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Sano M.,Keio University | Kamitsuji S.,StaGen Co. | Kamatani N.,StaGen Co. | Hong K.-W.,Centers for Disease Control and Prevention | And 5 more authors.
Human molecular genetics | Year: 2014

Previous reports have described several associations of PR, QRS, QT and heart rate with genomic variations by genome-wide association studies (GWASs). In the present study, we examined the association of ∼2.5 million SNPs from 2994 Japanese healthy volunteers obtained from the JPDSC database with electrocardiographic parameters. We confirmed associations of PR interval, QRS duration and QT interval in individuals of Japanese ancestry with 11 of the 45 SNPs (6 of 20 for QT, 5 of 19 for PR and 0 of 6 for QRS) observed among individuals of European, African and Asian (Indian and Korean) ancestries. Those results indicate that many of the electrocardiographic associations with genes are shared by different ethnic groups including Japanese. Possible novel associations found in this study were validated by Korean data. As a result, we identified a novel association of SNP rs4952632[G] (maps near SLC8A1, sodium-calcium exchanger) (P = 7.595 × 10(-6)) with PR interval in Japanese individuals, and replication testing among Koreans confirmed the association of the same SNP with prolonged PR interval. Meta-analysis of the Japanese and Korean datasets demonstrated highly significant associations of SNP rs4952632[G] with a 2.325-ms (95% CI, 1.693-2.957 ms) longer PR interval per minor allele copy (P = 5.598 × 10(-13)). Cell-type-specific SLC8A1 knockout mice have demonstrated a regulatory role of sodium-calcium exchanger in automaticity and conduction in sinoatrial node, atrium and atrioventricular node. Our findings support a functional role of sodium-calcium exchanger in human atrial and atrioventricular nodal conduction as suggested by genetically modified mouse models. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email:

Shimojima K.,Japan Science and Technology Agency | Shimojima K.,Tokyo Women's Medical University | Narita A.,StaGen Co. | Maegaki Y.,StaGen Co. | And 3 more authors.
BMC Research Notes | Year: 2014

Background: Owing to the number of genetic mutations that contribute to malformations of cortical development, identification of causative mutations in candidate genes is challenging. To overcome these challenges, we performed whole-exome sequencing in this study. Case presentation. A Japanese patient presented with microcephaly and severe developmental delay. Brain magnetic resonance imaging showed the presence of colpocephaly associated with lateral ventricle dilatation and the presence of a simplified gyral pattern. Hypoplasia of the corpus callosum and cerebellar vermis were also noted. Because Sanger sequencing is expensive, laborious, and time-consuming, whole-exome sequencing was performed and a de novo missense mutation in TUBA1A (E27Q) was identified. Conclusion: The novel mutation identified in this study was located in the genetic region that encodes the N-terminal domain of TUBA1A, a region of TUBA1A with few reported mutations. Retrospective assessment of the clinical and radiological features of this patient i.e., microcephaly, lissencephaly (pachygyria) with cerebellar hypoplasia, and corpus callosum hypoplasia indicated that the TUBA1A mutation did not lead to any contradictions. Because rapid and comprehensive mutation analysis by whole-exome sequencing is time- and cost-effective, it might be useful for genetic counseling of patients with sporadic malformations of cortical development. © 2014 Shimojima et al.; licensee BioMed Central Ltd.

PubMed | Fukuoka University, Tokyo Women's Medical University, Juntendo University, Juntendo Nerima Hospital and 7 more.
Type: Journal Article | Journal: PloS one | Year: 2015

Nucleotide alterations in the gene encoding proline-rich transmembrane protein 2 (PRRT2) have been identified in most patients with benign partial epilepsies in infancy (BPEI)/benign familial infantile epilepsy (BFIE). However, not all patients harbor these PRRT2 mutations, indicating the involvement of genes other than PRRT2. In this study, we performed whole exome sequencing analysis for a large family affected with PRRT2-unrelated BPEI. We identified a non-synonymous single nucleotide variation (SNV) in the voltage-sensitive chloride channel 6 gene (CLCN6). A cohort study of 48 BPEI patients without PRRT2 mutations revealed a different CLCN6 SNV in a patient, his sibling and his father who had a history of febrile seizures (FS) but not BPEI. Another study of 48 patients with FS identified an additional SNV in CLCN6. Chloride channels (CLCs) are involved in a multitude of physiologic processes and some members of the CLC family have been linked to inherited diseases. However, a phenotypic correlation has not been confirmed for CLCN6. Although we could not detect significant biological effects linked to the identified CLCN6 SNVs, further studies should investigate potential CLCN6 variants that may underlie the genetic susceptibility to convulsive disorders.

PubMed | Tokyo Women's Medical University, Fukuoka Childrens Hospital, Osaka Medical Center and Research Institute for Maternal and Child Health, StaGen Co. and NHO Shizuoka Institute of Epilepsy and Neurological Disorders
Type: | Journal: Human genome variation | Year: 2016

Next-generation sequencing (NGS) is widely used for the detection of disease-causing nucleotide variants. The challenges associated with detecting copy number variants (CNVs) using NGS analysis have been reported previously. Disease-related exome panels such as Illumina TruSight One are more cost-effective than whole-exome sequencing (WES) because of their selective target regions (~21% of the WES). In this study, CNVs were analyzed using data extracted through a disease-related exome panel analysis and the eXome Hidden Markov Model (XHMM). Samples from 61 patients with undiagnosed developmental delays and 52 healthy parents were included in this study. In the preliminary study to validate the constructed XHMM system (microarray-first approach), 34 patients who had previously been analyzed by chromosomal microarray testing were used. Among the five CNVs larger than 200kb that were considered as non-pathogenic CNVs and were used as positive controls, four CNVs was successfully detected. The system was subsequently used to analyze different samples from 27 patients (NGS-first approach); 2 of these patients were successfully diagnosed as having pathogenic CNVs (an unbalanced translocation der(5)t(5;14) and a 16p11.2 duplication). These diagnoses were re-confirmed by chromosomal microarray testing and/or fluorescence in situ hybridization. The NGS-first approach generated no false-negative or false-positive results for pathogenic CNVs, indicating its high sensitivity and specificity in detecting pathogenic CNVs. The results of this study show the possible clinical utility of pathogenic CNV screening using disease-related exome panel analysis and XHMM.

Shiraishi K.,National Cancer Center Research Institute | Kunitoh H.,National Cancer Center Hospital | Kunitoh H.,Mitsui Memorial Hospital | Daigo Y.,Shiga University of Medical Science | And 16 more authors.
Nature Genetics | Year: 2012

Lung adenocarcinoma is the most common histological type of lung cancer, and its incidence is increasing worldwide. To identify genetic factors influencing risk of lung adenocarcinoma, we conducted a genome-wide association study and two validation studies in the Japanese population comprising a total of 6,029 individuals with lung adenocarcinoma (cases) and 13,535 controls. We confirmed two previously reported risk loci, 5p15.33 (rs2853677, P combined = 2.8 × 10 -40, odds ratio (OR) = 1.41) and 3q28 (rs10937405, P combined = 6.9 × 10 -17, OR = 1.25), and identified two new susceptibility loci, 17q24.3 (rs7216064, P combined = 7.4 × 10 -11, OR = 1.20) and 6p21.3 (rs3817963, P combined = 2.7 × 10 -10, OR = 1.18). These data provide further evidence supporting a role for genetic susceptibility in the development of lung adenocarcinoma. © 2012 Nature America, Inc. All rights reserved.

PubMed | Red Cross, University of Chicago, Kanagawa Cancer Center, National Cancer Center Research Institute and 12 more.
Type: | Journal: Nature communications | Year: 2016

Lung adenocarcinoma driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Here we investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA class II at 6p21.32 (rs2179920; P =5.1 10(-17), per-allele OR=1.36) and 6p21.1 (FOXP4) (rs2495239; P=3.9 10(-9), per-allele OR=1.19) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma. This study indicates that multiple genetic factors underlie the risk of lung adenocarcinomas with EGFR mutations.

Sugaya Y.,StaGen Co. | Akazawa Y.,Waseda University | Saito A.,StaGen Co. | Kamitsuji S.,StaGen Co.
Journal of Human Genetics | Year: 2012

We developed a software program, NDesign, for the design of a study intended for detecting rare variants from next-generation sequencing (NGS) data. In this study design, the optimal depth of coverage and the average depth of coverage are first evaluated, and then the ability of the designed experiment to obtain a desired power is determined. NDesign has been developed to calculate both these depths, as well as to evaluate the power of the designed experiment. It has a simple implementation in the JavaScript language, and is expected to enable researchers to design optimal NGS studies. © 2012 The Japan Society of Human Genetics All rights reserved.

Japan Atomic Energy Agency, StaGen Co. and Smart Med Co. | Date: 2013-06-19

A liquid leakage detection system requiring no power supply from an outer source and configured to be relatively simple and moderate in price. A liquid leakage detection system (10) including an infusion tube (11), a syringe needle (12) coupled to the infusion tube (11), an absorbent element (16) adapted to be placed in the vicinity of a point (12a) of the syringe needle (12) to be pricked through a patient skin and a sensor unit (14) located on an upper side or within the absorbent element (16).

Japan Atomic Energy Agency, Smart Med Co. and StaGen Co. | Date: 2010-08-13

A liquid leakage detection system requiring no power supply from an outer source and configured to be relatively simple and moderate in price. A liquid leakage detection system (10) including an infusion tube (11), a syringe needle (12) coupled to the infusion tube (11), an absorbent element (16) adapted to be placed in the vicinity of a point (12a) of the syringe needle (12) to be pricked through a patient skin and a sensor unit (14) located on an upper side or within the absorbent element (16).

PubMed | University of Washington, Tokyo Metropolitan Institute of Medical Science, StaGen Co. and University of Tokyo
Type: Journal Article | Journal: The pharmacogenomics journal | Year: 2015

Statistical imputation of classical human leukocyte antigen (HLA) alleles is becoming an indispensable tool for fine-mappings of disease association signals from case-control genome-wide association studies. However, most currently available HLA imputation tools are based on European reference populations and are not suitable for direct application to non-European populations. Among the HLA imputation tools, The HIBAG R package is a flexible HLA imputation tool that is equipped with a wide range of population-based classifiers; moreover, HIBAG R enables individual researchers to build custom classifiers. Here, two data sets, each comprising data from healthy Japanese individuals of difference sample sizes, were used to build custom classifiers. HLA imputation accuracy in five HLA classes (HLA-A, HLA-B, HLA-DRB1, HLA-DQB1 and HLA-DPB1) increased from the 82.5-98.8% obtained with the original HIBAG references to 95.2-99.5% with our custom classifiers. A call threshold (CT) of 0.4 is recommended for our Japanese classifiers; in contrast, HIBAG references recommend a CT of 0.5. Finally, our classifiers could be used to identify the risk haplotypes for Japanese narcolepsy with cataplexy, HLA-DRB1*15:01 and HLA-DQB1*06:02, with 100% and 99.7% accuracy, respectively; therefore, these classifiers can be used to supplement the current lack of HLA genotyping data in widely available genome-wide association study data sets.

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