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Association of Common Variants in TNFRSF13B, TNFSF13, and ANXA3 with Serum Levels of Non-Albumin Protein and Immunoglobulin Isotypes in Japanese
Wael Osman, Yukinori Okada, Yoichiro Kamatani, Michiaki Kubo, Koichi Matsuda, Yusuke Nakamura
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032683
Abstract: We performed a genome-wide association study (GWAS) on levels of serum total protein (TP), albumin (ALB), and non-albumin protein (NAP). We analyzed SNPs on autosomal chromosomes using data from 9,103 Japanese individuals, followed by a replication study of 1,600 additional individuals. We confirmed the previously- reported association of GCKR on chromosome 2p23.3 with serum ALB (rs1260326, Pmeta = 3.1×10?9), and additionally identified the significant genome-wide association of rs4985726 in TNFRSF13B on 17p11.2 with both TP and NAP (Pmeta = 1.2×10?14 and 7.1×10?24, respectively). For NAP, rs3803800 and rs11552708 in TNFSF13 on 17p13.1 (Pmeta = 7.2×10?15 and 7.5×10?10, respectively) as well as rs10007186 on 4q21.2 near ANXA3 (Pmeta = 1.3×10?9) also indicated significant associations. Interestingly, TNFRSF13B and TNFSF13 encode a tumor necrosis factor (TNF) receptor and its ligand, which together constitute an important receptor-ligand axis for B-cell homeostasis and immunoglobulin production. Furthermore, three SNPs, rs4985726, rs3803800, and rs11552708 in TNFRSF13B and TNFSF13, were indicated to be associated with serum levels of IgG (P<2.3×10?3) and IgM (P<0.018), while rs3803800 and rs11552708 were associated with IgA (P<0.013). Rs10007186 in 4q21.2 was associated with serum levels of IgA (P = 0.036), IgM (P = 0.019), and IgE (P = 4.9×10?4). Our results should add interesting knowledge about the regulation of major serum components.
Genome Wide Association Study of Age at Menarche in the Japanese Population
Chizu Tanikawa, Yukinori Okada, Atsushi Takahashi, Katsutoshi Oda, Naoyuki Kamatani, Michiaki Kubo, Yusuke Nakamura, Koichi Matsuda
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063821
Abstract: Age at menarche (AAM) is a complex trait involving both genetic and environmental factors. To identify the genetic factors associated with AAM, we conducted a large-scale meta-analysis of genome-wide association studies using more than 15,000 Japanese female samples. Here, we identified an association between SNP (single nucleotide polymorphism) rs364663 at the LIN28B locus and AAM, with a P-value of 5.49×10?7 and an effect size of 0.089 (year). We also evaluated 33 SNPs that were previously reported to be associated with AAM in women of European ancestry. Among them, two SNPs rs4452860 and rs7028916 in TMEM38B indicated significant association with AAM in the same directions as reported in previous studies (P = 0.0013 with an effect size of 0.051) even after Bonferroni correction for the 33 SNPs. In addition, six loci in or near CCDC85A, LOC100421670, CA10, ZNF483, ARNTL, and RXRG exhibited suggestive association with AAM (P<0.05). Our findings elucidated the impact of genetic variations on AAM in the Japanese population.
Genome-Wide Association Study in Thai Tsunami Survivors Identified Risk Alleles for Posttraumatic Stress Disorder  [PDF]
Nuntika Thavichachart, Taisei Mushiroda, Thongchai Thavichachart, Ongart Charoensook, Anchalee Prasansuklab, Prathan Rutchatajumroon, Sookjaroen Tangwongchai, Puangsoi Worakul, Buranee Kanchanatawan, Siriluck Suppapitiporn, Atapol Sughondhabirom, Chutima Roomruangwong, Wasun Chantratita, Atsushi Takahashi, Michiaki Kubo, Naoyuki Kamatani, Yusuke Nakamura
Open Journal of Genetics (OJGen) , 2015, DOI: 10.4236/ojgen.2015.52004
Abstract: Posttraumatic stress disorder (PTSD) is a psychiatric disorder found in individuals afflicted by a traumatic event. Multiple environmental and genetic factors can contribute to PTSD susceptibility. Since it is rare to find members of the same family afflicted by the same catastrophic event, it is not practical to determine PTSD susceptibility genes by a gene linkage analysis. A natural disaster, such as the 2004 Tsunami, provided us with a rare chance for a genetic analysis of PTSD. To identify SNPs associated with PTSD susceptibility, we conducted a genome-association study (GWAS) in Thai-Tsunami survivors. Initial phase of the study with 396 chronic PTSD patients and 457 controls, we identified top ninety SNPs (P < 1 × 10-4), which were further assessed in the second phase with 395 chronic PTSD patients and 798 controls. Two SNPs (rs267950 and rs954406), were identified in the second phase, and subjected to fine mapping using a data set from both phases. SNP rs267943 showed the strongest association with PTSD susceptibility and was in complete linkage disequilibrium with SNP rs267950 with P = 6.15 × 10-8, OR = 1.46 and 95% CI = 1.19 - 1.79, reaching genome-wide significance. SNP rs267943 is located on chromosome 5 in the intron of the death-associated protein 1 (DAP1) gene and, when linked to a synthetic promoter, could regulate transcription. To our knowledge, this is the first GWAS for PTSD susceptibility in an Asian population which could provide an important insight into the genetic contribution of PTSD and may lead to new treatment strategies for PTSD.
Reconsideration of Augmentation Strategies in Electroconvulsive Therapy: Effects of the Concurrent Use of a Reduced Dose of Propofol with Divided Supplemental Remifentanil and Moderate Hyperventilation on Electroconvulsive Therapy-Induced Seizure Production and Adverse Events  [PDF]
Kohki Nishikawa, Michiaki Yamakage
Open Journal of Anesthesiology (OJAnes) , 2015, DOI: 10.4236/ojanes.2015.510040
Abstract: Background: Although several treatment strategies to enhance the efficacy of electroconvulsive therapy (ECT) have been discussed, there have been no reports on the combined use of these treatments. The purpose of this study was to evaluate the efficacy and safety of concurrent use of moderate hyperventilation and a reduced dose of propofol combined with divided remifentanil in ECT practice. Methods: Sixty patients scheduled to receive a total of 300 ECT treatments were randomly assigned to have the three interventions: a standard dose (1 mg/kg) of propofol (group P/N); a standard dose of propofol and moderate hyperventilation with end-tidal pressure of carbon dioxide (ETCO2) of 30 - 35 mmHg (group P/H); and a reduced dose (0.5 mg/kg) of propofol with divided supplemental remifentanil and moderate hyperventilation (group RP/H). Patients in group RP/H received remifentanil 1 μg/kg followed by propofol 0.5 mg/kg for unconsciousness and thereafter remifentanil 1 μg/kg immediately before the ECT stimulus. Results: Patients in group RP/H showed significantly longer durations of electroencephalographic (EEG) seizures in the early phase of ECT course (P < 0.01 and 0.05) and lower electrical stimulus in the late phase of ECT course (P < 0.05 in each) than those in groups P/N and P/H, respectively. Conclusions: The use of a reduced dose of propofol combined with divided supplemental remifentanil under moderate hyperventilation during ECT can offer advantages over the use of a standard dose of propofol with or without moderate hyperventilation in terms of more seizure augmentation and/or lower electrical stimulus.
Genome-Wide Association Study of Breast Cancer in the Japanese Population
Siew-Kee Low, Atsushi Takahashi, Kyota Ashikawa, Johji Inazawa, Yoshio Miki, Michiaki Kubo, Yusuke Nakamura, Toyomasa Katagiri
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076463
Abstract: Breast cancer is the most common malignancy among women in worldwide including Japan. Several studies have identified common genetic variants to be associated with the risk of breast cancer. Due to the complex linkage disequilibrium structure and various environmental exposures in different populations, it is essential to identify variants associated with breast cancer in each population, which subsequently facilitate the better understanding of mammary carcinogenesis. In this study, we conducted a genome-wide association study (GWAS) as well as whole-genome imputation with 2,642 cases and 2,099 unaffected female controls. We further examined 13 suggestive loci (P<1.0×10?5) using an independent sample set of 2,885 cases and 3,395 controls and successfully validated two previously-reported loci, rs2981578 (combined P-value of 1.31×10?12, OR = 1.23; 95% CI = 1.16–.30) on chromosome 10q26 (FGFR2), rs3803662 (combined P-value of 2.79×10?11, OR = 1.21; 95% CI = 1.15–.28) and rs12922061 (combined P-value of 3.97×10?10, OR = 1.23; 95% CI = 1.15–.31) on chromosome 16q12 (TOX3-LOC643714). Weighted genetic risk score on the basis of three significantly associated variants and two previously reported breast cancer associated loci in East Asian population revealed that individuals who carry the most risk alleles in category 5 have 2.2 times higher risk of developing breast cancer in the Japanese population than those who carry the least risk alleles in reference category 1. Although we could not identify additional loci associated with breast cancer, our study utilized one of the largest sample sizes reported to date, and provided genetic status that represent the Japanese population. Further local and international collaborative study is essential to identify additional genetic variants that could lead to a better, accurate prediction for breast cancer.
Limitations of Airway Dimension Measurement on Images Obtained Using Multi-Detector Row Computed Tomography
Tsuyoshi Oguma, Toyohiro Hirai, Akio Niimi, Hisako Matsumoto, Shigeo Muro, Michio Shigematsu, Takashi Nishimura, Yoshiro Kubo, Michiaki Mishima
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076381
Abstract: Objectives (a) To assess the effects of computed tomography (CT) scanners, scanning conditions, airway size, and phantom composition on airway dimension measurement and (b) to investigate the limitations of accurate quantitative assessment of small airways using CT images. Methods An airway phantom, which was constructed using various types of material and with various tube sizes, was scanned using four CT scanner types under different conditions to calculate airway dimensions, luminal area (Ai), and the wall area percentage (WA%). To investigate the limitations of accurate airway dimension measurement, we then developed a second airway phantom with a thinner tube wall, and compared the clinical CT images of healthy subjects with the phantom images scanned using the same CT scanner. The study using clinical CT images was approved by the local ethics committee, and written informed consent was obtained from all subjects. Data were statistically analyzed using one-way ANOVA. Results Errors noted in airway dimension measurement were greater in the tube of small inner radius made of material with a high CT density and on images reconstructed by body algorithm (p<0.001), and there was some variation in error among CT scanners under different fields of view. Airway wall thickness had the maximum effect on the accuracy of measurements with all CT scanners under all scanning conditions, and the magnitude of errors for WA% and Ai varied depending on wall thickness when airways of <1.0-mm wall thickness were measured. Conclusions The parameters of airway dimensions measured were affected by airway size, reconstruction algorithm, composition of the airway phantom, and CT scanner types. In dimension measurement of small airways with wall thickness of <1.0 mm, the accuracy of measurement according to quantitative CT parameters can decrease as the walls become thinner.
A Genome-Wide Association Study of Nephrolithiasis in the Japanese Population Identifies Novel Susceptible Loci at 5q35.3, 7p14.3, and 13q14.1
Yuji Urabe,Chizu Tanikawa,Atsushi Takahashi,Yukinori Okada,Takashi Morizono,Tatsuhiko Tsunoda,Naoyuki Kamatani,Kenjiro Kohri,Kazuaki Chayama,Michiaki Kubo,Yusuke Nakamura,Koichi Matsuda
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002541
Abstract: Nephrolithiasis is a common nephrologic disorder with complex etiology. To identify the genetic factor(s) for nephrolithiasis, we conducted a three-stage genome-wide association study (GWAS) using a total of 5,892 nephrolithiasis cases and 17,809 controls of Japanese origin. Here we found three novel loci for nephrolithiasis: RGS14-SLC34A1-PFN3-F12 on 5q35.3 (rs11746443; P = 8.51×10?12, odds ratio (OR) = 1.19), INMT-FAM188B-AQP1 on 7p14.3 (rs1000597; P = 2.16×10?14, OR = 1.22), and DGKH on 13q14.1 (rs4142110; P = 4.62×10?9, OR = 1.14). Subsequent analyses in 21,842 Japanese subjects revealed the association of SNP rs11746443 with the reduction of estimated glomerular filtration rate (eGFR) (P = 6.54×10?8), suggesting a crucial role for this variation in renal function. Our findings elucidated the significance of genetic variations for the pathogenesis of nephrolithiasis.
Haplotypes with Copy Number and Single Nucleotide Polymorphisms in CYP2A6 Locus Are Associated with Smoking Quantity in a Japanese Population
Natsuhiko Kumasaka, Masayuki Aoki, Yukinori Okada, Atsushi Takahashi, Kouichi Ozaki, Taisei Mushiroda, Tomomitsu Hirota, Mayumi Tamari, Toshihiro Tanaka, Yusuke Nakamura, Naoyuki Kamatani, Michiaki Kubo
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044507
Abstract: Smoking is a major public health problem, but the genetic factors associated with smoking behaviors are not fully elucidated. Here, we have conducted an integrated genome-wide association study to identify common copy number polymorphisms (CNPs) and single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) in Japanese smokers ( = 17,158). Our analysis identified a common CNP with a strong effect on CPD (rs8102683; ) in the 19q13 region, encompassing the CYP2A6 locus. After adjustment for the associated CNP, we found an additional associated SNP (rs11878604; ) located 30 kb downstream of the CYP2A6 gene. Imputation of the CYP2A6 locus revealed that haplotypes underlying the CNP and the SNP corresponded to classical, functional alleles of CYP2A6 gene that regulate nicotine metabolism and explained 2% of the phenotypic variance of CPD (ANOVA -test ). These haplotypes were also associated with smoking-related diseases, including lung cancer, chronic obstructive pulmonary disease and arteriosclerosis obliterans.
Longitudinal Study of Spatially Heterogeneous Emphysema Progression in Current Smokers with Chronic Obstructive Pulmonary Disease
Naoya Tanabe, Shigeo Muro, Susumu Sato, Shiro Tanaka, Tsuyoshi Oguma, Hirofumi Kiyokawa, Tamaki Takahashi, Daisuke Kinose, Yuma Hoshino, Takeshi Kubo, Toyohiro Hirai, Michiaki Mishima
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044993
Abstract: Background Cigarette smoke is the main risk factor for emphysema, which is a key pathology in chronic obstructive pulmonary disease (COPD). Low attenuation areas (LAA) in computed tomography (CT) images reflect emphysema, and the cumulative size distribution of LAA clusters follows a power law characterized by the exponent D. This property of LAA clusters can be explained by model simulation, where mechanical force breaks alveolar walls causing local heterogeneous lung tissue destruction. However, a longitudinal CT study has not investigated whether continuous smoking causes the spatially heterogeneous progression of emphysema. Methods We measured annual changes in ratios of LAA (LAA%), D and numbers of LAA clusters (LAN) in CT images acquired at intervals of ≥3 years from 22 current and 31 former smokers with COPD to assess emphysema progression. We constructed model simulations using CT images to morphologically interpret changes in current smokers. Results D was decreased in current and former smokers, whereas LAA% and LAN were increased only in current smokers. The annual changes in LAA%, D, and LAN were greater in current, than in former smokers (1.03 vs. 0.37%, p = 0.008; ?0.045 vs. ?0.01, p = 0.004; 13.9 vs. 1.1, p = 0.007, respectively). When LAA% increased in model simulations, the coalescence of neighboring LAA clusters decreased D, but the combination of changes in D and LAN in current smokers could not be explained by the homogeneous emphysema progression model despite cluster coalescence. Conversely, a model in which LAAs heterogeneously increased and LAA clusters merged somewhat in relatively advanced emphysematous regions could reflect actual changes. Conclusions Susceptibility to parenchymal destruction induced by continuous smoking is not uniform over the lung, but might be higher in local regions of relatively advanced emphysema. These could result in the spatially heterogeneous progression of emphysema in current smokers.
Validation of the japanese version of the sarcoidosis health questionnaire: A cross-sectional study
Kiminobu Tanizawa, Tomohiro Handa, Sonoko Nagai, Toru Oga, Takeshi Kubo, Yutaka Ito, Kizuku Watanabe, Kensaku Aihara, Kazuo Chin, Michiaki Mishima, Takateru Izumi
Health and Quality of Life Outcomes , 2011, DOI: 10.1186/1477-7525-9-34
Abstract: The SHQ was translated into Japanese following the forward-backward procedure. The reliability and validity of the Japanese version of the SHQ were examined. One hundred twenty-two Japanese patients with biopsy-proven sarcoidosis were evaluated by the SHQ, the Medical Outcomes Study 36-item short form (SF-36), the St. George's Respiratory Questionnaire (SGRQ), chest radiography, an electrocardiogram, laboratory blood tests, pulmonary function tests, an echocardiogram, and assessments of dyspnea and depressive symptoms. The SHQ was found to have acceptable levels of internal consistency (Cronbach's coefficient α values = 0.68 to 0.91). SHQ scores correlated significantly with scores on the SF-36 and SGRQ. The domain or total scores on the SHQ also significantly correlated with serum levels of the soluble interleukin-2 receptor, the percentage of the predicted forced vital capacity, pulmonary arterial systolic pressure, dyspnea, and depressive symptoms. Also, the SHQ scores of patients who had one or two organ systems affected by sarcoidosis were significantly different from those of patients who had three or more organ systems involvement.The Japanese version of the SHQ can be used to assess the HRQOL of patients with sarcoidosis.Sarcoidosis is a chronic and multisystem granulomatous disease of unknown etiology that can involve almost any organ system [1]. The assessment of overall disease burden is often challenging in sarcoidosis because of the disease's various clinical manifestations. Although spirometry and chest radiography are usually used to evaluate disease activity, these measures fail to address extrapulmonary lesions. As in other respiratory diseases, the patient's health-related quality of life (HRQOL) may be a useful measure to assess the systemic impact of sarcoidosis [2-4], and impaired HRQOL has been reported in sarcoidosis [5]. Given that sarcoidosis is a chronic disease for which there is no curative therapy yet [6], HRQOL could be the most importa
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