Browsing by Author "Nakamura, M."
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma(Oxford University Press, 2018) Shiga, Y.; Akiyama, M.; Nishiguchi, K.M.; Sato, K.; Shimozawa, N.; Takahashi, A.; Momozawa, Y.; Hirata, M.; Matsuda, K.; Yamaji, T.; Iwasaki, M.; Tsugane, S.; Oze, I.; Mikami, H.; Naito, M.; Wakai, K.; Yoshikawa, M.; Miyake, M.; Yamashiro, K.; Kashiwagi, K.; Iwata, T.; Mabuchi, F.; Takamoto, M.; Ozaki, M.; Kawase, K.; Aihara, M.; Aihara, M.; Yamamoto, T.; Kiuchi, Y.; Nakamura, M.; Ikeda, Y.; Sonoda, K.-H.; Ishibashi, T.; Nitta, K.; Iwase, A.; Shirato, S.; Oka, Y.; Satoh, M.; Sasaki, M.; Fuse, N.; Suzuki, Y.; Cheng, C. -Y.; Khor, C.C.; Baskaran, M.; Perera, S.; Aung, T.; Vithana, E. N.; Cooke Bailey, J.N; Kang, J.H.; Pasquale, L.R.; Haines, J.L.; Wiggs, J.L.; Burdon, K.P.; Gharahkhani, P.; Hewitt, A.W.; Mackey, D.A.; MacGregor, S.; Craig, J.E.; Rand Allingham, R.; Hauser, M.; Ashaye, A.; Budenz, D.L.; Akafo, S.; Williams, S.E.I.; Kamatani, Y.; Nakazawa, T.; Kubo, M.Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 diseaseassociated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P<5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians. © The Author(s) 2018. Published by Oxford University Press. All rights reserved.Item Large-scale survey for novel genotypes of Plasmodium falciparum chloroquine-resistance gene pfcrt(2012-03-28) Takahashi, N.; Tanabe, K.; Tsukahara, T.; Dzodzomenyo, M.; Dysoley, L.; Khamlome, B.; Sattabongkot, J.; Nakamura, M.; Sakurai, M.; Kobayashi, J.; Kaneko, A.; Endo, H.; Hombhanje, F.; Tsuboi, T.; Mita, T.Abstract Background In Plasmodium falciparum, resistance to chloroquine (CQ) is conferred by a K to T mutation at amino acid position 76 (K76T) in the P. falciparum CQ transporter (PfCRT). To date, at least 15 pfcrt genotypes, which are represented by combinations of five amino acids at positions 72-76, have been described in field isolates from various endemic regions. To identify novel mutant pfcrt genotypes and to reveal the genetic relatedness of pfcrt genotypes, a large-scale survey over a wide geographic area was performed. Methods Sequences for exon 2 in pfcrt, including known polymorphic sites at amino acid positions 72, 74, 75 and 76, were obtained from 256 P. falciparum isolates collected from eight endemic countries in Asia (Bangladesh, Cambodia, Lao P.D.R., the Philippines and Thailand), Melanesia (Papua New Guinea and Vanuatu) and Africa (Ghana). A haplotype network was constructed based on six microsatellite markers located -29 kb to 24 kb from pfcrt in order to examine the genetic relatedness among mutant pfcrt genotypes. Results In addition to wild type (CVMNK at positions 72-76), four mutant pfcrt were identified; CVIET, CVIDT, SVMNT and CVMNT (mutated amino acids underlined). Haplotype network revealed that there were only three mutant pfcrt lineages, originating in Indochina, Philippines and Melanesia. Importantly, the Indochina lineage contained two mutant pfcrt genotypes, CVIET (n = 95) and CVIDT (n = 14), indicating that CVIDT shares a common origin with CVIET. Similarly, one major haplotype in the Melanesian lineage contained two pfcrt genotypes; SVMNT (n = 71) and CVMNT (n = 3). In Africa, all mutant pfcrt genotypes were the CVIET of the Indochina lineage, probably resulting from the intercontinental migration of CQ resistance from Southeast Asia. Conclusions The number of CQ-mutant lineages observed in this study was identical to that found in previous studies. This supports the hypothesis that the emergence of novel CQ resistance is rare. However, in the mutant pfcrt genotypes, amino acid changes at positions 72, 74 and 75 appear to have recently been generated at least several times, producing distinct pfcrt mutant genotypes. The occurrence of new mutations flanking K76T may yield stronger resistance to CQ and/or a higher fitness than the original pfcrt mutant.Item Large-scale survey for novel genotypes of plasmodium falciparum chloroquine-resistance gene pfcrt.(2012-03-28) Takahashi, N.; Tanabe, K.; Tsukahara, T.; Dzodzomenyo, M.; Dosoley, L.; Khamlome, B.; Sattabongkot, S.; Nakamura, M.; Sakurai, M.; Kobayashi, J.; Kaneko, A.; Endo, H.; Hombhanje, F.; Tsuboi, T.; Mita, T.Background. In Plasmodium falciparum, resistance to chloroquine (CQ) is conferred by a K to T mutation at amino acid position 76 (K76T) in the P. falciparum CQ transporter (PfCRT). To date, at least 15 pfcrt genotypes, which are represented by combinations of five amino acids at positions 72-76, have been described in field isolates from various endemic regions. To identify novel mutant pfcrt genotypes and to reveal the genetic relatedness of pfcrt genotypes, a large-scale survey over a wide geographic area was performed. Methods. Sequences for exon 2 in pfcrt, including known polymorphic sites at amino acid positions 72, 74, 75 and 76, were obtained from 256 P. falciparum isolates collected from eight endemic countries in Asia (Bangladesh, Cambodia, Lao P.D.R., the Philippines and Thailand), Melanesia (Papua New Guinea and Vanuatu) and Africa (Ghana). A haplotype network was constructed based on six microsatellite markers located -29 kb to 24 kb from pfcrt in order to examine the genetic relatedness among mutant pfcrt genotypes. Results. In addition to wild type (CVMNK at positions 72-76), four mutant pfcrt were identified; CVIET, CVIDT, SVMNT and CVMNT (mutated amino acids underlined). Haplotype network revealed that there were only three mutant pfcrt lineages, originating in Indochina, Philippines and Melanesia. Importantly, the Indochina lineage contained two mutant pfcrt genotypes, CVIET (n = 95) and CVIDT (n = 14), indicating that CVIDT shares a common origin with CVIET. Similarly, one major haplotype in the Melanesian lineage contained two pfcrt genotypes; SVMNT (n = 71) and CVMNT (n = 3). In Africa, all mutant pfcrt genotypes were the CVIET of the Indochina lineage, probably resulting from the intercontinental migration of CQ resistance from Southeast Asia. Conclusions. The number of CQ-mutant lineages observed in this study was identical to that found in previous studies. This supports the hypothesis that the emergence of novel CQ resistance is rare. However, in the mutant pfcrt genotypes, amino acid changes at positions 72, 74 and 75 appear to have recently been generated at least several times, producing distinct pfcrt mutant genotypes. The occurrence of new mutations flanking K76T may yield stronger resistance to CQ and/or a higher fitness than the original pfcrt mutant. © 2012 Takahashi et al; licensee BioMed Central Ltd.