横田研究室業績一覧

2014	MuRF1 negatively regulates pathological cardiac hypertrophy through downregulation of calcineurin A. Circ Heart Fail. 2014 Diabetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium.  Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet. 2014; doi: 10.1038/ng.2897. A meta-analysis of genome-wide association studies for adiponectin level in East Asians identifies a novel locus near WDR11-FGFR2. Hum Mol Genet2014; 23(4):1108-1119
2013	Identification of a Glutamic Acid Repeat Polymorphism of ALMS1 as a Novel Genetic Risk Marker for Early-Onset Myocardial Infarction by Genome-Wide Linkage Analysis. Circ Cardiovasc Genet 2013 A genome-association study of a coronary artery disease risk variant. J Hum Genet 2013;58:120-126
2012	Association of genetic variants influencing lipid levels with coronary artery disease in japanese individuals. Plos One 2012; 7(9): e46385. doi:10.1371/journal. Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians. Diabetologia 2012;55:981-995 Meta-analysis of genome-wide association studies identifies 8 new loci for type 2 diabetes in East Asians. Nat Genet 2012;44(1):67-72 Meta-analysis identifies common variants associated with body mass index in east Asians. Nat Genet 2012;44(3):307-312 Genome-wide association study of coronary artery disease in the Japanese. Eur J Hum Genet 2012;20:333-340
2011	The ratio of adiponectin to homeostasis model assessment of insulin resistance is a powerful index of each component of metabolic syndrome in an aged Japanese population: results from the KING Study. Diabetes Res Clin Pr 2011;92:e61-e65 Relation of a common variant of the adiponectin gene to serum adiponectin concentration and metabolic traits in an aged Japanese population. Eur J Hum Genet 2011;19(3): 262-269 Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat Genet 2011;43(6):531-538
2010	Beneficial effects of growth hormone-releasing peptide on myocardial oxidative stress and left ventricular dysfunction in dilated cardiomyopathic hamsters. Circ J 2010;74(1):163-170 Mutation of ARHGAP9 in patients with coronary spastic angina. J Hum Genet 2010;55(1):42-49 Plasma resistin concentration determined by common variants in the resistin gene and associated with metabolic traits in an aged Japanese population. Diabetologia 2010;53(2):234-246 Blood pressure and hypertension are associated with 7 Loci in the Japanese population. Circulation 2010;121:2302-2309 Cumulative episodes of rejection altered myocardial sarcoplasmic reticulum Ca2+ -ATPase and ryanodine receptor-2 MRNA expression in heart transplant recipients. Int Heart J 2010;51(4):259-263
2009	Frequency, predictors and outcome of stent fracture after sirolimus-eluting stent implantation. Int J Cardiol 2009;133(3):321-326 Safety and efficacy of 2.5-mm sirolimus-eluting stent implantation at lower deployment pressure in very small vessels(<2.5mm). Coron Artery Dis 2009; 20(2):163-168 Exercise training alters left ventricular geometry and attenuates heart failure in dahl salt-sensitive hypertensive rats. Hypertension 2009;53:701-707 Xanthine oxidase inhibition improves left ventricular dysfunction in dilated cardiomyopathic hamsters. J Card Fail 2009;14(3):238-244 Relation of functional and morphological changes in mitochondria to myocardial contractile and relaxation reserves in asymptomatic to mildly symptomatic patients with hypertrophic cardiomyopathy. Eur Heart J 2009;30(15): 1853-1862 Mechanism of diastolic stiffening of the failing myocardium and its prevention by angiotensin receptor and calcium channel blockers. J Cardiovasc Pharmacol 2009;54(1):47-56 Beneficial effects of torasemide on systolic wall stress and sympathetic nervous activity in asymptomatic or mildly symptomatic patients with heart failure: Comparison with azosemide. J Cardiovasc Pharmacol 2009;53:468-473 Long-term administration of nifedipine attenuates cardiac remodeling and diastolic heart failure in hypertensive rats. Eur J Pharmacol 2009; 615:163-170 Genetic inhibition of calcineurin induces diastolic dysfunction in mice with chronic pressure overload. Am J Physiol Heart Circ Physiol 2009;297(5): 1814-1819
2008	Is it possible to predict which patients need distal protection during primary angioplasty? Int J Cardiol 2008;127(2):179-185 Pioglitazone attenuates cardiac hypertrophy in rats with salt-sensitive hypertension: role of activation of AMP-activated protein kinase and inhibition of Akt. J Hypertens 2008;26(8):1669-1676 Aortic pressure augmentation as a maker of cardiovascular risk in obstructive sleep apnea syndrome. Hypertens Res 2008;31(6):1109-1114 Dobutamine stress testing as a diagnostic tool for evaluation of myocardial contractile reserve in symptomatic or mildly symptomatic patients with dilated cardiomyopathy. JACC Cardiovasc Imaging  2008;1:718-726 Superoxide-dependent cathepsin activation is associated with hypertensive myocardial remodeling and represents a target for Angiotensin II type 1 receptor blocker treatment. Am J Pathol 2008;173(2):358-369
2007	Investigation of the relationship between sample size and risk factors for complex diseases based on a simulation study. Chem-Bio Inform J 2007; 7(1):1-11 Beneficial effect of bilevel positive airway pressure on left ventricular function in ambulatory patients with idiopathic dilated cardiomyopathy and central sleep apnea-hypopnea: A preliminary study. Chest 2007;131:1694-1701 Adolescent obesity adversely affects blood pressure and resting heart rate. Cir J 2007; 71:722-726 Inhibition of endogenous Mst1 prevents apoptosis and cardiac dysfunction without affecting cardiac hypertrophy after myocardial infarction. Circ Res 2007;100:1344-1352 Mechanisms underlying the impairment of ischemia-induced neovascularization in MMP-2-deficient mice. Circ Res 2007;100:904-913
2006	Changes with age in left ventricular function and volumes at rest and postexercise in postmenopausal women. Ann Nucl Med 2006;20(10):677-681 Differential myolysis of myocardium and skeletal muscle in hamsters with dilated cardiomyopathy: Beneficial protective effect of diltiazem. Circ J 2006;70: 1497-1502 Attenuation of ventricular hypertrophy and fibrosis in rats by pitavastatine: Potential role of the RhoA–extracellular signal-regulated kinase serum response factor signalling pathway. Clin Exp harmacol P 2006;33:1164-1171 Sex differences in the relationships between electrocardiographic abnormalities and the extent of left ventricular hypertrophy by echocardiography. Ann Noninvas Electro 2006;11(3): 222-229 The distal protection during primary percutaneous coronary intervention alleviates the adverse effects of large thrombus burden on myocardial reperfusion. Circ J 2006;70:232-238 Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure. J Cardiovasc Pharm 2006;47:770-779 Attenuation of oxidative stress and cardiac dysfunction by bisoprolol in an animal model of dilated cardiomyopathy. Biochem Bioph Res Co 2006: 350:105-113 Attenuation of cardiac dysfunction by a PPAR-α agonist is associated with down-regulation of redox-regulated transcription factors. J Mol Cell Cardiol 2006;41:318-329 Classification method for predicting the development of myocardial infarction by using the interaction between genetic and environmental factors. Transactions on Bioinformatics (IPSJ Digital Courier) 2006;47(2):48691-66709 Pravastatin increases survival and suppresses an increase in myocardial matrix metalloproteinase activity in a rat model of heart failure. Cardiovasc Res 2006;69:726-735 Elastolytic cathepsin induction/activation system exists in myocardium and is upregulated in hypertensive heart failure. Hypertension 2006;48: 979-987 Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats. Hypertension 2006;47: 656-664 Prognostic value of pacing-induced mechanical alternans in patients with mild to moderate idiopathic dilated cardiomyopathy in sinus rhythm. J Am Coll Cardiol 2006;47:1382-1389 Localization of cysteine protease, Cathepsin S, to the surface of vascular smooth muscle cells by association with Integrin αvβ3. Am J Pathol 2006; 168(2):685-694
2005	Overexpression of calmodulin induces cardiac hypertrophy by a calcineurin-dependent pathway. Biochem Biophys Res Commun 2005;338:1299-1305 Nicorandil promotes myocardial capillary and arteriolar growth in the failing heart of Dahl salt-sensitive hypertensive rats. Hypertension 2005;46:719-724 Mechanisms of the inhibitory effect of epigallocatechinα3βallate on cultured human vascular smooth muscle cell invasion. Arterioscler Thromb Vasc Biol 2005;25:1864-1870 Myocardial 123I-MIBG scintigraphy reflects left ventricular functional reserve in patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;46:909-91 Cardiac sympathetic dysfunction correlates with abnormal myocardial contractile reserve in dilated cardiomypathy ptients. J Am Coll Cardiol 2005;46:2061-2068 Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: a pilot study. Circulation 2005;112:2940-2945
2004	Serial alterations of b-adrenergic signaling in dilated  cardiomyopathic hamsters: Possible role of myocardial oxidative stress. Circ J 2004; 68:1051-1060 Genetic risk for coronary artery disease in individuals with or without type 2 diabetes. Mol Genet Metab 2004;81:282-290 Promising efficacy of primary gradual and prolonged balloon angioplasty in small coronary arteries: A randomized comparison with cutting balloon angioplasty and conventional balloon angioplasty. Am Heart J 004;147:41-48 Association of a 5178C→A (Leu237Met) polymorphism in the mitochondrial DNA with a low prevalence of myocardial infarction in Japanese individuals. Atherosclerosis 2004;175:281-286 Genetic risk for restenosis after coronary balloon angioplasty. Atherosclerosis 2004;174:181-187 Association of gene ploymorphisms with coronary artery disease among individuals with or without nonfamilial hypercholesterolemia. Atherosclerosis 2004;172:167-173 Lack of association of polymorphisms of the lymphotoxineαgene with myocardial infarction in Japanese. J Mol Med (Berl) 2004;82:477-483 Growth hormone–releasing peptide can improve left ventricular dysfunction and attenuate dilation in dilated cardiomyopathic hamsters. Cardiovasc Res 2004;61:30-38 Genetic risk and gene-environment interaction in coronary artery spasm in Japanese men and women. Eur Heart J 2004;25:970-977 Association of gene polymorphisms with coronary artery disease in low- or high-risk subjects defined by conventional risk factors. J Am Coll Cardiol 2004;44:209-210 Glucose intolerance, as reflected by hemoglobin A1c Level, is associated with the incidence and severity of transplant coronary artery disease. J Am Coll Cardiol 2004;43:1034-1041 Discrimination of nonobstructive hypertrophic cardiomyopathy from hypertensive left ventricular hypertrophy on the basis of strain rate imaging by tissue Doppler ultrasonography. Circulation 2004;110:3808-3814
2003	Prediction of the genetic risk of coronary artery disease from polymorphisms in candidate genes. Jpn Heart J 2003;44 suppl.:15-19 Risk of myocardial infarction and polymorphisms in candidate genes. N Eng J Med 2003;348:1176-1177 Validity and application of noninvasive measurement of blood pressure in hamsters. Exp Anim 2003;52:359-363 Progressive development of pulmonary hypertension leading to right ventricular hypertrophy assessed by echocardiography in rats. Exp Anim 2003;52: 285-294 Combined study with FDG PET and T1 SPECT in patients with idiopathic dilated cardiomyopathy. Nucl Med Commun 2003;24:1071-1080 Gene expression of FK506-binding proteins 12.6 and 12 during chicken development. Comp Biochem Physiol 2003;Part A 136:391-399 Heart selecticve expression of the chicken FK506-binding protein (FKBP) 12.6 gene during embryonic development. Dev Dyn 2003;226:33-41 Biphasic relaxation-frequency relation in patients with effort angina pectoris: A new marker of myocardial demand ischemia. Am Heart J 2003; 146:45-83 Nichorandil inhibits oxidative stress-induced apoptosis in cardiac myocytes through activation of mitochondria ATP-sensitive potassium channels and a nitrate-like effect. J Mol Cell Cardiol 2003;35:1505-1512 Relationship between exercise-induced myocardial ischmia and reduced left ventricular distensibility in patients with nonobstructive hypertrophic cardiomyopathy. J Nucl Med 2003;44:1717-1724 Prediction of genetic risk for hypertension. Hypertension 2003;41: 1035-1040 Effect of Nicorandil on left ventricular end-diastolic pressure during exercise in patients with hypertrophic cardiology. Eur Heart J 2003;24:1340-1348 Myocardial velocity gradient as a noninvasively determined index of left ventricular diastolic dysfunction in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003;42:278-285 Association of gene polymorphisms with coronary artery disease in low- or high-risk subjects defined by conventional risk factors. J Am Coll Cardiol 2003;42:1429-1437
2002	Clinical significance of changes in electrocardiographic R-wave voltage on chest leads in patients with acute anterior myocardial infarction. J Electrocardiol 2002;35:173-180 Effects of FK506 and rapamycin on formation of the neural tube in chick embryos. Anim Sci J 2002;73:229-234 Reduction in the extent of atherosclerosis in apolipoprotein E-deficient mice induced by electroporation-mediated transfer of the plasma platelet-activating factor acetylhydrolase gene into skeletal muscle. Prostaglandins Other Lipid Mediat 2002;70:107-118 Developmental changes of Ca2+ handling in mouse ventricular cells from early embryo to adulthood. Life Sci 2002; 71:1279-1292 AT1 receptor blockade attenuates cardiac hypertrophy and calcineurin activity in Dahl-salt hypertension. Hypertension 2002;40:168-174 Prognostic value of mechanical efficiency in ambulatory patients with idiopathic dilated cardiomyopathy in sinus rhythm. J Am Coll Cardiol 2002;39: 1264-1268 Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Eng J Med 2002;347:1916-1923
2001	Association of a G994→T (Val279→Phe) polymorphism of the plasma platelet-activating factor acetylhydrolase gene with myocardial damage in Japanese with nonfamilial hypertrophic cardiomyopathy.  J Hum Genet 2001;46: 436-441 Role of FK506-binding protein 12 in development of the chick embryonic heart. Biochem Biophys Res Commun 2001;283:613-620 Evaluation of left ventricular function using electrocardiographically  gated myocardial SPECT with 123I-labeled fatty acid analog. J Nucl Med 2001;42:1747-1756 Cardiac functional and structural alterations induced by endotoxin in rat: importance of platelet-activating factor. Crit Care Med 2001;29:609-617 Biphasic changes in left ventricular end-diastolic pressure during dynamic exercise in patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2001;38:335-343 Reduced myocardial sarcoplasmic reticulum Ca2+-ATPase mRNA expression and biphasic force-frequency relations in patients with hypertrophic cardiomyopathy. Circulation 2001:104:658-663
2000	Age related differences in electroencephalographic and cardiac arousal at the termination of sleep apnea/hypopnea. Intern Med 2000;39:375-380 Acute effects of a single low oral dose of pimobendan on left ventricular systolic and diastolic function in patients with congestive heart disease. J Cardiovasc Pharmacol 2000;35:897-905 Phenotypic variation of familial hypertrophic cardiomyopathy caused by the Phe110→Ile mutation in cardiac troponin T. Cardiology 2000;93:155-162 Different β-adrenergic regulation of myocardial contraction and relaxation between apical and nonobstructive hypertrophic cardiomyopathy. Am Heart J 2000;140:329-337 Correlations between plasma platelet-activating factor acetylhydrolase (PAF-AH) activity and PAF-AH genotype, age, and atherosclerosis in a Japanese population. Atherosclerosis 2000;150:209-216 Influence of movement arousal on circadian rhythm of blood pressure in obsructive sleep apnea syndrome. J Hypertens 2000;18:539-544 Association of a T29→C polymorphism of the transforming growth factor-β1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation 2000;101:2783-2787

関連する特許の出願・取得状況

発明者：横田充弘、他

心筋梗塞のリスク診断方法（特願2002-181580） ： 特許第4143756号（H20.6.27)

国際特許出願：PCT/JP03/03477 ： H15.3.20出願

米国7,521,181(H21.4.21)、米国（分割出願）7,745,137(H22.6,29)

中国ZL03814594.4（H21.3.25)、欧州1531180(H22.6.30)

韓国 特許第10-992972（H22.11.2）

冠動脈形成術後再狭窄リスク診断方法（特願2002-233041） ：　特許第4129908号(H20.5.30)

国際特許出願：PCT/JP03/03478 ： H15.3.20出願

米国7,645,572(H22.1.12)

冠動脈攣縮のリスク診断方法（特願2002-280031） ： 特許第4129910号(H20.5.30)

高血圧のリスク診断方法（特願2002-280034） ： 特許第4140329号（H20.6.20)

国際特許出願：PCT/JP03/12052 ： H15.9.22出願

米国7,572,576(H21.8.11)、中国ZL03822935.8(H22.5.12)

韓国10-2005-7005303 ： H15.3.20出願

心筋梗塞のリスク検査方法（特願2008-053196） ：特許第4385140号(H21.10.9)

冠動脈攣縮のリスク検査法（特願2010-516735） ： H21.5.22出願

心筋梗塞のリスク検査法 ： 特許第5432902号：H25.12.13

メタボリック症候群又は心血管疾患のリスク検査法及びリスク検査用キット
（特願2010-525575） ：H21.7.30出願

メタボリック症候群又はその構成疾患の評価法（特願2011-503572） ： H21.10.21出願

メタボリック症候群又はその関連疾患のリスク検査法及びリスク検査用キット（特願2009-57379） ： H21.3.11出願

インスリン抵抗性のリスク評価方法、空腹時血中インスリン濃度のリスク評価方法、及びインスリン抵抗性リスク評価用遺伝子多型タイピングキット（特願2009-172176） ： H21.7.23出願

心筋梗塞のリスク検査法（特願2012-545732） ： H25.2.6出願

競争的獲得資金

2007年度　独立行政法人　中小企業基盤整備機構

中小企業・ベンチャー挑戦支援事業のうち事業化支援事業
「生活習慣病の包括的リスク診断サービスとテーラーメイド・ライフスタイルマネージメントサービスの事業化」

2006年度(2006－2011) 名古屋市都市型産業研究施設開設補助金

2006年度　経済産業省　中部経済産業局

中小企業・ベンチャー挑戦支援事業のうち実用化研究開発事業
「生活習慣病の包括的リスク診断プログラムに関する研究開発」

2006年度　財団法人ＵＦＪベンチャー育成基金

研究開発助成金
「生活習慣病の包括的リスク診断システムとテーラーメイド・ヘルスケア システムの研究開発」

2006年度　ぎふ地域ベンチャー支援ネットワーク「ＮＯＢＵＮＡＧＡ21」

第2回ベンチャービジネス助成金
「生活習慣病の包括的リスク診断システムとテーラーメイド・ライフスタイルマネージメント・システムの開発」

開発の経緯

リスク判定開発の経緯・研究者の思い

はじまりは、心筋梗塞を予防したいという思いから・・

　1990年代、４０歳以上の従業員を４０００人以上抱えた製造業企業の循環器産業医をしていた横田教授は、日頃から従業員の健診結果、特に心電図やコレステロール・血圧に留意し、心筋梗塞を出さないような体制をとっていました。しかしある時期、事業所内に複数の発症者が出ました。
健診の結果ではコレステロールも血圧も正常であるのに、心筋梗塞になってしまった患者がいることに、横田教授は、「現在行っている健診では、予知が不充分であり、予防はできないのではないか・・・」と考え、何か良い方法がないかと調べました。
その頃、『心筋梗塞になりやすい遺伝子が見つかった』というアメリカの論文を読み、自分の遺伝的素因を予め知り、努力することで心筋梗塞になることを予防できるのではないかという思いから、1994年、名古屋大学にて遺伝子の研究を始めました。

事前に知ることで、できる予防

　こうした思いから始まった名古屋大学の研究は、地域の一般住民のご協力をいただき、国内最大規模の３万人の人の遺伝子を集めることができました。病気になった方とそうでない方の遺伝子を比較し、どの遺伝子を持った方が病気になりやすいのかを調べ、心筋梗塞や糖尿病などになりやすい遺伝子が分かってきました。 その頃、研究の中で判明した心筋梗塞になりやすい遺伝子をもった方が、４０歳代で心筋梗塞を発症し、お亡くなりになりました。
その方は、健康診断結果は異常がなく、唯一のリスク因子は「喫煙」していることでした。

　心筋梗塞や糖尿病などの生活習慣病は、たとえ病気になりやすい遺伝子を持っていたとしても、生活習慣に注意をすることで発症を防ぐことができます。遺伝子の影響は２割～４割と少なく、残りはその後の生活習慣（食事・運動・喫煙・ストレスなど）の影響を受けるからです。
この方の遺伝的なリスクを予め知り、厳しく禁煙をすすめていれば、発症を防げたのでは・・・。横田教授は、現在も研究を続けています。そしてその研究成果を社会に還元し、普及させるため、2006年にセラノスティック研究所を設立し、遺伝子情報と予知情報を活用したリスク判定サービスの開発を行っています。

セラノスティック研究所は、テーラーメイド予防医療の普及を目指します。

• 基礎となる研究成果
• 横田研究室業績一覧
• 関連する特許の出願・
  取得状況
• 競争的獲得資金
• 開発の経緯