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1、心筋梗塞関連遺伝子研究Laboratory for Cardiovascular Diseases田中敏博 TANAKA, Toshihiro心筋梗塞含循環器系疾患，一般診療医療費 20%以上占，危険因子解 明発症予防重要。，心筋梗塞関，環境要因面 危険因子程度明一方，日本人集団遺伝的要因 顧。同様生活習慣罹患者者 ，遺伝的要因明存在。群発症前診断生活習慣改善促 ，同定関連分子作用薬剤開発，心筋梗塞発症予防大 効果期待。具体的（1）SNP 心筋梗塞症関連検索， （2）心 筋梗塞関連遺伝子同定。， （3）SNP 当該遺伝子及転写，翻訳量 的変化，機能変化。以上解析，医療薬剤開発端緒 。1.検体採
2、取（田中，尾崎） 研究倫理委員会承認済同意書 取得後，患者採血 。現時点，大阪大学大学院医学系研究科病態情報 内科学大阪急性冠動脈症候群研究会（OACIS） ， 東京大学循環器内科協力得，3,000 超 得。2.SNP （田中，尾崎） 我用手法，心筋梗塞患者一般集団 SNP 頻度違（SNP ） ， 患者-対照研究。対象全領域 約 10 万 SNP ，東京大 学医科学研究所科学技術振興事業団共同研究 SNP （http:/snp.ims.u-tokyo.ac.jp）用 。，遺伝子領域内 SNP 19 万箇所同定，遺伝子領域内特化 SNP 用検索行，非常 効率研究進。 ，同遺伝子多型研究支援 共同
3、確立，大量高速 SNP 法用，約 70,000 SNP 終了，有意差 候補 SNP 複数同定。炎症関連分子 LTA 遺伝子内非常大有意差示 SNP 同定。1 領域存在 ，SNP 遺伝子発現量変化明 。，酸変化伴 SNP 同様非 常大有意差示。 E-selectin VCAM-1 発現誘導影響及明 ，LTA 心筋梗塞関連遺伝子強示唆 。 LTA 役割探，酵母 Two-hybrid 法 用 LTA 結合分子 2 単離。 遺伝子上 SNP 解析行 ，大有意差認，遺伝子心筋梗塞発症関連明。有意差認 SNP 2 遺伝子発現量制御， 2 発現量 LTA 細胞外分泌量制御 明。，LTA 心筋梗塞重要役割果考
4、 。Cardiovascular diseases including acute myocardial in- farction are the most common cause of death in Japan and their medical cost represents as much as 20% of total med-ical expense. Therefore, it is nationally beneficial to find risk factors for the prevention of myocardial infarction. To date,
5、some environmental risk factors such as smoking or high-fat diet have been revealed, but very little is knownof their genetic ones in Japanese population. Identification of genes related to myocardial infarction will surely enable us to identify high-risk group before onset. Through med- ical advice
6、 to improve their life style, as well as the drug development against molecules related to the disease, largebeneficial effect in the prevention of myocardial infarction will be expected. By means of a large-scale, case-control association study using gene-based single nucleotide polymorphism(SNP) m
7、arkers, we identified two SNPs in LTA, whichshowed statistically significant association with myocardial infarction. In vitro functional analyses revealed that one SNP in the coding region of LTA, which changed an aminoacid from threonine to asparagine, effected a two-fold in- crease in induction of
8、 several cell-adhesion molecules, in- cluding VCAM1, in vascular smooth-muscle cells of hu- man coronary artery. Moreover, the minor variant of the other SNP, in intron 1, enhanced the transcriptional level of LTA. Since these two SNPs showed complete linkage disequilibrium, this combination of gene
9、tic substitutions would likely result in several-fold increase of LTA activity and may play some role in the pathogenesis of MI. To further understand the role of LTA, we searched for molecules that interact with LTA. By yeast two hybridsystem, we identified one protein, galectin-2. Furthermore, SNP
10、 in the gene encoding this protein showed very signif-理研研究年報1265icant association with myocardial infarction. The signifi- cant SNP was shown to regulate extracellular level of LTA protein.These findings indicate the importance of LTA cascade in the pathogenesis of myocardial infarction.Research Sub
11、jects1. Identification of genes (SNPs) related to myocardial infarctionStaffLaboratory Head Dr. Toshihiro TANAKAResearch Scientist Dr. Kouichi OZAKITechnical StaffMs. Saori ABIKO Ms. Yoko ARIJI Ms. Miyuki OMOTEZAKO Ms. Kaori TABEI Ms. Maki TAKAHASHI Mr. Wataru YAMANOBE Ms. Mayumi YOSHIITrainees Mr.
12、Yusuke EBANA (Dept. Cardiovasc. Med., Tokyo Med. Den. Univ.) Mr. Nobuaki ISHII (Dept. Medicine, Nihon Univ. Sch. Medicine)誌 上 発 表Publications 雑誌 （原著論文） 印査読制度論文 The International HapMap Consortium,Tsunoda T., Sekine A., Tanaka T., and Nakamura Y.: “The Interna- tional HapMap Project”, Nature 426, 789
13、796 (2003). Nagahata T., Onda M., Emi M., Nagai H., Tsumagari K., Fujimoto T., Hirano A., Sato T., Nishikawa K., Akiyama F., Sakamoto G., Kasumi F., Miki Y., TanakaT., and Tsunoda T.: “Expression profiling to predict postoperative prognosis for estrogen receptor-negative breast cancers by analysis o
14、f 25,344 genes on a cDNA microarray”, Cancer Sci. 95, 218225 (2004). Onda M., Emi M., Nagai H., Yoshida A., Miyamoto S., Akaishi J., Asaka S., Mizutani K., Shimizu K., Nagahama M., Ito K., Tanaka T., and Tsunoda T.:“Comprehensive gene expression profiling of anaplastic thyroid cancers with cDNA microarray of 25344 genes”,Endocrine-Related Cancer 11, 843854 (2004). Tsunoda T., Lathrop G. M., Sekine A., Yamada R.
