Kyota Ashikawa
Shiga University of Medical Science
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Publication
Featured researches published by Kyota Ashikawa.
Cancer Science | 2011
Suyoun Chung; Hidewaki Nakagawa; Motohide Uemura; Lianhua Piao; Kyota Ashikawa; Naoya Hosono; Ryo Takata; Shusuke Akamatsu; Takahisa Kawaguchi; Takashi Morizono; Tatsuhiko Tsunoda; Yataro Daigo; Koichi Matsuda; Naoyuki Kamatani; Yusuke Nakamura; Michiaki Kubo
Recent genome‐wide association studies reported strong and reproducible associations of multiple genetic variants in a large “gene‐desert” region of chromosome 8q24 with susceptibility to prostate cancer (PC). However, the causative or functional variants of these 8q24 loci and their biological mechanisms associated with PC susceptibility remain unclear and should be investigated. Here, focusing on its most centromeric region (so‐called Region 2: Chr8: 128.14‐128.28 Mb) among the multiple PC loci on 8q24, we performed fine mapping and re‐sequencing of this critical region and identified SNPs (single nucleotide polymorphisms) between rs1456315 and rs7463708 (chr8: 128,173,119‐128,173,237 bp) to be most significantly associated with PC susceptibility (P = 2.00 × 10−24, OR = 1.74, 95% confidence interval = 1.56–1.93). Importantly, we show that this region was transcribed as a ∼13 kb intron‐less long non‐coding RNA (ncRNA), termed PRNCR1 (prostate cancer non‐coding RNA 1), and PRNCR1 expression was upregulated in some of the PC cells as well as precursor lesion prostatic intraepithelial neoplasia. Knockdown of PRNCR1 by siRNA attenuated the viability of PC cells and the transactivation activity of androgen receptor, which indicates that PRNCR1 could be involved in prostate carcinogenesis possibly through androgen receptor activity. These findings could provide a new insight in understanding the pathogenesis of genetic factors for PC susceptibility and prostate carcinogenesis. (Cancer Sci 2011; 102: 245–252)
Nature Genetics | 2012
Kouya Shiraishi; Hideo Kunitoh; Yataro Daigo; Atsushi Takahashi; Koichi Goto; Hiromi Sakamoto; Sumiko Ohnami; Yoko Shimada; Kyota Ashikawa; Akira Saito; Shun-ichi Watanabe; Koji Tsuta; Naoyuki Kamatani; Teruhiko Yoshida; Yusuke Nakamura; Jun Yokota; Michiaki Kubo; Takashi Kohno
Lung adenocarcinoma is the most common histological type of lung cancer, and its incidence is increasing worldwide. To identify genetic factors influencing risk of lung adenocarcinoma, we conducted a genome-wide association study and two validation studies in the Japanese population comprising a total of 6,029 individuals with lung adenocarcinoma (cases) and 13,535 controls. We confirmed two previously reported risk loci, 5p15.33 (rs2853677, Pcombined = 2.8 × 10−40, odds ratio (OR) = 1.41) and 3q28 (rs10937405, Pcombined = 6.9 × 10−17, OR = 1.25), and identified two new susceptibility loci, 17q24.3 (rs7216064, Pcombined = 7.4 × 10−11, OR = 1.20) and 6p21.3 (rs3817963, Pcombined = 2.7 × 10−10, OR = 1.18). These data provide further evidence supporting a role for genetic susceptibility in the development of lung adenocarcinoma.
Nature Genetics | 2011
Satoshi Arakawa; Atsushi Takahashi; Kyota Ashikawa; Naoya Hosono; Tomomi Aoi; Miho Yasuda; Yuji Oshima; Shigeo Yoshida; Hiroshi Enaida; Takashi Tsuchihashi; Keisuke Mori; Shigeru Honda; Akira Negi; Akira Arakawa; Kazuaki Kadonosono; Yutaka Kiyohara; Naoyuki Kamatani; Yusuke Nakamura; Tatsuro Ishibashi; Michiaki Kubo
Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the world, is a complex disease caused by multiple environmental and genetic risk factors. To identify genetic factors that modify the risk of exudative AMD in the Japanese population, we conducted a genome-wide association study and a replication study using a total of 1,536 individuals with exudative AMD and 18,894 controls. In addition to CFH (rs800292, P = 4.23 × 10−15) and ARMS2 (rs3750847, P = 8.67 × 10−29) loci, we identified two new susceptibility loci for exudative AMD: TNFRSF10A-LOC389641 on chromosome 8p21 (rs13278062, combined P = 1.03 × 10−12, odds ratio = 0.73) and REST-C4orf14-POLR2B-IGFBP7 on chromosome 4q12 (rs1713985, combined P = 2.34 × 10−8, odds ratio = 1.30). Fine mapping revealed that rs13278062, which is known to alter TNFRSF10A transcriptional activity, had the most significant association in 8p21 region. Our results provide new insights into the pathophysiology of exudative AMD.
Nature Genetics | 2014
Qiuyin Cai; Ben Zhang; Hyuna Sung; Siew-Kee Low; Sun-Seog Kweon; Wei Lu; Jiajun Shi; Jirong Long; Wanqing Wen; Ji-Yeob Choi; Dong-Young Noh; Chen-Yang Shen; Keitaro Matsuo; Soo-Hwang Teo; Mi Kyung Kim; Us Khoo; Motoki Iwasaki; Mikael Hartman; Atsushi Takahashi; Kyota Ashikawa; Koichi Matsuda; Min-Ho Shin; Min Ho Park; Ying Zheng; Yong-Bing Xiang; Bu-Tian Ji; Sue K. Park; Pei-Ei Wu; Chia-Ni Hsiung; Hidemi Ito
In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P = 8.82 × 10−9), rs10474352 at 5q14.3 (near the ARRDC3 gene; P = 1.67 × 10−9) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P = 4.25 × 10−8). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P = 0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.
Gastroenterology | 2011
Yukinori Okada; Keiko Yamazaki; Junji Umeno; Atsushi Takahashi; Natsuhiko Kumasaka; Kyota Ashikawa; Tomomi Aoi; Masakazu Takazoe; Toshiyuki Matsui; Atsushi Hirano; Takayuki Matsumoto; Naoyuki Kamatani; Yusuke Nakamura; Kazuhiko Yamamoto; Michiaki Kubo
BACKGROUND & AIMS There are many genetic factors that are associated with both ulcerative colitis (UC) and Crohns disease (CD). However, genetic factors that have distinct effects on UC and CD have not been examined. METHODS We performed a comparative genome-wide association study (GWAS) and a replication study using data from 748 patients with UC and 979 with CD, selected from a Japanese population. We conducted high-resolution (4-digit) genotyping of human leukocyte antigen (HLA) alleles in patients with UC and CD and additional 905 healthy individuals (controls). We performed haplotype-based analysis using data from the GWAS and HLA alleles to associate them with UC or CD. RESULTS The comparative GWAS and the replication study identified significant associations in the major histocompatibility complex region at 6p21 with UC and CD (rs9271366, P = 1.6 × 10⁻⁷⁰; odds ratio [OR] = 4.44). Haplotype-based analysis in the major histocompatibility complex region showed that HLA-Cw*1202-B*5201-DRB1*1502 haplotype was significantly associated with increased risk of UC compared with CD (P = 1.1 × 10⁻³³; OR = 6.58), accounting for most of the associations observed in the GWAS. Compared with the controls, this HLA haplotype significantly increases susceptibility to UC (P = 4.0 × 10⁻²¹; OR = 2.65), but reduces risk for CD (P = 1.1 × 10⁻⁷; OR = 0.40). Distinct effects of this HLA haplotype on UC and CD were independent of other HLA alleles and haplotypes (P = 2.0 × 10⁻¹⁹ and P = 7.2 × 10⁻⁵, respectively). CONCLUSIONS The HLA-Cw*1202-B*5201-DRB1*1502 haplotype increases susceptibility to UC but reduces risk for CD, based on a GWAS of a Japanese population.
Inflammatory Bowel Diseases | 2013
Atsushi Hirano; Keiko Yamazaki; Junji Umeno; Kyota Ashikawa; Masayuki Aoki; Takayuki Matsumoto; Shotaro Nakamura; Toshiharu Ninomiya; Toshiyuki Matsui; Fumihito Hirai; Takaaki Kawaguchi; Masakazu Takazoe; Hiroki Tanaka; Satoshi Motoya; Yutaka Kiyohara; Takanari Kitazono; Yusuke Nakamura; Naoyuki Kamatani; Michiaki Kubo
Background:A large-scale meta-analysis of a series of European genome-wide association studies revealed 71 susceptibility loci for Crohns disease (CD). However, it is not clear whether these susceptibility loci are also shared with Japanese populations. Methods:We genotyped 71 single-nucleotide polymorphisms (SNPs) comprising 1311 CD cases and 6585 controls of Japanese descent, and their associations with CD were evaluated using the Cochran–Armitage trend test. In addition, genotype–phenotype analyses were conducted on the SNPs showing associations with Japanese CD based on the Montreal classification. Results:Twenty-seven SNPs showed at least nominal association (P < 0.05) and 11 of them remained significant even after Bonferroni correction (P < 0.0007). Despite high statistical power, we could not find any association in 17 loci. Moreover, SNPs in 9 loci were rare or absent in the Japanese population. Genetic variations involved in the innate immune system (NOD2, ATG16L1, and IRGM) showed no association with CD susceptibility in the Japanese population. Genotype–phenotype analyses showed that rs3810936, a marker of TNFSF15, correlated with severe CD phenotypes. Conclusions:Our study suggests that there is a differential genetic background of CD susceptibility between Japanese and European populations.
Stroke | 2009
Tomonaga Matsushita; Michiaki Kubo; Koji Yonemoto; Toshiharu Ninomiya; Kyota Ashikawa; Bailing Liang; Jun Hata; Yasufumi Doi; Takanari Kitazono; Setsuro Ibayashi; Mitsuo Iida; Yutaka Kiyohara; Yusuke Nakamura
Background and Purpose— After the first genomewide association study of ischemic stroke identified PDE4D as a susceptible gene, many replication studies have been conducted. However, the validity of the association has remained controversial because of the heterogeneity of both genetic markers and phenotypes. Methods— We investigated the association between variations of PDE4D and ischemic stroke by 3 methods: single-marker, haplotype, and tag-single nucleotide polymorphism (SNP) analyses. In the single-marker analysis, we evaluated the association using 2 large case–control samples (1112 cases and 1112 control subjects in a sample obtained from Kyushu, Japan, and 1711 cases and 1786 control subjects in BioBank Japan) and a prospective cohort with 14 years of follow-up. These samples were analyzed both separately and pooled. Haplotype and tag-SNP analyses were performed using the 2 case–control samples together. Results— In single-marker association tests, we found no significant association in the same direction among the 6 SNP reported in the initial study and ischemic stroke subtypes. Haplotype analysis revealed no significant association between the region around the 5′-end of the gene and combined atherothrombotic and cardioembolic infarction. Rs7730070, a SNP located around the 3′-end of PDE4D, showed the lowest nominal probability value by tag-SNP analysis but was not significant after adjustment for multiple testing (adjusted probability value =0.36). Conclusions— These results suggest that variations in PDE4D are not associated with ischemic stroke risk in the Japanese population.
Scientific Reports | 2015
Daichi Shigemizu; Yukihide Momozawa; Testuo Abe; Takashi Morizono; Keith A. Boroevich; Sadaaki Takata; Kyota Ashikawa; Michiaki Kubo; Tatsuhiko Tsunoda
Whole exome sequencing (WXS) is widely used to identify causative genetic mutations of diseases. However, not only have several commercial human exome capture platforms been developed, but substantial updates have been released in the past few years. We report a performance comparison for the latest release of four commercial platforms, Roche/NimbleGen’s SeqCap EZ Human Exome Library v3.0, Illumina’s Nextera Rapid Capture Exome (v1.2), Agilent’s SureSelect XT Human All Exon v5 and Agilent’s SureSelect QXT, using the same DNA samples. Agilent XT showed the highest target enrichment efficiency and the best SNV and short indel detection sensitivity in coding regions with the least amount of sequencing. Agilent QXT had slightly inferior target enrichment than Agilent XT. Illumina, with additional sequencing, detected SNVs and short indels at the same quality as Agilent XT, and showed the best performance in coverage of medically interesting mutations. NimbleGen detected more SNVs and indels in untranslated regions than the others. We also found that the platforms, which enzymatically fragment the genomic DNA (gDNA), detected more homozygous SNVs than those using sonicated gDNA. We believe that our analysis will help investigators when selecting a suitable exome capture platform for their particular research.
Psychiatric Genetics | 2012
Tomoyuki Ohara; Toshiharu Ninomiya; Yoichiro Hirakawa; Kyota Ashikawa; Akira Monji; Yutaka Kiyohara; Shigenobu Kanba; Michiaki Kubo
APOE is an established susceptibility gene for late-onset Alzheimer’s disease (LOAD). Recent genome-wide association studies have identified many additional susceptibility genes for LOAD in populations of European descent. However, there is little information on whether or not genetic variants in these genes are associated with other ethnicities. To investigate the association of seven genes identified by genome-wide association studies, we carried out a case–control study using 825 LOAD cases and 2934 controls in the Japanese population. For the APOE gene, APOE-&egr;4 carriers had a 4.54-fold higher risk than APOE-&egr;4 noncarriers after adjusting for age and sex (P=4.6×10–27). For other genes, the single-nucleotide polymorphism in the PICALM gene was significantly associated with LOAD (P=0.02, odds ratio=1.23). There was no significant interaction between PICALM and APOE-&egr;4 carrier status (P for interaction=0.68). Our data indicate that PICALM is also a susceptibility gene for LOAD in the Japanese population.
PLOS ONE | 2013
Siew-Kee Low; Atsushi Takahashi; Kyota Ashikawa; Johji Inazawa; Yoshio Miki; Michiaki Kubo; Yusuke Nakamura; Toyomasa Katagiri
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.