Yokohama-shi, Japan
Yokohama-shi, Japan

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Meguro A.,Yokohama City University | Inoko H.,Tokai University | Ota M.,Shinshu University | Katsuyama Y.,Shinshu University | And 7 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Background: Behçet disease (BD) is a rare, chronic, systemic, inflammatory disorder characterised by recurrent ocular, genital and skin lesions. Although its aetiology is still uncertain, an intricate interplay between the environment (eg, viruses) and the host seems to initiate and/or perpetuate the disease, although the mechanism remains speculative. Since the identification of HLA-B*5101 (and more recently of MICA) as a susceptibility locus for BD, the identification of additional genetic locus/loci, whether inside, or perhaps more importantly outside the MHC has clearly stalled. Objective: To carry out a genome-wide association study (GWAS) of BD. Methods: 300 Japanese patients with BD and an equal number of controls were recruited. The samples were screened using a dense panel of 23 465 microsatellites (MS) covering the entire genome. Results: The six best (of a total of 147) positively associated MS with BD were identified. Of these six, two were located within the human leucocyte antigen (HLA) class I region itself. Although one of these was clearly reminiscent of the association with HLA-B, the second, not in linkage disequilibrium with the former, was in the telomeric side of the class I region and remained to be formally identified. HLA genotyping and haplotype analysis conclusively led to the deciphering of a dual, independent, contribution of two HLA alleles to the pathogenesis of BD: HLA-B*5101 and HLA-A*26. Conclusions: This GWAS highlights the premier genetic susceptibility locus for BD as the major histocompatibility complex itself, wherein reside two independent loci: HLA-B and HLA-A.


Saadat K.A.S.M.,University of Tokyo | Murakami Y.,Kyushu University | Tan X.,University of Tokyo | Nomura Y.,University of Tokyo | And 4 more authors.
FEBS Open Bio | Year: 2014

In this study, we show augmented autophagy in the retinal pigment epithelial cell line ARPE-19 when cultured in the presence of the lipofuscin pigment A2E. A2E alone does not induce RPE cell death, but cell death was induced in the presence of A2E with the autophagy inhibitor 3-methyladenine (3MA), with a concomitant increase in the generation of mitochondrial reactive oxygen species. On the other hand, the ATP production capacity of mitochondria was decreased in the presence of A2E, and pharmacological inhibition of autophagy had no additional effects. The altered mRNA expression level of mitochondrial function markers was confirmed by real-time polymerase chain reaction, which showed that the antioxidant enzymes SOD1 and SOD2 were not reduced in the presence of A2E alone, but significantly suppressed with the addition of 3MA. Furthermore, transmission electron micrography revealed autophagic vacuole formation in the presence of A2E, and inhibition of autophagy resulted in the accumulation of abnormal mitochondria with loss of cristae. Spheroid culture of human RPE cells demonstrated debris accumulation in the presence of A2E, and this accumulation was accelerated in the presence of 3MA. These results indicate that autophagy in RPE cells is a vital cytoprotective process that prevents the accumulation of damaged cellular molecules. © 2014 The Authors.


Yoshida M.,Kyorin University | Meguro A.,Yokohama City University | Yoshino A.,Yokohama City University | Nomura N.,Yokohama City University | And 2 more authors.
Clinical Ophthalmology | Year: 2013

Purpose: Polymorphisms in the insulin-like growth factor 1 (IGF1) gene were previously associated with high or extreme myopia in Caucasian and Chinese populations. In the present study, we investigated whether IGF1 polymorphisms are associated with high myopia in a Japanese population. Methods: A total of 446 Japanese patients with high myopia (#-9.00 diopters) and 481 Japanese healthy controls (+1.50 diopters to -1.50 diopters) were recruited. We genotyped seven tagging single-nucleotide polymorphisms (SNPs) in IGF1 and assessed allelic and haplotypic diversity in cases and controls. Results: There were no statistically signifcant differences in the allele frequencies of IGF1 SNPs and genotypes between cases and controls (P.0.05). However, the A allele of rs5742629 and the G allele of rs12423791 were associated with a moderately increased risk of high myopia (odds ratio [OR] =1.20 and OR =1.21, respectively) with borderline statistical signifcance (P=0.0502, corrected P (Pc) =0.21 and P=0.064, Pc=0.29, respectively). The haplotype consisting of the A allele of rs5742629 and the G allele of rs12423791 was marginally associated with the risk of high myopia (P=0.041; OR =1.21); this association was not signifcant after correction (Pc=0.19). Conclusion: We found that the IGF1 SNPs are not signifcantly associated with high myopia in our Japanese population. Our results are in contrast to a previous study in which extreme myopia cases had signifcantly higher frequencies of the G allele of rs5742629 and the C allele of rs12423791 than controls. Therefore, the IGF1 SNPs may not be important factors for susceptibility to high myopia in all populations. Further genetic studies are needed to elucidate the possible contributions of the IGF1 region to the development of high myopia. © 2013 Yoshida et al.


Sada T.,Yokohama City University | Ota M.,Shinshu University | Katsuyama Y.,Shinshu University | Meguro A.,Yokohama City University | And 7 more authors.
Human Immunology | Year: 2011

Action of Toll-like receptors (TLRs) is deeply associated with defense mechanisms of the innate and adaptive immune responses to microbial pathogens. There have been reports of genetic polymorphisms within the TLR7 gene being closely related to a variety of inflammatory and infectious diseases. Behçet's disease (BD) is an autoinflammatory disease, and the pathogenesis has yet to be fully discovered. We investigated whether polymorphisms of Toll-like receptor 7 (TLR7) are associated with BD by analyzing the frequency of eight single nucleotide polymorphisms (SNPs) within 200 Japanese BD patients and 102 randomized controls. We genotyped nine SNPs in the TLR7 gene and assessed the allele/genotype diversity between cases and controls for all SNPs. In all eight SNPs, statistically significant differences were not observed between cases and controls. © 2011 American Society for Histocompatibility and Immunogenetics.


Nakasato H.,Yokohama City University | Uemoto R.,Yokohama City University | Kawagoe T.,Yokohama City University | Okada E.,Okada Eye Clinic | Mizuki N.,Yokohama City University
British Journal of Ophthalmology | Year: 2012

Aim: To describe a new method of removing dislocated nuclear fragments smaller than one-fourth the size of the lens nucleus through the sclerocorneal incision made for cataract surgery. Methods: Dislocated lens nuclear fragments on the surface of the retina were removed from six eyes of six consecutive patients. An anterior vitreous cutter with a 27-gauge chandelier endoilluminator (Twinlight illumination) tied to its sleeve was inserted into the eye through the incision made for cataract surgery and used for core vitrectomy. A fragmatome with another 27-gauge chandelier endoilluminator (Twinlight illumination) fibre was used to grasp and move the larger dislocated nuclear fragments into the anterior chamber where they were divided and removed. Results: All dislocated nuclear fragments were removed through the incision for cataract surgery, and a posterior chamber lens was implanted in each patient without major complications. Conclusions: The procedure can be used to remove dislocated lens nuclear fragments from the surface of the retina through the incision for cataract surgery. Neither a second surgery, which would require three ports, nor the body of instruments for vitreal surgery are needed with this procedure.


Mizuki N.,Yokohama City University | Meguro A.,Yokohama City University | Ota M.,Shinshu University | Ohno S.,Hokkaido University | And 18 more authors.
Nature Genetics | Year: 2010

Behçet's disease is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent ocular symptoms, oral and genital ulcers and skin lesions. We conducted a genome-wide association study in a Japanese cohort including 612 individuals with Behçet's disease and 740 unaffected individuals (controls). We identified two suggestive associations on chromosomes 1p31.3 (IL23R-IL12RB2, rs12119179, P = 2.7 × 10 -8) and 1q32.1 (IL10, rs1554286, P = 8.0 × 10-8). A meta-analysis of these two loci with results from additional Turkish and Korean cohorts showed genome-wide significant associations (rs1495965 in IL23R-IL12RB2, P = 1.9 × 10-11, odds ratio = 1.35; rs1800871 in IL10, P = 1.0 × 10-14, odds ratio = 1.45). © 2010 Nature America, Inc. All rights reserved.


Yoshida M.,Kyorin University | Meguro A.,Yokohama City University | Okada E.,Okada Eye Clinic | Nomura N.,Yokohama City University | Mizuki N.,Yokohama City University
Molecular Vision | Year: 2013

Purpose: The fibroblast growth factor 10 (FGF10) gene polymorphism rs339501 was previously reported to be associated with high myopia in a Chinese population. In the present study, we investigated whether FGF10 polymorphisms are associated with extreme myopia in a Japanese population as well. Methods: A total of 433 Japanese patients with extreme myopia (≤ -10.00 diopters) and 542 Japanese healthy controls (+1.50 to -1.50 diopters) were recruited. We genotyped seven tagging single-nucleotide polymorphisms (SNPs), including rs339501, in FGF10. We also performed an imputation analysis to evaluate the potential association of ungenotyped FGF10 SNPs, and 34 SNPs were imputed. Results: It was found that rs339501 and rs12517396 exhibited the strongest association with extreme myopia (p=3.9 × 10-4, corrected p [Pc]=0.0030). A significant association was also observed for rs10462070 (p=6.5 × 10-4, Pc=0.0059). These three SNPs were in strong linkage disequilibrium (D' ≥0.99, r2 ≥0.96). However, the frequency of the A allele of rs339501 was increased in cases compared to controls, which differs from the increased frequency of the G allele in cases in the previous Chinese population. Conclusions: Three FGF10 SNPs in complete linkage disequilibrium-rs339501, rs12517396, and rs10462070-were associated with extreme myopia in the Japanese population, and the risk allele of rs339501 differed from the previous Chinese population. Therefore, these three SNPs may not be an important risk factor for susceptibility to extreme myopia. Further studies are needed to elucidate the possible contribution of the FGF10 region in the development of extreme myopia. © 2013 Molecular Vision.


Miyata N.,Okada Eye Clinic
Japanese Journal of Clinical Ophthalmology | Year: 2016

Purpose: To report the outcome of extended tucking of Müller muscle with CO2 laser for blepharoptosis. Cases and Method: This retrospective study was made on 264 eyes of 132 cases who received surgery for blepharoptosis in the past 25 months. The series comprised 39 males and 93 females. The age ranged from 34 to 88 years, average 67 years. Blepharoptosis was due to ageing in 106 cases, to extended wear of contact lens in 23 cases, and to prior surgery in 3 cases. All the cases received simultaneous ptosis surgery in both eyes. Tucking of Müller muscle was performed by 10 mm or more. Results: Duration of surgery averaged 33.2 ± 5.8 minutes. In all the cases, it was possible to tuck the of Müller muscle in a clear view with minimum bleeding. After surgery, MRD improved in all cases by an average of 3.0 ± 1.1 mm. After surgery, corneal erosion developed in 7 eyes and bleeding in one eye. Conclusion: Extended tucking of Müller muscle with CO2 laser was safe, reliable and minimally invasive for blepharoptosis.


PubMed | Yokohama City University, Human Genome Research Institutes, Aoto Eye Clinic and Okada Eye Clinic
Type: | Journal: Clinical ophthalmology (Auckland, N.Z.) | Year: 2016

Many studies have investigated the relationship of the lumican gene (We recruited 1,585 Japanese patients with high myopia (spherical equivalent [SE] <-9.00 diopters [D]) and 1,011 Japanese healthy controls (SE -1.00 D). The rs3759223 variant was genotyped using the TaqMan assay, and the allelic and genotypic diversity among cases and controls was analyzed according to the SE level.In the allelic tests, the odds ratio (OR) for the T allele of rs3759223 tended to increase with the progression of SE, and the highest OR (1.56) was found in patients with SE <-15 D in both eyes. The OR of the T allele tended to increase with the progression of SE in the additive, dominant, and recessive inheritance models. However, we found no significant associations for any of the alleles or genotype models.These data support the possibility that the


PubMed | Yokohama City University, Human Genome Research Institutes, Aoto Eye Clinic, Okada Eye Clinic and Azabu University
Type: | Journal: Clinical ophthalmology (Auckland, N.Z.) | Year: 2015

Many studies have investigated the relationship of paired box 6 (PAX6) gene polymorphisms with the risk of high myopia, but the results across studies remain inconsistent and ambiguous. In the present work, we investigated whether PAX6 polymorphisms are associated with high myopia in a Japanese population.A total of 1,585 Japanese patients with high myopia (spherical equivalent [SE] <-9.00 diopters [D]) and 1,011 Japanese healthy controls (SE-1.00 D) were recruited. To compare genotype frequencies between cases and controls, we genotyped five single nucleotide polymorphisms in the PAX6 gene that are reportedly associated with high/extreme myopia: rs662702, rs3026393, rs644242, rs3026390, and rs667773.For rs662702, rs644242, and rs667773, odds ratios (ORs) for their risk alleles tended to increase with the progression of SE and axial length in the additive and recessive models. Of these, rs644242 had the highest OR (2.56) in patients with SE<-15 D in both eyes in the recessive model. On the other hand, for rs3026393 and rs3026390, the ORs for their risk alleles tended to increase according to the progression of SE and axial length in the dominant model. Of the two, rs3026393 had the highest OR (2.32) in patients with SE<-15 D in both eyes in the dominant model. However, no significant associations were identified in this study.We found that these PAX6 single nucleotide polymorphisms were associated with an increased risk of extreme myopia. Although the results, which are in agreement with some previous studies, did not reach statistical significance, PAX6 single nucleotide polymorphisms may be important risk factors for the development of extreme myopia. Further genetic studies with larger sample sizes and taking into account the degree of myopia are needed to clarify the contribution of PAX6 variants in myopia development.

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