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J Ohashi

Publications and source records attributed to J Ohashi.

At least 19 recordsLinked to original sources
PubMed2006

A genomic analysis of adult T-cell leukemia.

Adult T-cell leukemia (ATL) is an intractable malignancy of CD4+ T cells that is etiologically associated with infection by human T-cell leukemia virus-type I. Most individuals in the chronic stage of ATL eventually undergo progression to a highly aggressive acute stage. To clarify the mechanism responsible for this stage progression, we isolated CD4+ cells from individuals in the chronic (n=19) or acute (n=22) stages of ATL and subjected them to profiling of gene expression with DNA microarrays containing >44,000 probe sets. Changes in chromosome copy number were also examined for 24 cell specimens with the use of microarrays harboring approximately 50,000 probe sets. Stage-dependent changes in gene expression profile and chromosome copy number were apparent. Furthermore, expression of the gene for MET, a receptor tyrosine kinase for hepatocyte growth factor (HGF), was shown to be specific to the acute stage of ATL, and the plasma concentration of HGF was increased in individuals in either the acute or chronic stage. HGF induced proliferation of a MET-positive ATL cell line, and this effect was blocked by antibodies to HGF. The HGF-MET signaling pathway is thus a potential therapeutic target for ATL.

Cell Line, Tumor↗
PubMed2006

HLA-A, HLA-B, and HLA-DRB1 alleles and haplotypes in Naxi and Han populations in southwestern China (Yunnan province).

The frequencies of the human leukocyte antigen alleles HLA-A, HLA-B, and HLA-DRB1 and the A-B-DRB1, A-B, and B-DRB1 haplotypes were studied in Naxi and Yunnan Han populations using polymerase chain reaction (PCR)-sequence-specific amplification for alleles A and B and a PCR-microtiter plate hybridization method for the DRB1 allele. A total of 8 A, 19 B, and 30 DRB1 alleles were found in the Naxi population, and 15 A, 21 B, and 36 DRB1 alleles were found in Yunnan Han population. The common A-B-DRB1 haplotypes in the Naxi population were A*24-B*15-DRB1*1202, A*11-B*15-DRB1*0405, A*11-B*15-DRB1*1202, A*11-B*38-DRB1*08032, and A*11-B*55-DRB1*0405; the common A-B haplotypes were A*11-B*15, A*11-B*38, and A*24-B*15; and the common B-DRB1 haplotypes were B*15-DRB1*1202, B*38-DRB1*08032, and B*48-DRB1*1201. In the Yunnan Han population, the common A-B-DRB1 haplotypes were A*24-B*15-DRB1*1501, A*24-B*46-DRB1*08032, and A*24-B*15-DRB1*1201; the common A-B haplotypes were A*24-B*15, A*24-B*46, and A*34-B*46; and the common B-DRB1 haplotypes were B*15-DRB1*1501, B*46-DRB1*09012, and B*46-DRB1*1401. Phylogenetic tree and principal component analyzes based on HLA-A, HLA-B, and DRB1 allele frequencies suggested that the Naxi ethnic group belongs to the southern Chinese groups, while the Yunnan Han population is a characteristic population located intermediate between northern and southern Chinese groups, although they live in the southwest of China.

Alleles↗
PubMed2006

Estimation of the species-specific mutation rates at the DRB1 locus in humans and chimpanzee.

To estimate the species-specific mutation rates at the DRB1 locus in humans and chimpanzee, we analyzed the nucleotide sequence of a 37.6-kb chimpanzee chromosomal segment containing the entire Patr-DRB1*0701 allele and the flanking nongenic region and we compared it with two corresponding human sequences containing the HLA-DRB1*070101 allele using the sequence of HLA-DRB1*04011 as an outgroup. Because the allelic pair of HLA-DRB1*070101 and Patr-DRB1*0701 shows the lowest number of substitutions between the two species, it appears that these sequences diverged close to the time of the humans-chimpanzee divergence (6 million years ago). Alignment of the nucleotide sequences for HLA-DRB1*070101 and Patr-DRB1*0701 alleles showed that they share a high degree of similarity, suggesting that the studied chromosomal segments with these sequences have not been subjected to recombination since the humans-chimpanzee divergence. Comparison of the flanking 10.6 kb of nongenic sequences revealed an average of 41.5 and 83 single nucleotide substitutions in humans and chimpanzee, respectively. Thus, the species-specific nucleotide substitution rates in the flanking nongenic region were estimated to be 6.53 x 10(-10) and 1.31 x 10(-9) per site per year in humans and chimpanzee, respectively. Unexpectedly, the estimated rate in humans was twofold lower than in chimpanzee (P < 10(-3), Tajima's relative rate test) and lower than the average substitution rate in the human genome. Because the nucleotide substitution rate in nongenic regions free from selection is expected to be equal to the mutation rate, the estimated substitution rate should correspond to the species-specific mutation rate at the DRB1 locus. Our results strongly suggest that the mutation rate at DRB1 locus differs among species.

Alleles↗
PubMed2005

Absence of an association between the polymorphisms in the genes encoding adiponectin receptors and type 2 diabetes.

AIMS/HYPOTHESIS: Secreted by adipocytes, adiponectin is a hormone that acts as an antidiabetic and anti-atherogenic adipokine. We recently cloned the genes encoding two adiponectin receptors (ADIPOR1 and ADIPOR2). The aim of this study was to examine whether ADIPOR1 and/or ADIPOR2 play a major role in genetic susceptibility to insulin resistance or type 2 diabetes in the Japanese population. METHODS: By direct sequencing and a search of public databases, we identified single nucleotide polymorphisms (SNPs) in ADIPOR1 and ADIPOR2, and investigated whether these SNPs are associated with insulin resistance and type 2 diabetes in the Japanese population. RESULTS: The linkage disequilibrium (LD) in the chromosomal region of ADIPOR1 was almost completely preserved, whereas the LD in ADIPOR2 was less well preserved. None of the SNPs in ADIPOR1 or ADIPOR2 were significantly associated with insulin resistance or type 2 diabetes. No differences in ADIPOR1 or ADIPOR2 haplotype frequencies were observed between type 2 diabetic and non-diabetic subjects. CONCLUSIONS/INTERPRETATION: Genetic variations in ADIPOR1 or ADIPOR2 are unlikely to lead to a common genetic predisposition to insulin resistance or type 2 diabetes in the Japanese population.

Diabetes Mellitus, Type 2↗
PubMed2005

Application of the stepwise focusing method to optimize the cost-effectiveness of genome-wide association studies with limited research budgets for genotyping and phenotyping.

The recent cataloguing of a large number of SNPs enables us to perform genome-wide association studies for detecting common genetic variants associated with disease. Such studies, however, generally have limited research budgets for genotyping and phenotyping. It is therefore necessary to optimize the study design by determining the most cost-effective numbers of SNPs and individuals to analyze. In this report we applied the stepwise focusing method, with two-stage design, developed by Satagopan et al. (2002) and Saito & Kamatani (2002), to optimize the cost-effectiveness of a genome-wide direct association study using a transmission/disequilibrium test (TDT). The stepwise focusing method consists of two steps: a large number of SNPs are examined in the first focusing step, and then all the SNPs showing a significant P-value are tested again using a larger set of individuals in the second focusing step. In the framework of optimization, the numbers of SNPs and families and the significance levels in the first and second steps were regarded as variables to be considered. Our results showed that the stepwise focusing method achieves a distinct gain of power compared to a conventional method with the same research budget.

Cost Control↗
PubMed2004

DNA microarray analysis of natural killer cell-type lymphoproliferative disease of granular lymphocytes with purified CD3-CD56+ fractions.

Natural killer (NK) cell-type lymphoproliferative disease of granular lymphocytes (LDGL) is characterized by the outgrowth of CD3(-)CD16/56(+) NK cells, and can be further subdivided into two distinct categories: aggressive NK cell leukemia (ANKL) and chronic NK lymphocytosis (CNKL). To gain insights into the pathophysiology of NK cell-type LDGL, we here purified CD3(-)CD56(+) fractions from healthy individuals (n=9) and those with CNKL (n=9) or ANKL (n=1), and compared the expression profiles of >12 000 genes. A total of 15 'LDGL-associated genes' were identified, and a correspondence analysis on such genes could clearly indicate that LDGL samples share a 'molecular signature' distinct from that of normal NK cells. With a newly invented class prediction algorithm, 'weighted distance method', all 19 samples received a clinically matched diagnosis, and, furthermore, a detailed cross-validation trial for the prediction of normal or CNKL status could achieve a high accuracy (77.8%). By applying another statistical approach, we could extract other sets of genes, expression of which was specific to either normal or LDGL NK cells. Together with sophisticated statistical methods, gene expression profiling of a background-matched NK cell fraction thus provides us a wealth of information for the LDGL condition.

Adolescent↗
PubMed2004

Association of Fcgamma receptor IIb polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian populations.

The association of Fcgamma receptor (FcgammaR) polymorphisms with systemic lupus erythematosus (SLE) has been demonstrated in various populations; however, the results have been inconsistent. We recently identified a single-nucleotide polymorphism encoding a non-synonymous substitution, Ile232Thr (I232T), of FCGR2B and its association with SLE in Japanese and in Thais. Multiple functional FcgammaR genes with polymorphisms (FCGR2A, FCGR2B, FCGR3A, and FCGR3B) cluster in 1q23, and some of them are in linkage disequilibrium (LD). To differentiate contributions from multiple-linked loci, comparison of different populations may provide useful information. In this study, we analyzed the above four FCGR polymorphisms of the Chinese patients and controls for the association with SLE. FCGR2A-H131R, FCGR2B-I232T, FCGR3A-F176V, and FCGR3B genotypes were determined in 167 Chinese patients with SLE and 129 healthy controls. Association was examined using case-control analysis. Allele frequencies of FCGR2B-232T and FCGR3A-176F were significantly increased in SLE [odds ratio (OR) = 1.67 and OR = 1.41, respectively]. Interestingly, while these alleles had a tendency of positive LD in the controls, FCGR2B-232T was in positive association with FCGR3A-176V in SLE, suggesting that these two alleles were associated with SLE in an independent manner. Comparison between SLE with and without nephritis indicated significant association of FCGR2B-232T with nephritis (OR = 2.65). When the present results were combined with our previous data on the Japanese and the Thais using meta-analytic methods, highly significant and independent association was observed for FCGR2B and FCGR3A genotypes. These results strongly suggested that FCGR2B is a common susceptibility factor to SLE in the Asians.

Adult↗
PubMed2004

Application of discordant sib-pair linkage analysis for mapping minor histocompatibility antigen loci in a novel graft-vs-host-disease model.

Graft-vs-host disease (GVHD) is an adverse effect of allogenic bone marrow transplantation. Although a major cause of GVHD following bone marrow transplantation is incompatibility of major histocompatibility antigen (human leukocyte antigen, HLA) in donor-recipient pairs, the incompatibility of minor histocompatibility antigen (mHa) is known as another cause, especially in HLA-matched donor-recipient pairs. In 1998, Lunetta and Rogus proposed the use of discordant sib-pair (DSP) linkage analysis for detecting mHa and calculated the statistical power using the GVHD model, assuming single mHa locus with multiple alleles. Recently, we proposed a different GVHD model, assuming multiple mHa loci with two alleles (biallelic), considering the single-nucleotide polymorphisms. When the effect of each mHa locus on the occurrence of GVHD is independent, the possible triangle for DSP proposed by Lunetta and Rogus is not optimum, but a new possible triangle, named here as GVHD region, is needed. We evaluated, based on Monte Carlo simulation, the test criteria [log of odds (lod) score cutoffs] and power of DSP using the GVHD region for various parameter sets. The GVHD region showed a higher power than the DSP and entire regions in plausible situations. Our results suggest that the application of GVHD region to DSP is effective for the screening of mHa loci.

Genetic Linkage↗
PubMed2004

Molecular polymorphism of ABO blood group gene in Austronesian and non-Austronesian populations in Oceania.

A number of archeological, linguistic, and genetic studies have been carried out on the peopling of the Pacific, while the origin of Polynesians or the Lapita people is still open to debate. The Lapita people are believed to have populated the Bismarck Archipelago more than 3600 years ago. However, their Melanesian descendants still living in the Bismarck Archipelago have not been genetically clarified yet. To address this question, polymorphism of the ABO blood group gene was investigated in the following three populations who are considered to be almost free from recent admixtures: (i) Balopa islanders as Austronesian (AN)-speaking Melanesians living in the northwestern end of the Bismarck Archipelago; (ii) Gidra as non-Austronesian (NAN)-speaking Melanesians in southwestern lowlands of Papua New Guinea; and (iii) Tongan living in Ha'apai island as AN-speaking Polynesians. Interestingly, there were marked differences in allele frequencies of ABO*A101 and ABO*A102 among the three populations. The allele frequencies of ABO*A101 and ABO*A102 were 7.9 and 19.3% in Balopa, 23.2 and 0.0% in Gidra, and 2.9 and 25.0% in Tongan. Both phylogenetic and correspondence analyses suggested that Balopa was more close to Tongan than to Gidra and that Balopa was genetically placed between Tongan and Asian populations. Our results imply that Balopa may be Melanesian descendants of the Lapita people who populated the Bismarck Archipelago.

ABO Blood-Group System↗
PubMed2003

A single-nucleotide substitution from C to T at position -1055 in the IL-13 promoter is associated with protection from severe malaria in Thailand.

We examined a possible association of single-nucleotide polymorphisms (SNPs) in the promoters of IL-3, IL-4, and IL-13 genes on the 5q31-33, IL-3 -16T>C, IL-4 -590T>C, and IL-13 -1055C>T, with severity of malaria in 361 adult malaria patients in Thailand. The IL-13 -1055T allele showed a significant association with protection from severe malaria (OR 0.51, 95% CI 0.32-0.80; P=0.0032 by the chi(2) test), while allele frequencies of IL-3 -16T>C and IL-4 -590T>C were not statistically different between mild and severe malaria patients. An IL-13 -1055C>T has been reported to alter the regulation of IL-13 production. Thus, IL-13 -1055T may show resistance to severe malaria through the alteration of IL-13 production.

Adolescent↗
PubMed2002

The expected power of genome-wide linkage disequilibrium testing using single nucleotide polymorphism markers for detecting a low-frequency disease variant.

The expected power of genome-wide linkage disequilibrium (LD) testing for a low-frequency disease variant was examined using a simple genetic model in which the degree of LD between the disease variant and the adjacent single nucleotide polymorphism (SNP) marker decreases in proportion to the number of generations since the LD-generating event. In this study, the frequency of the SNP marker being in complete LD with a low-frequency disease variant at the LD-generating event was regarded as the random variable having the probability distribution expected from the neutral infinite sites model, which enables us to derive the formula for calculating the expected power of genome-wide LD testing without determining the allele frequency of the associated SNP marker. Such a treatment is essential for the evaluation of the power of LD testing, because the frequency of the associated marker allele is always unknown. The main results obtained are as follows: (1) genome-wide LD testing with a case-control design could identify a disease variant with a high penetrance, while a low-frequency disease variant showing a low penetrance is difficult to detect; (2) although the degree of LD increases as the number of markers increases, the power of LD testing does not necessarily increase after the significance level is adjusted by the Sidák correction or the Bonferroni correction based on the number of testings; (3) the use of SNP markers with only high-frequency minor alleles is more powerful for detecting LD even with a low-frequency disease variant than the use of SNP markers with both high- and low-frequency minor alleles. Thus, the study design of LD testing must be evaluated prior to the investigation. The present study will provide a guideline for determining the number of SNP markers and the range of SNP allele frequencies suitable for genome-wide LD testing.

Gene Frequency↗
PubMed2002

Association of HLA-A*3303-B*4403-DRB1*1302 haplotype, but not of TNFA promoter and NKp30 polymorphism, with postherpetic neuralgia (PHN) in the Japanese population.

Herpes zoster is a common disease caused by reactivation of the varicella zoster virus (VZV). In a small number of herpes zoster patients, pain persists beyond 4 weeks or more after healing of vesicular eruptions; this condition is termed postherpetic neuralgia (PHN). Positive associations of human histocompatibility leukocyte antigens (HLA) class I antigens, A33 and B44, with PHN in the Japanese population have been reported. Our hypothesis is that susceptibility genes to PHN might exist in the HLA region and the study objective is to further examine possible associations of genes in HLA class I, II and III regions, HLA-A, -B, -DRB1, tumor necrosis factor alpha (TNFA) promoter, and a natural killer cell activating receptor, NKp30 polymorphisms with PHN. Although TNFA or NKp30 in the class III region had been considered as a candidate locus, we found no associations of TNFA promoter or NKp30 polymorphisms with PHN in this study. We demonstrated that HLA-A*3303, -B*4403 and -DRB1*1302 alleles were significantly associated with PHN (P = 0.0007 for A*3303, P = 0.001 for B*4403 and P = 0.001 for DRB1*1302). The frequency of the HLA-A*3303-B*4403-DRB1*1302 haplotype was also significantly higher in the PHN patients than in the healthy controls (P = 0.0039). Our results suggest that this haplotype might be related to the pathogenesis of PHN.

Adult↗
PubMed2001

Systematic search for single nucleotide polymorphisms in the insulin gene: evidence for a high frequency of -23T-->A in Japanese subjects.

It has recently been shown that the A/A genotype at g.-23 of the insulin gene correlates with impaired insulin secretion in response to body weight gain in subjects of European descent. To examine whether there are single nucleotide polymorphisms (SNPs) in the insulin gene associated with type 2 diabetes, all exons with their flanking sequences for 113 Japanese type 2 diabetic patients and 99 nondiabetic control subjects were analyzed using PCR direct sequencing. We have only found g.-23T --> A, 806G --> C, 1128T --> C, and 1141A --> C, which have previously been reported in alpha (A-C-C-C) and beta (T-G-T-A) alleles. The allele frequency of -23T --> A in control Japanese subjects was 97.4%, whereas that in Europeans is about 30%. The A/A genotype was found in 94 of 99 Japanese subjects (94.9%) and the allele frequencies of 806G --> C, 1128T --> C, and 1141A --> C were all 96.5%. The estimated haplotype frequencies were (A-C-C-C) (96.0%), (T-G-T-A) (2.0%), (A-G-T-A) (1.5%), and (T-C-C-C) (0.5%). No association of these SNPs or haplotypes with type 2 diabetes was evident. Thus, the A/A genotype at the g.-23 of insulin gene was generally high in Japanese subjects, which could account for the fact that they typically secrete lower levels of insulin.

Adult↗
PubMed2001

The power of genome-wide association studies of complex disease genes: statistical limitations of indirect approaches using SNP markers.

Genome-wide association studies using a dense map of single nucleotide polymorphism (SNP) markers seem to enable us to detect a number of complex disease genes. In such indirect association studies, whether susceptibility genes can be detected is dependent not only on the degree of linkage disequilibrium between the disease variant and the SNP marker but also on the difference in their allele frequencies. These factors, as well as penetrance of the disease variant, influence the statistical power of such approaches. However, the power of indirect association studies is not well understood. We calculated the number of individuals necessary for the detection of the disease variant in both direct and indirect association studies with a case-control design. The result shows that a remarkable reduction in the statistical power of indirect studies, compared with that of direct ones, is unavoidable in the genome-wide screening of complex disease genes. If there is a large difference in allele frequency between the disease variant and the marker, the disease variant cannot be detected. Because the frequency of the disease variant is unknown, SNP markers with various allele frequencies, or a large number of SNP markers, must be used in indirect association studies. However, if the number of SNP markers is increased, the obtained P value may not reach the significance level due to the Bonferroni adjustment. Thus, to test a possible association between functional variants and a complex disease directly, we should identify such SNPs in as many genes as possible for use in genome-wide association studies.

Gene Frequency↗
PubMed2001

Genetic link between Asians and native Americans: evidence from HLA genes and haplotypes.

We have been studying polymorphisms of HLA class I and II genes in East Asians including Buryat in Siberia, Mongolian, Han Chinese, Man Chinese, Korean Chinese, South Korean, and Taiwan indigenous populations in collaboration with many Asian scientists. Regional populations in Japan, Hondo-Japanese, Ryukyuan, and Ainu, were also studied. HLA-A, -B, and -DRB1 gene frequencies were subjected to the correspondence analysis and calculation of DA distances. The correspondence analysis demonstrated several major clusters of human populations in the world. "Mongoloid" populations were highly diversified, in which several clusters such as Northeast Asians, Southeast Asians, Oceanians, and Native Americans were observed. Interestingly, an indigenous population in North Japan, Ainu, was placed relatively close to Native Americans in the correspondence analysis. Distribution of particular HLA-A, -B, -DRB1 alleles and haplotypes was also analyzed in relation to migration and dispersal routes of ancestral populations. A number of alleles and haplotypes showed characteristic patterns of regional distribution. For example, B39-HR5-DQ7 (B*3901-DRB1*1406-DQB1*0301) was shared by Ainu and Native Americans. A24-Cw8-B48 was commonly observed in Taiwan indigenous populations, Maori in New Zealand, Orochon in Northeast China, Inuit, and Tlingit. These findings further support the genetic link between East Asians and Native Americans. We have proposed that various ancestral populations in East Asia, marked by different HLA haplotypes, had migrated and dispersed through multiple routes. Moreover, relatively small genetic distances and the sharing of several HLA haplotypes between Ainu and Native Americans suggest that these populations are descendants of some Upper Paleolithic populations of East Asia.

Alleles↗
PubMed2001

Comparison of statistical power between 2 * 2 allele frequency and allele positivity tables in case-control studies of complex disease genes.

In case-control studies of complex disease genes, allele frequencies or allele positivities at candidate loci or markers are compared between cases and controls. Although 2 x 2 contingency tables based on allele frequency and allele positivity are generally used to perform simple statistical tests (e.g. a comparison of two proportions and a chi2 test), little is known about the difference in power between the two tables. In this study, we investigated the number of subjects required to obtain a power of 1-beta with a significance level of alpha for the allele frequency and allele positivity tables. A large difference in the required number of subjects was found between the two tables. Allele positivity tables were suitable for the detection of susceptibility alleles showing a dominant mode of inheritance (MOI). On the other hand, allele frequency tables were suitable for the identification of susceptibility alleles showing a recessive MOI or a multiplicative MOI. In the case of an additive MOI, a suitable table was determined by combining the frequency of the susceptibility allele and the penetrance. These results imply that there are cases in which true association is detected based on one contingency table and is not detected based on another. A simulation analysis revealed that the type I error rate was not much inflated under the null hypothesis of no association, even when a statistical test was performed twice using both allele frequency and allele positivity tables. In contrast, under the alternative hypothesis, the loss of power was marked when a test was performed once using an unsuitable table. In conclusion, statistical tests should be performed using both tables, without adjustment of multiplicity, in case-control studies of complex disease genes when the study objective is exploratory.

Alleles↗