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Masakazu Nakano,
Yoko Ikeda,
Yuichi Tokuda, Masahiro Fuwa,
Natsue Omi,
Morio Ueno,
Kojiro Imai,
Hiroko Adachi,
Masaaki Kageyama,
Kazuhiko Mori,
Shigeru Kinoshita,
Kei Tashiro
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ABSTRACT: To date, only a small portion of the genetic variation for primary open-angle glaucoma (POAG), the major type of glaucoma, has been elucidated.
We examined our two data sets of the genome-wide association studies (GWAS) derived from a total of 2,219 Japanese subjects. First, we performed a GWAS by analyzing 653,519 autosomal common single-nucleotide polymorphisms (SNPs) in 833 POAG patients and 686 controls. As a result, five variants that passed the Bonferroni correction were identified in CDKN2B-AS1 on chromosome 9p21.3, which was already reported to be a significant locus in the Caucasian population. Moreover, we combined the data set with our previous GWAS data set derived from 411 POAG patients and 289 controls by the Mantel-Haenszel test, and all of the combined variants showed stronger association with POAG (P<5.8 × 10(-10)). We then subdivided the case groups into two subtypes based on the value of intraocular pressure (IOP)--POAG with high IOP (high pressure glaucoma, HPG) and that with normal IOP (normal pressure glaucoma, NPG)--and performed the GWAS using the two data sets, as the prevalence of NPG in Japanese is much higher than in Caucasians. The results suggested that the variants from the same CDKN2B-AS1 locus were likely to be significant for NPG patients.
In this study, we successfully identified POAG-associated variants in the CDKN2B-AS1 locus using a Japanese population, i.e., variants originally reported as being associated with the Caucasian population. Although we cannot rule out that the significance could be due to the differences in sample size between HPG and NPG, the variants could be associated specifically with the vulnerability of the optic nerve to IOP, which is useful for investigating the etiology of glaucoma.
PLoS ONE 01/2012; 7(3):e33389. · 4.09 Impact Factor
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The British journal of ophthalmology 07/2011; 95(7):1030-1. · 2.92 Impact Factor
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Mayumi Ueta,
Chie Sotozono,
Masakazu Nakano,
Takazumi Taniguchi,
Tomohito Yagi,
Yuichi Tokuda, Masahiro Fuwa,
Tsutomu Inatomi,
Norihiko Yokoi,
Kei Tashiro,
Shigeru Kinoshita
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ABSTRACT: Stevens-Johnson syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucosa. They often affect the ocular surface and can result in permanent visual dysfunction.
We sought to discover genetic markers for SJS/TEN susceptibility.
We performed a genome-wide association study with 60 patients and 300 control subjects. We applied stringent filter and visual assessments for selecting single nucleotide polymorphisms (SNPs) and a high false discovery rate threshold. We fine-mapped the region where a candidate SNP was found and confirmed the results by means of sequencing. We evaluated the function of agonist-activated prostaglandin E receptor 3 (EP3), the gene for which contained several SNPs, in regulating cytokine production in human conjunctival epithelial (CE) cells. The expression levels of EP3 in the CE cells from patients and control subjects were also compared.
We identified 3 SNPs that passed the false discovery rate threshold. One (rs17131450) was close to the EP3 gene. Therefore we analyzed the EP3 region in detail and identified 5 other SNPs. We confirmed the association between SJS/TEN and all 6 SNPs. Activated EP3 was expressed in control CE cells, and it suppressed polyI:C-stimulated cytokine production, suggesting that EP3 might help prevent ocular surface inflammation. Concordantly, the EP3 levels were much lower in the CE cells of the patients than in those of the control subjects.
We demonstrated, using both genetic and functional analyses, that EP3 could be a key player in the pathogenesis of SJS/TEN accompanied by ocular complications.
The Journal of allergy and clinical immunology 10/2010; 126(6):1218-25.e10. · 9.17 Impact Factor
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Masakazu Nakano,
Yoko Ikeda,
Takazumi Taniguchi,
Tomohito Yagi, Masahiro Fuwa,
Natsue Omi,
Yuichi Tokuda,
Masami Tanaka,
Kengo Yoshii,
Masaaki Kageyama,
Shigeta Naruse,
Akira Matsuda,
Kazuhiko Mori,
Shigeru Kinoshita,
Kei Tashiro
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ABSTRACT: Primary open-angle glaucoma (POAG) is the major type of glaucoma. To discover genetic markers associated with POAG, we examined a total of 1,575 Japanese subjects in a genome-wide association study (stage 1) and a subsequent study (stage 2). Both studies were carried out at a single institution. In the stage 1 association study, we compared SNPs between 418 POAG patients and 300 control subjects. First, low-quality data were eliminated by a stringent filter, and 331,838 autosomal SNPs were selected for analysis. Poorly clustered SNPs were eliminated by a visual assessment, leaving 255 that showed a significant deviation (P < 0.001) in the allele frequency comparison. In the stage 2 analysis, we tested these 255 SNPs for association in DNA samples from a separate group of 409 POAG and 448 control subjects. High-quality genotype data were selected and used to calculate the combined P values of stages 1 and 2 by the Mantel-Haenszel test. These analyses yielded 6 SNPs with P < 0.0001. All 6 SNPs showed a significant association (P < 0.05) in stage 2, demonstrating a confirmed association with POAG. Although we could not link the SNPs to the annotated gene(s), it turned out that we have identified 3 genetic loci probably associated with POAG. These findings would provide the foundation for future studies to build on, such as for the metaanalysis, to reveal the molecular mechanism of the POAG pathogenesis.
Proceedings of the National Academy of Sciences 08/2009; 106(31):12838-42. · 9.68 Impact Factor
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ABSTRACT: The role of the glucocorticoid receptor (GR) and pregnane X receptor (PXR) in the regulation of female-predominant expression of mouse CYP3A44 by glucocorticoid hormones was evaluated using a primary culture of female mouse hepatocytes, as the expression was suppressed in adrenalectomized female mice, restored by dexamethasone (DEX) treatment and was not detected in male mouse livers. Glucocorticoid hormones, such as DEX, hydrocortisone, and corticosterone, 11beta-[4-dimethylamino] phenyl-17beta-hydroxy-17-[1-propynyl]estra-4,9-diene-3-one (RU486), antagonists for GR and an agonist for PXR, and rifampicin, an agonist for PXR, were chosen to investigate the relationship of GR/PXR activation and Cyp3a44 gene expression. Glucocorticoid-inducible expression of CYP3A44 was not suppressed but rather was increased by RU486. Treatment of GR expression plasmid-transfected hepatocytes with DEX concentration dependently enhanced the expression of PXR as well as CYP3A44 mRNAs. A synergistic effect of DEX at submicromolar concentrations and rifampicin is observed. Furthermore, transfection of PXR and retinoid X receptor-alpha (RXRalpha) also showed prominent induction of CYP3A44 mRNA by DEX. These results suggest that DEX plays a dual role in CYP3A44 expression: first, direct activation of the Cyp3a44 gene by the PXR-RXRalpha complex, and, second, indirect activation of the Cyp3a44 gene through the induction of PXR gene expression by the GR pathway.
Drug Metabolism and Disposition 11/2007; 35(10):1880-5. · 3.73 Impact Factor
