Showing papers by "Atsushi Takahashi published in 2013"

Seven new loci associated with age-related macular degeneration

Abstract: Age-related macular degeneration (AMD) is a common cause of blindness in older individuals To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry We identified 19 loci associated at P < 5 × 10(-8) These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined Our findings provide new directions for biological, genetic and therapeutic studies of AMD

Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis.

Abstract: Shiro Ikegawa and colleagues report a genome-wide association study for adolescent idiopathic scoliosis (AIS). They identify one locus associated with AIS on chromosome 6q24.1 in Japanese individuals, which was also replicated in individuals of Han Chinese and European ancestry.

High-density genotyping study identifies four new susceptibility loci for atopic dermatitis

Abstract: Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

Abstract: Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.

Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3.

Abstract: Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, affecting around 2% of adolescents worldwide. Genetic factors play an important role in its etiology. Using a genome-wide association study (GWAS), we recently identified novel AIS susceptibility loci on chromosomes 10q24.31 and 6q24.1. To identify more AIS susceptibility loci relating to its severity and progression, we performed GWAS by limiting the case subjects to those with severe AIS. Through a two-stage association study using a total of ∼12,000 Japanese subjects, we identified a common variant, rs12946942 that showed a significant association with severe AIS in the recessive model (P = 4.00×10−8, odds ratio [OR] = 2.05). Its association was replicated in a Chinese population (combined P = 6.43×10−12, OR = 2.21). rs12946942 is on chromosome 17q24.3 near the genes SOX9 and KCNJ2, which when mutated cause scoliosis phenotypes. Our findings will offer new insight into the etiology and progression of AIS.

Genome‐wide association study of chemotherapeutic agent‐induced severe neutropenia/leucopenia for patients in Biobank Japan

Abstract: Chemotherapeutic agents are notoriously known to have a narrow therapeutic range that often results in life-threatening toxicity. Hence, it is clinically important to identify the patients who are at high risk for severe toxicity to certain chemotherapy through a pharmacogenomics approach. In this study, we carried out multiple genome-wide association studies (GWAS) of 13 122 cancer patients who received different chemotherapy regimens, including cyclophosphamide- and platinum-based (cisplatin and carboplatin), anthracycline-based (doxorubicin and epirubicin), and antimetabolite-based (5-fluorouracil and gemcitabine) treatment, antimicrotubule agents (paclitaxel and docetaxel), and topoisomerase inhibitors (camptothecin and etoposide), as well as combination therapy with paclitaxel and carboplatin, to identify genetic variants that are associated with the risk of severe neutropenia/leucopenia in the Japanese population. In addition, we used a weighted genetic risk scoring system to evaluate the cumulative effects of the suggestive genetic variants identified from GWAS in order to predict the risk levels of individuals who carry multiple risk alleles. Although we failed to identify genetic variants that surpassed the genome-wide significance level (P < 5.0 × 10−8) through GWAS, probably due to insufficient statistical power and complex clinical features, we were able to shortlist some of the suggestive associated loci. The current study is at the relatively preliminary stage, but does highlight the complexity and problematic issues associated with retrospective pharmacogenomics studies. However, we hope that verification of these genetic variants through local and international collaborations could improve the clinical outcome for cancer patients.

Difference between the mechanisms of propylene production from methanol and ethanol over ZSM-5 catalysts

Abstract: We investigated the difference between the mechanisms of methanol conversion and ethanol conversion to propylene over ZSM-5 catalysts. The mechanism of methanol conversion depended on the Si/Al2 ratio, whereas the mechanism of ethanol conversion did not. We believe that at a high Si/Al2 ratio, propylene was produced from methanol via dimethyl ether by means of the hydrocarbon pool mechanism. In contrast, at a low Si/Al2 ratio, dimethyl ether was dehydrated to ethylene, which was then directly converted to propylene. In the case of ethanol conversion, propylene was produced from ethylene, which was formed by intramolecular dehydration. We propose that ethylene was transformed to a carbene species, which was a transient intermediate for direct production of propylene.

Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia

Abstract: Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a two-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox-proportional hazards model. One hundred and fifty-four genetically European patients were used for the primary analysis. An intronic single nucleotide polymorphism (SNP) in ABCC3 (rs4148405) was associated with a significantly shorter DFS (hazard ratios (HR)=3.2, P=5.6 × 10(-6)) in our primary cohort. In addition, a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, P=0.001 for 154 European ancestry; HR=1.7, P=0.028 for 125 non-European patients). Thus, for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT.

Genome-Wide Association Study of Breast Cancer in the Japanese Population

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.

HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese: a genome-wide association study.

Abstract: Hepatitis C virus (HCV) establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA) on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs) in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10-5). After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (Pcombined = 3.59 × 10−16, odds ratio [OR] = 0.79). Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72). This nucleotide substitution causes an amino acid substitution (R55P) in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype.

Genome wide association study of age at menarche in the Japanese population.

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.

A genome-wide association study of chemotherapy-induced alopecia in breast cancer patients

Abstract: Chemotherapy-induced alopecia is one of the most common adverse events caused by conventional cytotoxic chemotherapy, yet there has been very little progress in the prevention or treatment of this side effect. Although this is not a life-threatening event, alopecia is very psychologically difficult for many women to manage. In order to improve the quality of life for these women, it is important to elucidate the molecular mechanisms of chemotherapy-induced alopecia and develop ways to effectively prevent and/or treat it. To identify the genetic risk factors associated with chemotherapy-induced alopecia, we conducted a genome-wide association study (GWAS) using DNA samples from breast cancer patients who were treated with chemotherapy. We performed a case-control association study of 303 individuals who developed grade 2 alopecia, and compared them with 880 breast cancer patients who did not show hair loss after being treated with conventional chemotherapy. In addition, we separately analyzed a subset of patients who received specific combination therapies by GWASs and applied the weighted genetic risk scoring (wGRS) system to investigate the cumulative effects of the associated SNPs. We identified an SNP significantly associated with drug-induced grade 2 alopecia (rs3820706 in CACNB4 (calcium channel voltage-dependent subunit beta 4) on 2q23, P = 8.13 × 10-9, OR = 3.71) and detected several SNPs that showed some suggestive associations by subgroup analyses. We also classified patients into four groups on the basis of wGRS analysis and found that patients who classified in the highest risk group showed 443 times higher risk of antimicrotubule agents-induced alopecia than the lowest risk group. Our study suggests several associated genes and should shed some light on the molecular mechanism of alopecia in chemotherapy-treated breast cancer patients and hopefully will contribute to development of interventions that will improve the quality of life (QOL) of cancer patients.

Production of propylene from ethanol over ZSM-5 co-modified with zirconium and phosphorus

Abstract: Production of propylene from ethanol was studied over ZSM-5 co-modified with zirconium and phosphorus (P/Zr/ZSM-5). XRD and NH3-TPD were used to characterize P/Zr/ZSM-5 together with H-ZSM-5 and the zirconium modified ZSM-5 (Zr/ZSM-5) for comparison. It was found that the concentration of strong acid sites on P/Zr/ZSM-5 was significantly reduced by the impregnation of phosphorus into Zr/ZSM-5. In the ethanol-to-propylene reaction, P/Zr/ZSM-5 exhibited a better catalytic performance than H-ZSM-5 and Zr/ZSM-5. The in situ UV–Vis spectrum of the ethanol adsorbed P/Zr/ZSM-5 revealed that the species of non desorbed aromatics were hardly produced and thus the formation of carbonaceous deposits was inhibited by the phosphorus modification.

Whole-genome-wide association study in the Bulgarian population reveals HHAT as schizophrenia susceptibility gene.

Abstract: OBJECTIVE: Schizophrenia, the most common major psychiatric disorder (or group of disorders), entails severe decline of higher functions, principally with alterations in cognitive functioning and reality perception. Both genetic and environmental factors are involved in its pathogenesis; however, its genetic background still needs to be clarified. The objective of the study was to reveal genetic markers associated with schizophrenia in the Bulgarian population. METHODS: We have conducted a genome-wide association study using 554 496 single nucleotide polymorphisms (SNPs) in 188 affected and 376 unaffected Bulgarian individuals. Subsequently, the 100 candidate SNPs that revealed the smallest P-values were further evaluated in an additional set of 99 case and 328 control samples. RESULTS: We found a significant association between schizophrenia and the intronic SNP rs7527939 in the HHAT gene (P-value of 6.49×10 with an odds ratio of 2.63, 95% confidence interval of 1.89-3.66). We also genotyped additional SNPs within a 58-kb linkage disequilibrium block surrounding the landmark SNP. CONCLUSION: We suggest rs7527939 to be the strongest indicator of susceptibility to schizophrenia in the Bulgarian population within the HHAT locus.

Impact of PSCA variation on gastric ulcer susceptibility.

Abstract: Peptic ulcer is one of the most common gastrointestinal disorders with complex etiology. Recently we conducted the genome wide association study for duodenal ulcer and identified disease susceptibility variations at two genetic loci corresponding to the Prostate stem cell antigen (PSCA) gene and the ABO blood group (ABO) gene. Here we investigated the association of these variations with gastric ulcer in two Japanese case-control sample sets, a total of 4,291 gastric ulcer cases and 22,665 controls. As a result, a C-allele of rs2294008 at PSCA increased the risk of gastric ulcer with odds ratio (OR) of 1.13 (P value of 5.85×10−7) in an additive model. On the other hand, SNP rs505922 on ABO exhibited inconsistent result between two cohorts. Our finding implies presence of the common genetic variant in the pathogenesis of gastric and duodenal ulcers.

Correction: Genome Wide Association Study of Age at Menarche in the Japanese Population

Abstract: The affiliation of the editor, Chunyan He, is incorrect. The correct affiliation is: Richard M. Fairbanks School of Public Health, Indiana University, USA.

Al-modified mesoporous silica for efficient conversion of methanol to dimethyl ether

Abstract: The aim of this work was to design efficient mesoporous heterogeneous catalysts for the reaction of conversion of methanol to dimethyl ether (DME). Mesostructured silica and aluminosilicate solids were synthesized using an original synthesis procedure enabling the elaboration of structurally homogeneous solids at atmospheric pressure and using a food grade templating agent. The prepared solids consisted of mesoporous silica and aluminosilicates with aluminium contents of 0.76, 1.11 and 1.60 wt%. These solids were characterized by XRD, N2-physisorption and TEM. Their efficiency in the catalytic reaction of conversion of methanol to DME was subsequently correlated with their structural and acidic properties. The sample exhibiting a pore diameter of 2.2 nm for a Si/Al ratio of 27 showed remarkable performances with a methanol conversion as high as 80% at 598 K (7.5 vol% MeOH; 50 mg of catalyst; GHSV = 26,000 cm3 h−1 g−1) and a total selectivity to DME.

MgO Based Magnetic Tunnel Junctions With Co $_{20}$ Fe $_{60}$ B $_{20}$ Sensing Layer for Magnetic Field Sensors

Abstract: We applied Co20Fe60B20 layers with thicknesses from 1.2 to 1.5 nm to the sensing layers of MgO based magnetic tunnel junctions (MTJs) with spin-valve-type structures annealed at 350 °C for magnetic field sensors. The CoFeB layer on MgO had in-plane magnetic anisotropy and also slight perpendicular magnetic anisotropy that originated at the MgO/CoFeB interface. MR characteristics of high reversibility and linearity were confirmed at a CoFeB thickness of 1.3 nm. We consider that the hysteresis-free properties of the sensing layer were obtained by the balance between in-plane magnetization and other components in magnetization including out-of-plane magnetization.

Plant monitoring control system

Abstract: PROBLEM TO BE SOLVED: To execute plant monitoring control without interruption at the time of an accident of loss of all power supply or the likeSOLUTION: A plant monitoring control system includes: a plurality of control devices 2-1 comprising an external signal input/output section 8 for inputting/outputting a power supply voltage and process state signals 33-1 through 33-n from/to multiple monitoring control object apparatuses 3-1 through 3-n consisting of a plurality of types, a power supply device 6, a power supply abnormality monitoring section 9 for detecting abnormality of the power supply device 6, a control device arithmetic section 7, an abnormal time change-over section 10 that is provided between the control device arithmetic section 7 and the external signal input/output section 8 and has a plurality of change-over switches, a first terminal selection section 11a for outputting the power supply voltage to the predetermined monitoring control object apparatuses via the plurality of change-over switches and a second terminal selection section 10b for inputting the predetermined process state signals via the change-over switches; and a portable terminal device 12 comprising a type input section 13 for inputting types of the monitoring control object apparatuses 3-1 through 3-n, a type selection section 14, a power supply generation section 15 and a backup monitoring control section 16