FINAL REPORT For Japan-Korea Joint Research Project AREA

Transcription

1 (Form4-2) FINAL REPORT For Japan-Korea Joint Research Project AREA 1. Mathematics & Physics 2. Chemistry & Material Science 3. Biology 4. Informatics & Mechatronics 5. Geo-Science & Space Science 6. Medical Science 7. Humanities & Social Sciences 1. Research Title: Comprehensive analysis of pathogenesis and genome diversities involved in the coronary atherosclerosis in Korea and Japan 2. Term of Research: From July 1, 2010 To March 31, Total Budget a. Financial Support by JSPS: Total amount: 2,400 thousand yen 1 st Year 1,200 thousand yen 2 nd Year 1,200 thousand yen 3 rd Year 0 thousand yen b. Other Financial Support : Total amount: 5,000 thousand yen 4. Project Organization a. Japanese Principal Researcher Name Institution / Department Position Akinori Kimura Dentadical University/ b. Korean Principal Researcher Name Institution / Department Position Jeong Euy Park Sung Kyun Kwan University School of Medicine/ 1

2 c. List of Japanese-side Participants (Except for Principal Researcher) Name Institution/Department Position Masaaki Muramatsu / Masayuki Yoshida / Bioethics Research Center Toshiaki Nakajima / Associate Takuro Arimura / Assistant Taeko Naruse / Research Associate Taisuke Ishikawa / PhD student Jiambo An / PhD student d. List of Korean-side Participants (Except for Principal Researcher) Name Institution/Department Position Seung Hyuk Cho Sungkyunkwan University School of Associate Medicine/ Young Bien Song Sungkyunkwan University School of Assistant Medicine/ Sung-A Chang Sungkyunkwan University School of Assistant Medicine/ Dukhwan Kim Sungkyunkwan University School of Associate Medicine/ Bok-Soo Lee Sungkyunkwan University School of Research Medicine/ Hyo Jung Koo Sungkyunkwan University School of Research Assistant Medicine/ So Ra Jun Sungkyunkwan University School of Research Assistant Jong-Yong Lee Medicine/ Korean NIH/ Center for Genome Science Chief Researcher 2

3 5. Number of Exchanges during the Final Fiscal Year* a. from Japan to Korea *Japanese fiscal year begins April 1. Name Home Institution Duration Host Institution Akinori Kimura Masaaki Muramatsu Masayuki Yoshida Takuro Arimura Taisuke Ishikawa Total: 5 persons Total: 15 man-days Numbers of Exchanges during the past fiscal years FY2009: Total persons FY2010: Total 5 persons b. from Korea to Japan Name Home Institution Duration Host Institution Total: 0 persons Total: 0 man-days Numbers of Exchanges during the past fiscal years FY2009: Total persons FY2010: Total 0 persons 3

4 6. Objective of Research Cardiovascular disease is one of the most frequent causes of deaths in well developed countries. Among the cardiovascular diseases coronary artery disease (CAD) based on the coronary atherosclerosis is the most important disease to be urgently overcome since it is the leading causes of mortality and morbidity in the modern countries. Classical genetic studies demonstrated that genetic variance contributed in 40-60% of the development of CAD and recent approaches in genome medicine, both candidate gene approaches and genome-wide association studies have revealed several disease-associated loci or more specifically disease-associated SNPs for CAD. However, not all of the reported association with specific loci or SNPs could be replicated in other studies. This is partly due to that the contribution of each genetic factor is not large enough to be replicated or each association is restricted to specific ethnic group. Therefore, the identification of genetic factors with relatively strong contribution to the disease in Asian populations is crucial to reveal the pathogenesis, to assess the risk factors, and to develop preventive and therapeutic strategy for CAD. The Japanese principal investigator and Korean principal investigator have started the collaboration to identify the genetic factors for CAD in Since then, candidate gene analysis and more recently genome-wide association studies were performed on the collaboration basis as well as in the independent studies. Our collaboration studies have revealed that among a total of twelve disease-associated loci reported from large association studies in European populations and Japanese populations, only two loci, 9p21 and BRAP, could be replicated in both Japanese and Korean. It should be noted that synergistic contribution of 9p21 and BRAP was demonstrated by our study. On the other hand, our genome-wide association study has revealed that MKL1 is a novel disease gene for CAD in both Japanese and Korean. This association was replicated by another Japanese cohort and then could be listed-up as the third CAD loci that showed reproducible association. In addition, we have identified several other CAD-associated loci for Japanese or Korean, which should be replicated in Korean or Japanese, respectively. The goal of this research project is to decipher the human genome diversities involved in the development of coronary atherosclerosis in the presence or absence of classical risk factors and to develop a method which can be applied to personalized medicine and a novel strategy for preventing the disease. 4

5 7. Methodology The collaborative research was performed by the methodology indicated below. 1. Genomic DNAs extracted from peripheral blood of patients with coronary artery disease (CAD) and control individuals selected at random from the general population were collected in both Japan and Korea. The DNA samples were subjected to the SNP analyses of candidate genes/loci previously deciphered by whole-genome association studies independently performed by the Japanese and Korean investigators. Previous studies revealed that 9p21, BRAP, and MKL1 were commonly associated with CAD in both Japanese and Korean. In this project, SNPs other than these genes/loci were investigated. In addition, the association between 9p21 and CAD was further investigated by the world-wide meta-analysis study. 2. Pathological and biochemical studies of the atherosclerotic regions from CAD patients and a well-known model for the atherosclerosis, ApoE knock-out (ApoE-KO) mice. Specimen from the atherosclerotic region in human patients and ApoE-KO mice were examined for the expression of BRAP and MKL1. 3. Functional role of MKL1 in atherosclerosis was examined at the cellular level. Because we found in the collaboration study that MKL1 was highly expressed in macrophages, we investigated the role of MKL1 in differentiation of macrophages by using THP-1 cells. 4. Creating a novel animal model for atherosclerosis, based on the findings obtained in the previous collaboration project. We previously revealed that a promoter SNP of MKL1, which showed higher transcriptional activity, was significantly associated with coronary atherosclerosis in both Japan and Korea. Therefore, MKL1 transgenic (MKL1-TG) mice overexpressing the MKL1 gene were created. 5