l10llllllll3ll6lIliIlittliiIIIIIlII IttliiIIIIIlII I10.50−0.5naeM−1retsuCrenaeMtsuCnaeMretsuC5 retsuCretsuCnaeM1 retsuC10.50−0.5naeMretsuC retsuCretsuCnaeM retsuC10.50−0.510.50−0.5PB_GMMB_GMesocuG_GMdeMbuPtrA_GMdpL_GMyregndoCitazitiroiraugeRPTCPEDyawhaPyronoC1ABHCTCLDLGTCBWCLDHULGPBDMBPBSevoNPB_GMMB_GMtrA_GMdpL_GMyreesocuG_GMyawhaPitazitiroirPTCPEDdeMbuPnoCLDLaugeRgndoCyroCLDHULGC1ABHCTMBCBWGTPBSPBDevoNAUAUCardiovascular diseases cause more than 15% of the deaths in the Japanese 2 retsuC4 retsuC0246024C024BW_GM024024C0246BW_GMScoreHNF1APCSK9HPAPOERESTABCA1LDLRAPOBPLPP3SCARB1LPACELSR2PHACTR1PRKAR1ALPIN3ATP2B1DAB2IPPLCG2SORBS2FOXL1MTMR3HMGCRSCDBACH1TNFSF10COL6A3PLA2G12BFGF1CELKCNE1TSPAN14TRIM5SERPINH1OTX1ADSLSIRT3ITGB5RASGEF1BPLTPGIGYF2SMAD7CXCL12CTSHMAP1SMRASTNS1HTRA1DOCK5TAB2WT1BMPR2KLPRDM16KLF4HHIPL1CDC123COG5IL16NELFCDPALLDHDGFL1MERTKEHBP1L1CLOCKMARK3PROCREDNRAMITFCDKN2BZFPM2ARID4ALIPAFHL3TBXAS1PECAM1CDH13STAT6PID1GATA6ZEB2CCT6AACTR2YBX3ATP1B1TENT5ASDC1ZNF827FDX1IRX1IL6RLPLMYL2VEGFATRIB1DHX58ARHGEF26FLT1APOA5TMEM106BTMEM204DOK7ABHD2KCTD10PRKCEC1SSPECC1LAPOMRGS19PCCBJCADNAT2RAB23TLR51.510.50−0.5LMOD1VAMP8ABCG5COL4A2PDE5AMC4RTGFB2FGD6SEMA5AARHGAP15BMPR1BAXLGCGPTX3HSD17B12FARP1APEHCORO6NCALDSRRTBX20C11orf58SLC37A4GEMUTP18LYRM2AGTSWAP70LOXL1FN1MYH11FESSMAD3GUCY1A1ADAMTS3TCF21FGD5PDGFDPTGISDCLRE1BARHGAP42ARNTLHOXC4ARHGEF12F7BCAS3CTSKNGFSH3PXD2AGLP1RFADS2ITGB3PDE3ACFDP1EIF2B2ZC3HC1PHBMAD1L1FIGNFGF5TWIST1COPRSScore26population and represent more than 20% of the total medical expenses in Japan. Thus, it is important for our society to understand the pathogenesis of these disorders and to uncover new therapeutic targets for their treatment. To achieve these goals, we aim to discover the precise genetic mechanisms under-lying those diseases by utilizing leading-edge technologies, such as whole ge-nome sequencing and artificial intelligence. Additionally, we conduct research to push forward the clinical applications of genetic information in the field of cardiovascular medicine.Our current diseases of interest are coronary artery diseases (CAD), atrial fibrillation (AF), Kawasaki disease (KD), peripheral artery disease (PAD), chronic thromboembolic pulmonary hypertension (CTEPH), cancer therapy-related cardiac dysfunction (CTRCD), and heart failure (HF). We are currently seeking 1) to understand the genetic causes of CAD/AF and the genetic dif-ferences between Japanese and European populations; 2) to develop a novel genetic analysis method to solve the “P greater than N” scenario, where the sample size is small, but the number of variants to be analyzed is large; 3) to elucidate the mechanism of CTEPH/CTRCD using human omics data from patients in multiple hospitals; 4) to develop a more sophisticated genetic risk scoring system in the CAD and AF projects by artificial intelligence; and 5) to develop a comprehensive system to prioritize variants of unknown significance using massively parallel in vitro assays with artificial intelligence. In the process, we play a central role in the AMED national GRIFIN project for cardiovascular disease.We are conducting our research with not only a scientific mind, but also a clinical eye, because our ultimate goal is to provide improved diagnostic/man-agement/therapeutic approaches for patients suffering from these cardiovascu-lar diseases.Figure: Functional clustering and causal gene prioritization of 175 genome-wide significant loci for coronary artery diseaseWe performed trans-ancestry genome-wide analysis for coro-nary artery disease (CAD). One hundred seventy-five genome-wide significant loci were identified and clustered into six clusters by k-means clustering of Z-scores. Heatmaps show the normalized Z-score of each lead variant for CAD-polygenic risk score associated phenotypes. Red color indicates positive-, and blue color indicates negative- normalized Z-value. Z-values are aligned to CAD risk-increasing alleles. The bar charts on the right of the heatmaps indicate the cluster-mean effect on the phenotypes. Each locus was annotated with the prioritized genes based on the functional evidence that is shown on the upper side of each heatmap. The lowermost bar-charts indicate the total scores for annotated genes. MGI, Mouse Genome Informatics; BP, blood pressure; BMI, body mass index; WBC, white blood cell.Recent Major PublicationsKoyama S, Ito K, Terao C, Akiyama M, Horikoshi M, Momozawa Y, Matsunaga H, Ieki H, Ozaki K, Onouchi Y, Takahashi A, Nomura S, Morita H, Akazawa H, Kim C, Seo JS, Higasa K, Iwasaki M, Yam-aji T, Sawada N, Tsugane S, Koyama T, Ikezaki H, Takashima N, Tanaka K, Arisawa K, Kuriki K, Naito M, Wakai K, Suna S, Sakata Y, Sato H, Hori M, Sakata Y, Matsuda K, Murakami Y, Aburatani H, Kubo M, Matsuda F, Kamatani Y, Komuro I. Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease. Nat Genet 10, 5 (2020)Matsumoto T, Kodera S, Shinohara H, Ieki H, Yamaguchi T, Higashikuni Y, Kiyosue A, Ito K, Ando J, Takimoto E, Akazawa H, Morita H, Komuro I. Diagnosing Heart Failure from Chest X-Ray Images Using Deep Learning. Int Heart J 61, 781 (2020)Matsunaga H, Ito K, Akiyama M, Takahashi A, Koyama S, No-mura S, Ieki H, Ozaki K, Onouchi Y, Sakaue S, Suna S, Ogishima S, Yamamoto M, Hozawa A, Satoh M, Sasaki M, Yamaji T, Sawada N, Iwasaki M, Tsugane S, Tanaka K, Arisawa K, Ikezaki H, Takashi-ma N, Naito M, Wakai K, Tanaka H, Sakata Y, Morita H, Sakata Y, Matsuda K, Murakami Y, Akazawa H, Kubo M, Kamatani Y, Ko-muro I. Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease. Circ Genom Precis Med 13, e002670 (2020)Invited presentationsIto K. Cardiomyopathy Learning from Cancer and Cancer Therapy “Pathogenesis of Cardiomyopathy Revealed by Ge-nomic Analysis of CTRCD” The 6th Japan Society for the Study of Cardiomyopathy (Online) August 2020Ito K. The Japanese Foundation for the Advancement of Sci-ence Symposium on Preventing Cardiovascular Diseases in the Future “Risk stratification by polygenic score” The 84th Annual Meeting of the Japanese Circulation Society (Online) July-August 2020Ito K. Genomic Medicine Update “Genomic research in coronary artery disease” The 84th Annual Meeting of the Japanese Circu-lation Society (Online) July-August 2020Ito K. Precision Medicine Targeting Atrial Fibrillation and Car-diogenic Embolism “Genome-wide Association Study for Atrial fibrillation and Precision Medicine” The 84th Annual Meeting of the Japanese Circulation Society (Online) July-August 2020Laboratory for Cardiovascular Genomics and InformaticsTeam Leader: Kaoru Ito
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