Regional differences in frailty among older adults with type 2 diabetes: a multicenter cross-sectional study in Japan.

BACKGROUND: Social environment may broadly impact multifaceted frailty; however, how environmental differences influence frailty in older adults with diabetes remains unclear. This study aimed to investigate regional differences in frailty in urban and rural areas among older adults with diabetes. METHODS: This cross-sectional study was conducted as part of the frailty prevention program for older adults with diabetes study. Older adults aged 60-80 years who could independently perform basic activities of daily living (ADLs) were enrolled sequentially. Trained nurses obtained patient background, complications, body weight, body composition, blood tests, grip strength, frailty assessment, and self-care score results. Regional differences in frailty were evaluated using logistic and multiple linear regression analyses. RESULTS: This study included 417 participants (269 urban and 148 rural). The prevalence of robustness was significantly lower in rural areas than in urban areas (29.7% vs. 43.9%, p = 0.018). Living in rural areas was associated with frailty (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.38-4.71) and pre-frailty (OR 2.10, 95%CI 1.30-3.41). Lower instrumental ADL (B 0.28, standard error [SE] 0.073) and social ADL (B 0.265, SE 0.097) were characteristics of rural residents. CONCLUSIONS: Regional differences in frailty were observed. Older adults with diabetes living in rural areas have a higher risk of frailty owing to a decline in instrumental and social ADLs. Social environment assessment and intervention programs that include communication strategies to enable care and social participation across environments are crucial to the effective and early prevention of frailty.

Relationship Between Frailty and Diabetic Pharmacologic Therapy in Older Adults with Type 2 Diabetes: A Cross-Sectional Study.

BACKGROUND: Older adults with diabetes mellitus require drug treatment considering their frailty, cognitive function, and hypoglycemia. OBJECTIVE: We investigated the association between diabetic pharmacologic therapy and both diabetic complications and frailty across eight diabetes-specific outpatient clinics nationwide. METHODS: Participants (aged 60-80 years) who had type 2 diabetes and did not require nursing care were included in the study. Basic attributes, patient background, complications, hypoglycemic status, body weight, body composition, blood tests, grip strength, and Kihon Checklist (a frailty index) and self-care scores were obtained. Descriptive statistics, t-test, chi-square test, and regression analyses were employed for evaluation. RESULTS: Overall, 417 participants were included (224 men, 193 women, mean age 70.1 ± 5.4 years, diabetes duration 14.9 ± 10.9 years, body mass index 24.5 ± 3.8, glycated hemoglobin 7.22 ± 0.98%, proportion of individuals with frailty and prefrailty, 19.9% and 41.0%, respectively). All drugs were used more frequently in prefrailty conditions. Each diabetes medication was related to complications, body composition, and frailty, as follows: sulfonylurea (lower hypoglycemia); glinide (severe hypoglycemia, retinopathy, weaker grip strength, high Kihon Checklist score, decreased physical activities); alpha-glucosidase inhibitors (no association); biguanide (high body mass index, high body fat, stronger grip strength); thiazolidinedione (decreased instrumental activities of daily living); dipeptidyl-peptidase-4 inhibitors (no association); sodium-glucose cotransporter 2 inhibitors; retinopathy, high body mass index and Kihon Checklist score, and depressive mood); glucagon-like peptide-1 receptor agonists (high body mass index and body fat and poor nutritional status); and insulin preparations (hypoglycemia, retinopathy, neuropathy, nephropathy, cardiovascular diseases, weaker grip strength, and high Kihon Checklist score and physical inactivity). CONCLUSIONS: Some formulations, such as glinide, sodium-glucose cotransporter 2 inhibitors, and insulin, are associated with an increased frequency of frailty, warranting careful and individualized diabetes treatment.

Delayed sleep-wake rhythm is associated with cognitive dysfunction, social dysfunction, and deteriorated quality of life in patients with major depressive disorder.

Background: The delayed sleep-wake phase is commonly observed in major depressive disorder (MDD) and thought to be associated with functional impairments. This study aimed to evaluate the relationship between the delayed sleep-wake phase, cognitive dysfunction, social dysfunction, and quality of life in patients with MDD. Methods: This cross-sectional design included 33 outpatients with MDD. Objective sleep-wake rhythm was assessed by actigraphy. Functional impairments were evaluated by the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J), World Health Organization Disability Assessment Schedule (WHO-DAS), and Euro QOL 5 dimensions (EQ5D). Results: Actigraphic assessment of the delayed sleep-wake phase (midpoint of sleep) was significantly correlated with the composite score of the BACS-J (r = -0.489, p = 0.010), WHO-DAS score (r = 0.466, p = 0.014), and EQ5D score (r = 0.472, p = 0.013). No significant correlation was found between the other actigraphic sleep parameters (sleep latency, total sleep time, and sleep efficiency) and functional impairments. Conclusion: Our study's results suggested that the delayed sleep-wake phase is associated with cognitive dysfunction, social dysfunction, and deteriorated quality of life in patients with MDD. Clinicians should pay attention to the sleep-wake rhythm in patients with MDD in clinical settings.

Implementation of a shared decision-making training program for clinicians based on the major depressive disorder guidelines in Japan: A multi-center cluster randomized trial.

Background: Although shared treatment decision-making with patients requires attention, it is not widely implemented, particularly in the field of psychiatry. The aim of this study was to assess whether a shared decision-making (SDM) training program for clinicians based on the major depressive disorder (MDD) guidelines improved the perceived involvement of the decision process for patients with MDD. Methods: A multi-center cluster-randomized controlled intervention of a clinician training program based on the Japanese MDD guidelines using related decision aids compared to usual care was conducted among 56 clinicians from 23 institutions. A total of 124 patients with MDD were enrolled in this study. The primary outcomes were the scores of the Shared Decision Making-Questionnaire-9 (SDM-Q-9) and Decision Conflict Scale (DCS) after the first visit to the outpatient clinics. The secondary outcomes were patients' satisfaction, quality of life, trust in clinicians, and depressive symptoms. Additionally, we evaluated all the observed outcomes at the first and third months of follow-up. Results: The scores of the SDM-Q-9 in the SDM training program group were significantly higher than those in the control group at the first visit. However, no significant difference in the DCS scores was found between the two groups. There was no intervention effect for secondary outcomes and the outcomes at the first- and third-month follow-up visits. Conclusion: The clinician training program based on the Japanese MDD guidelines can be useful for implementation of SDM. Additional research is needed to confirm the efficacy of this SDM training program. Clinical trial registration: [https://www.umin.ac.jp/], identifier [UMIN000034397].

Effects of transdiagnostic group treatment for sleep disturbances in adult attention-deficit/hyperactivity disorders and autistic spectrum disorder: a pilot study.

Although adult patients with attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often have sleep problems, few studies have verified the effect of a psychological approach specific to sleep-wake rhythms on these sleep disturbances. Therefore, the aim of this pilot study was to develop a trans-diagnostic approach with sleep scheduling and regularity of sleep duration as core modules, and to examine the effect of the intervention in adult ADHD and/or ASD subjects with sleep disturbances. This was a within-group pilot study. Ten patients with adult ADHD and/or ASD with sleep disturbances (10 males, age: 27.4 ± 5.6 years) took part in a 90-min weekly group intervention for 5 weeks. All participants were assessed on scales for sleep complaints, anxiety, depression, and symptoms of ADHD and ASD before and after the intervention, and at 3-month follow-up. The results showed that the intervention significantly improved sleep disturbances at post-intervention (p = 0.003, d = 1.30, 95% CI 0.31-2.28) and at the 3-month follow-up (p = 0.035, d = 0.41, 95% CI - 0.48 to 1.30). In addition, attention switching for ASD symptoms was significantly reduced post-intervention (p = 0.031, d = 1.16, 95% CI 0.19-2.13). This is the first pilot study of a trans-diagnostic group approach for adult ADHD and/or ASD with sleep disturbances. The intervention primarily led to an improvement of sleep disturbances, followed by improvement of disease-specific symptoms in adult subjects with ADHD and ASD.

Improving Employment Through Interpersonal Psychotherapy: A Case Series of Patients With Treatment-Refractory Depression.

Patients with treatment-refractory depression (TRD) have significantly great losses in work productivity and employment. Interpersonal psychotherapy (IPT) is considered an approach for the treatment of TRD. However, the effectiveness of IPT in patients with TRD remains unclear. In this study, we report cases of TRD patients who underwent IPT after a detailed evaluation, along with their employment status. Of 112 patients who experienced 1-week examination administration for TRD at Kyorin University Hospital, which aimed to determine appropriate diagnosis and treatment approaches for each patient, four patients who met the criteria for major depressive disorder according to DSM-IV-TR and were determined suitable for IPT were included in this report. Two patients had moderate, one had mild, and one had remission levels of depressive symptoms according to the Montgomery-Asberg Depression Rating Scale at the time of admission. All four patients completed the scheduled sessions of IPT (6-16 sessions) in the outpatient clinic and achieved remission. All four patients attained full-time employment within 6 months after receiving IPT. This study suggests that the appropriate selection of IPT might be effective for TRD patients, possibly leading to positive outcomes, including work productivity and employment status.

Association of sleep duration on workdays or free days and social jetlag with job stress.

AIM: The aim of this study was to investigate the impact of sleep problems on job stress in office workers. METHODS: This study included 4645 office workers from 29 companies who completed the study questionnaires between April 2017 and April 2019 in Japan. Sleep duration was assessed based on the participants' subjective sleep schedule on workdays and free days. The midpoint of sleep on free days (sleep-corrected) and social jetlag were calculated in accordance with the Munich Chronotype Questionnaire. To assess job stress, we used the 57-item Brief Job Stress Questionnaire. RESULTS: Multivariate logistic regression analysis revealed that the following factors were significantly associated with high job stress in office workers: a sleep duration <6 h on workdays (OR = 1.77, 95% CI = 1.46-2.15, P < 0.001), a sleep duration <6 h on free days (OR = 1.40, 95% CI = 1.05-1.87, P = 0.022), a sleep duration of at least 8 h on free days (OR = 1.31, 95% CI = 1.06-1.60, P = 0.011), and more than 2 h of social jetlag (OR = 1.33, 95% CI = 1.04-1.70, P = 0.022). CONCLUSION: This study suggests that insufficient sleep, long sleep durations on free days, and social jetlag may be associated with high job stress in office workers.

Validation of the Japanese version of the Sleep Hygiene Practice Scale.

OBJECTIVE: This study sought to validate the Japanese version of the Sleep Hygiene Practices Scale (SHPS-J). PATIENTS/METHODS: A cross-sectional questionnaire-based study was conducted via the internet. In total, 854 participants (435 men, 419 women; mean age, 42.91 ± 11.54 years) were asked to complete all scales, and 283 of them were asked to complete the same scales two weeks later. The survey consisted of the SHPS-J, the Japanese version of the Insomnia Severity Index (ISI-J), and the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J). The SHPS-J was developed according to the International Society for Pharmacoeconomics and Outcomes Research Task Force for Translation and Cultural Adaption. For the analysis, participants were divided into three groups: insomnia syndrome, insomnia symptoms, and good sleep groups. RESULTS: The SHPS-J had good test-retest reliability (ICC: 0.55-0.76) and adequate internal consistency (α = 0.54-0.74), except with regard to eating/drinking behaviors. The factorial validity of the four-factor structure was confirmed through a confirmatory factor analysis; however, one item related to eating/drinking behaviors had no significant factor loading. The construct validity was confirmed through a correlation analysis between each domain of the SHPS-J and ISI-J (r = 0.19-0.60, p < 0.01). The results of clinical validation confirmed that all domains of the SHPS-J were significantly higher for individuals with insomnia than for good sleepers. CONCLUSIONS: This study confirmed both the reliability and validity of the SHPS-J.

Development and Validity of the Japanese Version of the Pre-Sleep Arousal Scale.

Hyperarousal, defined as increased levels of cortical activity and cognitive-emotional reactivity induced by stress, is suggested to be a key factor in insomnia. In particularly, pre-sleep arousal constitutes one of the major features of insomnia. The Pre-Sleep Arousal Scale is the best-known measure used to evaluate pre-sleep arousal. However, a well-validated Japanese version of the scale (PSAS-J) has not yet been established. The aim of this research was to develop and validate such a scale. A cross-sectional questionnaire-based study was conducted via the internet. In total, 237 of 300 participants (mean age 43.28 ± 11.19 years) completely responded to the questionnaires as followed: the PSAS-J, the Insomnia Severity Index, Ford Insomnia Response to Stress Test, and Dysfunctional Beliefs and Attitudes about Sleep Scale. In addition, the participants were divided into two groups: insomniacs and normal sleepers. As a result, the PSAS-J had a two-factor structure similar to that of the original version, i.e., somatic and cognitive arousal subscales. The internal consistency (α = 0.85 to 0.90) and test-retest reliability (r = 0.67 to 0.78) were high. Correlations between the PSAS-J and the above-mentioned scales ranged from 0.35 to 0.53. Discriminant validity showed that the PSAS-J was distinct from the Ford Insomnia Response to Stress Test and Dysfunctional Beliefs and Attitudes about Sleep Scale. The PSAS-J scores were significantly higher in insomniacs than in normal sleepers. Our results suggest that the PSAS-J has high reliability and validity and that this scale is adequate for assessing pre-sleep arousal.

Effects of a Tailored Brief Behavioral Therapy Application on Insomnia Severity and Social Disabilities Among Workers With Insomnia in Japan: A Randomized Clinical Trial.

Importance: According to the stepped-care model, there is a medium to large effect size for using cognitive behavioral therapy for insomnia that is delivered digitally, such as a smartphone application. However, it has been reported that studies using fully automated cognitive behavioral therapy for insomnia applications without expert support have high dropout rates. Objective: To examine the effects of using a fully automated and individually tailored brief behavior therapy for insomnia (BBTI) applications for 2 weeks on insomnia-related symptoms, social disabilities, and work productivity among workers with insomnia in Japan. Design, Setting, and Participants: This intent-to-treat prospective parallel-group randomized clinical trial included participants 20 years or older with Insomnia Severity Index (ISI) scores of 8 or higher. Participants were recruited via internet advertisements and workplace flyers and randomized to tailored BBTI, standard BBTI, self-monitoring with sleep diaries, or a waiting list control group. The study was conducted from September 21, 2017, to February 23, 2018. Data were analyzed from February 24, 2018, to February 22, 2019. Interventions: A personalized BBTI and standard BBTI intervention, both of which included sleep scheduling, relaxation, sleep hygiene, and sleep diaries, administered via smartphone application. Main Outcomes and Measures: Primary outcomes were insomnia severity, measured using the Japanese version of the Insomnia Severity Index, and social disabilities, measured using the Japanese version of the Sheehan Disability Scale. Secondary outcomes were dysfunctional beliefs, sleep reactivity, and work productivity. All measures were taken before and after the intervention and at 1-month and 3-month follow-ups. Results: A total of 92 participants (mean [SD] age, 42.7 [11.5] years; 60 [65%] men) were randomized and included in analysis, with 24 participants assigned to tailored BBTI, 23 participants assigned to standard BBTI, 23 participants assigned to self-monitoring, and 22 participants assigned to the waiting list control group. At baseline, there were no significant differences among groups on any demographic characteristics or outcome measures. The results of the intent-to-treat analysis showed an interaction effect for all outcome measures. Compared with the waiting list control group, the BBTI interventions were more effective for reduction of insomnia severity (tailored BBTI: Hedges g = -1.64 [95% CI, -2.32 to -0.96]; P < .001; standard BBTI: g = -1.28 [95% CI, -1.93 to -0.63]; P < .001), social disabilities relating to social life (tailored BBTI: g = -1.33 [95% CI, -1.97 to -0.68]; P < .001; standard BBTI: g = -0.84 [95% CI, -1.46 to -0.22]; P = .009), and dysfunctional beliefs (tailored BBTI: g = -1.17 [95% CI, -1.80 to -0.54]; P < .001; standard BBTI: g = -0.84 [95% CI, -1.46 to -0.23]; P = .02) at the 3-month follow-up. Tailored BBTI quickly reduced insomnia severity (1-month follow-up: g = -0.85 [95% CI, -1.46 to -0.24]). Tailored BBTI was only more effective for improvement of work performance (g = -1.09 [95% CI, -1.71 to -0.46]; P = .005), social disabilities related to family life (g = -0.89 [95% CI, -1.51 to -0.28]; P = .005), and sleep reactivity (g = -1.09 [95% CI, -1.72 to -0.46]; P = .007) compared with the waiting list control group at the 3-month follow-up. The tailored BBTI led to improved worker productivity compared with standard BBTI (g = 0.94 [95% CI, 0.33 to 1.55]; P = .01) at the 3-month follow-up. Conclusions and Relevance: These findings suggest that an application for individually tailored BBTI is an inexpensive and effective treatment for insomnia. In future research, it would be informative to investigate the reasons for dropout during the follow-up period. Trial Registration: umin.ac.jp/ctr Identifier: UMIN000036572.

A static magnetic field inhibits the expression of platelet-derived growth factor-AA in human oral squamous cell carcinoma.

Magnetic attachments are commonly used for overdentures. The deleterious effects of exposure to magnetic flux on human health have not been substantiated so far; nevertheless, there is a need to understand the extent of magnetic field exposure in the oral area resulting from the use of magnetic attachments. The purpose of this study was to investigate the influence of a magnetic field on oral squamous cell carcinoma. Tumor cells cultured on a magnetic plate were compared with those not cultured on a magnetic plate (controls). The cells were seeded at a density of 1 × 105 cells/well and cultured for 6 days. The influence of the magnetic field on cytokine production was examined by cytokine array analysis. Secretion of platelet-derived growth factor-AA (PDGF-AA) was measured by enzyme-linked immunosorbent assay and Western blotting. The expression of PDGF-AA messenger RNA was examined by real-time polymerase chain reaction, whereas nuclear factor-kappa B activity was measured by luciferase assay. The results indicated that the magnetic field inhibited the secretion of PDGF-AA, thereby inhibiting PDGF-AA-induced expression, thus reducing the risk of cancer recurrence.

Highly-efficient and angle-independent zero-order half waveplate at broad visible wavelength based on Au nanofin array embedded in dielectric.

A Au nanofin array embedded in SiO2 was designed and fabricated to achieve an achromatic half waveplate with high transmittance at visible wavelengths. On the basis of the waveguide theory of nanogaps and the Fresnel reflection theory, nanofin array is calculated to have ideal properties for an achromatic half-waveplate in the visible band from 560 to 660 nm with the transmittance of around 50%. A Au nanofin array with a height of 830 nm and a period of 400 nm was fabricated through a sidewall-deposition process and overcoating with spin on glass. The polarization microscopy results showed that both transmittance greater than 50% and retardation of 165° at broadband wavelengths ranging from 600 to 800 nm were simultaneously achieved. It was also demonstrated that retardation had little dependence on the incident angle.

Large-scale East-Asian eQTL mapping reveals novel candidate genes for LD mapping and the genomic landscape of transcriptional effects of sequence variants.

Profiles of sequence variants that influence gene transcription are very important for understanding mechanisms that affect phenotypic variation and disease susceptibility. Using genotypes at 1.4 million SNPs and a comprehensive transcriptional profile of 15,454 coding genes and 6,113 lincRNA genes obtained from peripheral blood cells of 298 Japanese individuals, we mapped expression quantitative trait loci (eQTLs). We identified 3,804 cis-eQTLs (within 500 kb from target genes) and 165 trans-eQTLs (>500 kb away or on different chromosomes). Cis-eQTLs were often located in transcribed or adjacent regions of genes; among these regions, 5' untranslated regions and 5' flanking regions had the largest effects. Epigenetic evidence for regulatory potential accumulated in public databases explained the magnitude of the effects of our eQTLs. Cis-eQTLs were often located near the respective target genes, if not within genes. Large effect sizes were observed with eQTLs near target genes, and effect sizes were obviously attenuated as the eQTL distance from the gene increased. Using a very stringent significance threshold, we identified 165 large-effect trans-eQTLs. We used our eQTL map to assess 8,069 disease-associated SNPs identified in 1,436 genome-wide association studies (GWAS). We identified genes that might be truly causative, but GWAS might have failed to identify for 148 out of the GWAS-identified SNPs; for example, TUFM (P = 3.3E-48) was identified for inflammatory bowel disease (early onset); ZFP90 (P = 4.4E-34) for ulcerative colitis; and IDUA (P = 2.2E-11) for Parkinson's disease. We identified four genes (P<2.0E-14) that might be related to three diseases and two hematological traits; each expression is regulated by trans-eQTLs on a different chromosome than the gene.

Recombinant measles virus vaccine expressing the Nipah virus glycoprotein protects against lethal Nipah virus challenge.

Nipah virus (NiV) is a member of the genus Henipavirus, which emerged in Malaysia in 1998. In pigs, infection resulted in a predominantly non-lethal respiratory disease; however, infection in humans resulted in over 100 deaths. Nipah virus has continued to re-emerge in Bangladesh and India, and person-to-person transmission appeared in the outbreak. Although a number of NiV vaccine studies have been reported, there are currently no vaccines or treatments licensed for human use. In this study, we have developed a recombinant measles virus (rMV) vaccine expressing NiV envelope glycoproteins (rMV-HL-G and rMV-Ed-G). Vaccinated hamsters were completely protected against NiV challenge, while the mortality of unvaccinated control hamsters was 90%. We trialed our vaccine in a non-human primate model, African green monkeys. Upon intraperitoneal infection with NiV, monkeys showed several clinical signs of disease including severe depression, reduced ability to move and decreased food ingestion and died at 7 days post infection (dpi). Intranasal and oral inoculation induced similar clinical illness in monkeys, evident around 9 dpi, and resulted in a moribund stage around 14 dpi. Two monkeys immunized subcutaneously with rMV-Ed-G showed no clinical illness prior to euthanasia after challenge with NiV. Viral RNA was not detected in any organ samples collected from vaccinated monkeys, and no pathological changes were found upon histopathological examination. From our findings, we propose that rMV-NiV-G is an appropriate NiV vaccine candidate for use in humans.

Segmental copy number loss in the region of Semaphorin 4D gene in patients with acetabular dysplasia.

Acetabular dysplasia (AD) appears to be a multi-factorial disease, which may involve both genetic and environmental factors and whose pathogenesis remains obscure. The present study aims to identify a genetic variation that might confer risk of AD. We performed whole-genome screening of a copy number variation (CNV) using a deCODE-Illumina CNV beadchip with 20 female AD patients and 131 control subjects. Subsequently, Agilent's region-targeted high-density oligonucleotide tiling microarray was used to analyze 64 female AD patients and 32 female control subjects. By sequential analyses, we found a copy number loss in 18 of 64 AD patients, but none in the 32 controls. The loss occurred within a 472 kb region on 9q22.2, which harbors the gene for Semaphorin 4D (Sema4D; 18/64 vs. 0/32, p = 4.81 × 10(-4) , OR = 25.86). We suggest that a copy number loss of the Sema4D gene region may play a role in the etiology of AD.

Frequent loss of genome gap region in 4p16.3 subtelomere in early-onset type 2 diabetes mellitus.

A small portion of Type 2 diabetes mellitus (T2DM) is familial, but the majority occurs as sporadic disease. Although causative genes are found in some rare forms, the genetic basis for sporadic T2DM is largely unknown. We searched for a copy number abnormality in 100 early-onset Japanese T2DM patients (onset age <35 years) by whole-genome screening with a copy number variation BeadChip. Within the 1.3-Mb subtelomeric region on chromosome 4p16.3, we found copy number losses in early-onset T2DM (13 of 100 T2DM versus one of 100 controls). This region surrounds a genome gap, which is rich in multiple low copy repeats. Subsequent region-targeted high-density custom-made oligonucleotide microarray experiments verified the copy number losses and delineated structural changes in the 1.3-Mb region. The results suggested that copy number losses of the genes in the deleted region around the genome gap in 4p16.3 may play significant roles in the etiology of T2DM.

Functional polymorphisms in carboxylesterase1A2 (CES1A2) gene involves specific protein 1 (Sp1) binding sites.

Carboxylesterase 1 (CES1) is involved in metabolic activation of a variety of prodrugs into active derivatives and plays an important role in pharmacokinetics. We previously reported that a single nucleotide polymorphism (SNP), -816A/C of the CES1A2 gene associates with the responsiveness to an angiotensin-converting enzyme (ACE) inhibitor, imidapril, whose activity is achieved by CES1. To identify relevant functional polymorphisms, we re-sequenced the CES1A2 promoter region ( approximately 1kb) in 100 Japanese hypertensive patients. Altogether 10 SNPs and one insertion/deletion (I/D) were identified, among which seven SNPs and one I/D residing between -62 and -32 were in almost complete linkage disequilibrium (D'=1.00, r2=0.97). They consisted a minor and a major haplotype, the allele frequencies of which were 22% and 74%, respectively. The minor haplotype possessed two putative Sp1 binding sites while the major haplotype did not have any Sp1 binding site. The minor haplotype had a higher transcription and Sp1 binding activities than the major haplotype, invitro. The original -816A/C was in high linkage disequilibrium with these haplotypes (D'=0.92, r2=0.85), and well agreed with the efficacy of imidapril medication. These results suggest that the Sp1 binding site variation in the CES1A2 promoter is functional, and are good candidates for the pharmacogenetic studies of CES1-activated drugs.

Common null variant, Arg192Stop, in a G-protein coupled receptor, olfactory receptor 1B1, associated with decreased serum cholinesterase activity.

AIM: Non-functioning single nucleotide polymorphisms (nSNPs) that result in premature termination codons, that is null-alleles of the respective genes, may have phenotypic effects on clinical parameters. We conducted association studies involving several G-protein coupled receptors (GPCRs) that harbor nSNPs, using clinical parameters of liver function in a general population consisting of 2969 Japanese adults. METHODS: SNP typings were performed with TaqMan and Invader assays. Quantitative associations between genotypes and clinical parameters were analyzed by analysis of variance. Linkage disequilibrium (LD) was tested by Haploview Version 3.3. Haplotype-based association was performed using the haplo.stats program. RESULTS: A significant correlation (P = 0.0057) was identified between serum cholinesterase activity (CHE) and an nSNP (Arg192Stop) in the olfactory receptor (OR) 1B1 gene, a member of the GPCR gene family. This nSNP was associated with decreased serum CHE (P = 0.0013). LD analysis based on eight selected SNPs at the locus revealed three LD blocks. The Arg192Stop nSNP was located on the second LD block, which covered one-third of the 3'-portion of the gene. CONCLUSION: These results suggested that the null-allele of OR1B1 might affect metabolism of serum cholinesterase in carriers of this nSNP.

Association of CC chemokine ligand 5 genotype with urinary albumin excretion in the non-diabetic Japanese general population: the Takahata study.

Albuminuria is an early marker of vascular damage, and its development in diabetic nephropathy is associated with genotype of inflammatory CC chemokine ligand 5 (CCL5). This study investigated whether the association of CCL5 and albuminuria is a general phenomenon. We characterized a Japanese population consisting of 2,749 non-diabetic individuals over 40 years in Takahata, Japan. The urine albumin-creatinine ratio (UACR) was obtained from morning spot urine. We genotyped SNPs within the CCL5 gene that displayed frequent minor allele frequencies in Japanese (i.e., rs2107538, rs2280789, rs3817655 and rs9909416). Assessment of possible association and linkage disequilibrium (LD) revealed that all four SNP genotypes are correlated significantly with UACR (P = 0.004-0.005), and these four SNPs variations showed an obvious consistency of genotypes by detecting almost complete linkage disequilibrium (D' = 1 and r (2) > 0.95). We found two exclusive haplotypes in the CCL5 gene (haplotype1: rs2107538G/rs2280789T/rs3817655T/rs9909416G, frequency 0.64 and haplotype2: rs2107538A/rs2280789C/rs3817655A/rs9909416A, frequency 0.35) among the population. A significant association with elevated UACR was identified with haplotype1 (P = 0.002). Homozygotes for haplotype1 displayed strikingly-elevated UACR (48.5 +/- 6.6 mg/g, n = 1,116) compared to the rest (28.6 +/- 1.6 mg/g, n = 1,530) (P = 0.001). In conclusion, these results suggested that genetic variation of CCL5 might be an important risk factor for albuminuria in the non-diabetic Japanese general population.

A nonfunctioning single nucleotide polymorphism in olfactory receptor gene family is associated with the forced expiratory volume in the first second/the forced vital capacity values of pulmonary function test in a Japanese population.

The forced expiratory volume in the first second (FEV1.0)/the forced vital capacity (FVC) is an important index of a single forced expiration. Ectopic expression of the human olfactory receptor (OR) gene family in the lungs has suggested its potential involvement of respiratory physiology. We hypothesized that the individual variability of FEV1.0/FVC value may be attributed to the genetic variance of the OR gene family caused by the nonfunctioning SNPs (nSNPs). We conducted quantitative trait locus (QTL) analyses of population having the 7 OR gene nSNPs and FEV1.0/FVC values by ANOVA, in 2970 samples in the Yamagata Takahata cohort. We found significant association of one nSNP [rs10838851, OR, family 4, subfamily X, member 1 (OR4X1) gene, Tyr273Ter*] with FEV1.0/FVC (%) (P = 0.008). The FEV1.0/FVC value (%) of population having OR4X1 gene nSNP Ter*/Ter*, Ter*/Tyr, and Tyr/Tyr were 78.9 +/- 0.2, 78.2 +/- 0.2, and 77.7 +/- 0.4, respectively. Haplotype-based analysis of the OR4X1 gene with FEV1.0/FVC values demonstrated that two exclusive haplotypes [Hap-1/Hap-2 (frequency 0.669/0.330): SNP1 (rs7106648)T/A-SNP2 (rs871249)G/A-SNP3 (rs713325)G/A-SNP4 (rs10838851)A (Ter*)/T (Tyr)-SNP5 (rs4752923)G/A-SNP6 (rs960640)G/A] were significantly associated with FEV1.0/FVC values (global P = 0.005). These results suggest that OR4X1 may be one of the genes that contribute to the individual variability of FEV1.0/FVC value in pulmonary function test.