  Project Year: 2017.04  -  2020.03 

  Direct: 3,100,000 (YEN)  Overheads: 930,000 (YEN)  Total: 4,030,000 (YEN)

• Screening for high risk patients of pelvic organ prolapse focused on polymorphisms of collagen and early intervention by pelvic floor rehabilitation

  Grant-in-Aid for Young Scientists(B)

  Project Year: 2017.04  -  2020.03 

  Investigator(s): Ashikari Asuka 

  Direct: 3,100,000 (YEN)  Overheads: 4,030,000 (YEN)  Total: 930,000 (YEN)

  　View Summary

  Cause of pelvic organ prolapse (POP) is well known for acquired risk factor (e.g. parity, age and obesity), however we focused on genetic risk factor of POP that has been reported in European and American populations. Collagen and elastin are main structures of female pelvic tissues. So we investigated whether single nucleotide gene polymorphisms (SNP) of collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1) and lysyl oxidase-like (LOXL)-1/4 were associated with the onset of POP in Japanese women. We investigated each genotype of the SNPs by using TaqMan SNP genotyping assay. The polymorphism of LOXL-4, an enzyme which is essential for extracellular matrix remodeling, had relationship to the onset of POP in Japanese women(Odds ratio 3.8-4.5). The knowledge of acquired risk factors and this kind of genomic background in patients with POP would help to improve surgical indications or to prevent POP by earlier conservative interventions.

• Screening for high risk patients of pelvic organ prolapse focused on polymorphisms of collagen and early intervention by pelvic floor rehabilitation

  Grant-in-Aid for Young Scientists(B)

  Project Year: 2017.04  -  2020.03 

  Investigator(s): Ashikari Asuka 

  Direct: 3,100,000 (YEN)  Overheads: 4,030,000 (YEN)  Total: 930,000 (YEN)

  　View Summary

  Cause of pelvic organ prolapse (POP) is well known for acquired risk factor (e.g. parity, age and obesity), however we focused on genetic risk factor of POP that has been reported in European and American populations. Collagen and elastin are main structures of female pelvic tissues. So we investigated whether single nucleotide gene polymorphisms (SNP) of collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1) and lysyl oxidase-like (LOXL)-1/4 were associated with the onset of POP in Japanese women. We investigated each genotype of the SNPs by using TaqMan SNP genotyping assay. The polymorphism of LOXL-4, an enzyme which is essential for extracellular matrix remodeling, had relationship to the onset of POP in Japanese women(Odds ratio 3.8-4.5). The knowledge of acquired risk factors and this kind of genomic background in patients with POP would help to improve surgical indications or to prevent POP by earlier conservative interventions.

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