臺灣博碩士論文加值系統

近十年來，腦血管疾病位居台灣人十大死因前三位之一，除了民國88、93、96、97年退居第三名外，一直以來是主死因中的第二位，僅次於癌症。其中，梗塞型中風(或稱缺血型中風；ischemic stroke)是腦血管疾病發生的主要類型，約占70%。造成梗塞型中風發生的原因主要來自動脈粥狀硬化所引發一系列反應所致。在動脈粥狀硬化的發展上，血小板的趨附有助於初期白血球對於內皮的通透，到了晚期斑塊的脫落及血栓的形成上亦與血小板的聚集黏附密不可分。誘使體內血小板趨附聚集的過程被稱之為凝血作用(coagulation cascade)。凝血因子的形成與體內維生素K的循環(Vit. K cycle)有關，在還原態維生素K(Vit. K hydroquinone)轉化成環氧化態維生素K(Vit. K epoxide)的過程上產生的羧化反應，使得凝血因子能夠功能化並進行後續凝血反應；而體內的環氧化態維生素K則必須透過環氧化態維生素K還原酶(Vitamin K 2,3-Epoxide Reductase, VKOR)的作用將其轉化成還原態以供下次羧化作用進行時利用。因此本研究欲探討VKOR上主控其活性的次單元蛋白-VKORC1(環氧化態維生素K還原酶複合體次單元1號)之危險基因型及其危險單套型與缺血性中風發病危險性的相關性。
本研究選取缺血性中風病患986名，並透過頻率匹配其年齡與性別後，得到986位社區對照。在資料收集上，以結構式問卷經標準化流程收集其社會人口學變項、相關危險因子及疾病史等資料。血液生化值部分則是抽取禁食八小時以上之周邊靜脈血液量測。在基因型的判定上，使用聚合酶鏈鎖反應(Polymerase Chain Reaction)及限制片段長度多形性(Restriction Fragment Length Polymorphism)的方式。統計分析上使用邏輯式迴歸模式，分析VKORC1基因多形性及其單套型(haplotype)與缺血性中風之間的相關性，並計算其危險對比值與95%信賴區間。
結果顯示，在調整傳統危險因子之後，VKORC1 上-1639位點攜帶AG或GG基因型者、+1173位點為CT或CC者、+2255位點帶CT或CC者，相較於攜帶其對應之野生型(wild type)的人高出1.4-1.5倍的風險罹患缺血性中風。進一步分析由此三個基因多形性位點所組合的單套型與缺血性中風間的關係，發現到在調整傳統危險因子後，VKORC1 單套型組合為GCC者相較於ATT的人來說，高出1.45倍的風險罹患缺血性中風。在雙套型(diplotype)的分析上發現到，帶ATT/GCC或是帶GCC/GCC雙套型者，其罹患缺血性中風的風險較雙套型為ATT/ATT者高出1.5倍。
另外，本次研究亦發現，VKORC1基因多形性與糖尿病之間對於疾病的風險上，具有協同作用之影響存在。在調整其他可能的傳統危險因子後，罹患糖尿病且又攜帶危險單套型組合者，其罹病風險較沒有糖尿病且無攜帶危險單套型者高出6.1倍。
最後，本研究亦分析VKORC1基因多形性與缺血性中風病人施用口服抗凝血藥物-warfarin之劑量間相關性。在調整年齡，性別，體重，並控制個體INR值後發現到，基因多形性與藥物施用劑量之間是有相關性存在的，攜帶危險基因型的病人，warfarin施用的劑量明顯高於基因型為野生型的病人。
總結前述，本次研究發現，VKORC1 基因多形性及其單套型與罹患缺血性中風的風險有關，且可能是獨立的危險因子，並發現在評估疾病的風險上，VKORC1 基因多形性與糖尿病間具有協同作用的影響；進一步利用TOAST分類標準區分缺血性中風亞型後，可以在因大動脈血管粥樣硬化所導致的缺血性中風亞型裡觀察到更顯著的結果。另外也發現到，VKORC1 基因多形性及其單套型與缺血性中風患者施用warfarin藥物劑量的個體差異有關，其單套型可以解釋掉7%個體施用劑量之差異。

Atherothrombosis which include atherosclerosis and thrombosis is a main cause of ischemic stroke. Among the process, aggregation and adherence of activated platelets and coagulation cascade are related to form thrombus, and then causing thrombosis. The known vitamin K-dependent proteins include coagulation factors VII, IX, X, prothrombin, and Gas 6 (which be able to facilitate the adherence of activated platelets) are modified by γ-carboxylation (a kind of post-translation). Recent study showed that vitamin K 2,3-epoxide reductase (VKOR) is the rate limiting step of γ-carboxylation, and the genetic polymorphism of vitamin K epoxide reductase complex subunit 1 (VKORC1), which is a subunit to control the activity of VKOR, have been found to affect warfarin dose response through effects on the formation of vitamin K hydroquinone, a cofactor forγ-carboxylation of vitamin K–dependent proteins, which is involved in the coagulation cascade and has a potential impact on atherosclerosis. This study will investigate the association of genetic polymorphisms of VKORC1 on risk of ischemic stroke. In the study sample, we included 986 ischemic stroke patients, and through age and gender matching to find out 986 community control subjects. The related risk factors of ischemic stroke were collected by standardized questionnaire, and used PCR-RFLP to do genotyping. The odds ratio and 95% confidence interval on risk of ischemic stroke was calculated by unconditional logistic regression model. We found that the presence of the risk allele of the A-1639G, T+1173C, T+2255C loci of VKORC1 conferred 1.5 times the risk of ischemic stroke, and found the GCC haplotype was the most dangerous combination of VKORC1. Besides, we also found that genetic polymorphism of VKORC1 was a modifier, which had synergistic effect on the risk of ischemic stroke with diabetes mellitus, if subject carried GCC haplotype and been diagnosed diabetes mellitus, then who conferred 6 times the risk of ischemic stroke. Finally, we found that patient, who was treated by warfarin, carried GCC haplotype need to take higher dosage of warfarin. In conclusion, the genetic polymorphism of VKORC1 may serve as a novel genetic marker for the risk of ischemic stroke and warfarin-sensitive.

第一章 前言 ................................................................................................................ 1
第二章 文獻探討 ...................................................................................................... 3
第一節 缺血性中風 ................................................................................................... 3
第二節 環氧化維生素K 還原酶 ............................................................................... 14
第三章 研究目的 .................................................................................................... 24
第四章 研究假設 .................................................................................................... 25
第五章 研究架構 .................................................................................................... 26
第六章 材料原理與方法 .................................................................................... 27
第一節 研究對象 ................................................................................................... 27
第二節 檢體與資料收集 ........................................................................................ 28
第三節 實驗方法 ................................................................................................... 31
第四節 研究信效度................................................................................................ 37
第五節 維生素K 循環相關蛋白測定 .................................................................... 40
第六節 資料處理與統計分析 ................................................................................ 44
第七章 結果 .............................................................................................................. 46
第一節 研究對象基本人口學與生理生化值 ............................................................. 46
第二節 VKORC1 基因多形性與缺血性中風相關性分析 .................................... 51
第三節 VKORC1 單套型、雙套型與缺血性中風相關性分析 .............................. 62
第四節 缺血性中風傳統危險因子與VKORC1 基因多形性之交互作用分析 ...... 73
第五節 VKORC1 基因多形性與缺血性中風病人服用warfarin 藥物個體劑量差異
之相關性分析 ............................................................................................ 87
第六節 VKORC1 基因多形性與維生素K 依賴蛋白表現 .................................... 92
第八章 討論 .............................................................................................................. 96
第一節 傳統危險因子與缺血性中風 ......................................................................... 96
第二節 VKORC1 基因多形性與缺血性中風 ....................................................... 98
第三節 VKORC1 基因多形性與傳統危險因子的交互作用 .................................102
第四節 VKORC1 基因多形性與缺血性中風病人warfarin 施用劑量個體差異..107
第九章 研究限制 .................................................................................................. 109
第十章 結論 ................................................................................................... .111
引用文獻 ........................................................................................................ .112
附表一 對照組危險因子篩選問卷(北醫附醫預防保健中心用) ......... 124
附表二 中風危險因子篩選問卷(北醫中風防治先驅性計用) .............. 129
附表三 台灣腦中風學會 腦中風登錄表 .......................................... 139

Abbott RD, Rodriguez BL, Burchfiel CM, Curb JD. Physical activity in older middle-aged men and reduced risk of stroke: the Honolulu Heart Program. Am J Epidemiol. 1994;139:881-893.

Abbott RD, Wilson PW, Kannel WB, Castelli WP. High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction. The Framingham Study. Arteriosclerosis. 1988;8:207-11.

Anderson CS, Carter KN, Hackett ML, Feigin V, Barder PA, Broad JB, Bonita R, Auckland Regional Comm. Trend in stroke incidence in Auckland, New Zealand, during 1981 to 2003. Stroke. 2005;36:2087-2093.

Anne Angelillo-Scherrer, Pablo Garcia de Frutos, Cristina Aparicio, Els Melis1, Pierre Savi, Florea Lupu, Jef Arnout, Mieke Dewerchin, Marc F.Hoylaerts, Jean-Marc Herbert, Désiré Collen, Björn Dahlbäck & Peter Carmeliet Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nature Medicine. 2001;7:215-221.

Arnold ML, Lichy C, Werner I, Radbruch A, Wagner S, Grond-Ginsbach C. Single nucleotide polymorphisms in the VKORC1 gene and the risk of stroke in the Southern German population. J Thromb Haemost. 2008;100:614-617.

Barrett, J.C., B. Fry, J. Maller, and M.J. Daly. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263-265.

Berger K, Ajani UA, Kase CS, J. Michael Gaziano, Julie E. Buring, RobertJ. Glynn and CharlesH. Hennekens Light-to-moderate alcohol consumption and the risk of stroke among U.S. male physicians. NEJM. 1999;341:1557-1564.

Binkley S, MacCorquodale D, Thayer S, Doisy E. The isolation of vitamin K. J Biol Chem. 1939;130:219–234

Boden-Ablala B, Gu Q, Kargman DE, Lipset C, Shea S, Hauser WA, Paik M, Sacco RL. Increased stroke incidence in Blacks and Hispanics: the Northern Manhattan Stroke Study. Neurology. 1995;45(suppl 4):A300.
Burchfiel CM, Curb JD, Rodriguez BL, Abbott RD, Chiu D, Yano K. Glucose intolerance and 22-year stroke incidence: the Honolulu Heart Program. Stroke. 1994;25:951-957.

Caroline S. Fox, Sean Coady, Paul D. Sorlie, Ralph B. D’Agostino, Sr, Michael J. Pencina, Ramachandran S. Vasan, James B. Meigs, Daniel Levy and Peter J. Savage
Increasing Cardiovascular Disease Burden Due to Diabetes Mellitus: The Framingham Heart Study. Circulation. 2007;115:1544-1550.

Castelli WP, Doyle JT, Gordon T, Hames CG, Hjortland MC, Hulley SB, Kagan A, Zukel WJ. HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation. 1977;55(5):767-772.

Castelli WP. Cholesterol and lipids in the risk of coronary artery disease--the Framingham Heart Study. Can J Cardiol. 1988;4 (Suppl A):5A-10A.

Cuilin Zhang, MD, PhD; Kathryn M. Rexrode, MD, MPH; Rob M. van Dam, PhD; Tricia Y. Li, MD, MS; Frank B. Hu, MD, PhD. Abdominal Obesity and the Risk of All-Cause, Cardiovascular, and Cancer Mortality Sixteen Years of Follow-Up in US Women. Circulation. 2008;117:1658-1667.

D. W. Stafford. The vitamin K cycle. J Thromb Haemost. 2005;3:1873-1878.

Dam H. Cholesterinstoffwechsel in huhnereriern and hunchen. Biochim Zeitschrift 1929;215: 475–92.

Dam H. The antihaemorraghic activity vitamin of the chick. Nature. 1935;135:652–3.

Dan K. Kiely, Philip A. Wolf, L. Adrienne Cupples, Alexa S. Beiser, and William B. Kannel. Physical Activity and Stroke Risk: The Framingham Study. Am J Epidemiol. 1994;140:608-20.

David J. Schneider. Abnormalities of coagulation, platelet function, and fibrinolysis associated with syndromes of insulin resistance. Coronary Artery Disease. 2005;16:473–476.



Da-Yun Jin, Jian-Ke Tie, Darrel W. Stafford. The Conversion of Vitamin K Epoxide to Vitamin K Quinone and Vitamin K Quinone to Vitamin K Hydroquinone Uses the Same Active Site. Biochemistry. 2007;46:7279-7283.

Demosthenes B Panagiotakos, Christos Pitsavos, Christina Chrysohoou, Ioannis Skoumas and Christodoulos Stefanadis. Five-year incidence of cardiovascular disease and its predictors in Greece: the ATTICA study. Vascular Medicine. 2008;13:113-121.

Dexter Canoy, MPhil, MD, PhD; S. Matthijs Boekholdt, MD, PhD; Nicholas Wareham, MBBS, FRCP; Robert Luben, BSc; Ailsa Welch, PhD; Sheila Bingham, PhD; Iain Buchan, MD, FFPH; Nicholas Day, PhD, FRS; Kay-Tee Khaw, MBBChir, FRCP. Body Fat Distribution and Risk of Coronary Heart Disease in Men and Women in the European Prospective Investigation Into Cancer and Nutrition in Norfolk Cohort. A Population-Based Prospective Study. Circulation. 2007;116:2933-2943.

DK Kiely, PA Wolf, LA Cupples, AS Beiser and RH Myers. Familial aggregation of stroke. The Framingham Study. Stroke. 1993;24:1366-1371.

Gillum RF. Stroke in blacks. Stroke. 1988;19:1-9.

Gullov, A.L., Koefoed, B.G. and Petersen, P. Bleeding complications to long-term oral anticoagulant therapy. J. Thromb. Thrombolysis. 1994;1:17-25.

Herrmann S-M, Whatling C, Brand E, Nicaud V, Gariepy J, Simon A, Evans A, Ruidavets J-B, Arveiler D, Luc G, Tiret L, Henney A, Cambien F. Polymorphisms of the human matrix Gla protein (MGP) gene, vascular calcification, and myocardial infarction. Arterioscler Thromb Vasc Biol. 2000;20:2386 –2393.

HH Hu, WY Sheng, FL Chu, CF Lan and BN Chiang. Incidence of stroke in Taiwan. Stroke. 1992;23:1237-1241.

Hirsh, J. Antithrombotic therapy in deep vein thrombosis and pulmonary embolism. Am. Heart J. 1992;123:1115–1122.

Howard G, Anderson R, Sorlie P, Andrews V, Backlund E, Burke GL. Ethnic differences in stroke mortality between non-Hispanic whites, Hispanic whites, and blacks: the National Longitudinal Mortality Study. Stroke. 1994;25:2120-2125.

HP Adams, Jr, BH Bendixen, LJ Kappelle, J Biller, BB Love, DL Gordon and EE Marsh. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment Stroke. 1993;24:35-41.

Hsiang-Yu Yuan, Jin-Jer Chen, M.T. Michael Lee, Ju-Chieh Wung, Ying-Fu Chen, Min-Ji Charng, Ming-Jen Lu, Chi-Ren Hung, Chun-Yu Wei, Chien-Hsiun Chen, Jer-Yuarn Wu and Yuan-Tsong Chen. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum. Mol. Genet. 2005;14:1745-1751.

J . Oldenburg,M. Watzka,S. Rost, C. R. Muller. VKORC1: molecular target of coumarins. Journal of Thrombosis and Haemostasis. 2007;5 (Suppl. 1):1–6.

Johannes Oldenburg, Carville G. Bevans, Clemens R. Muller, and Matthias Watzka
Vitamin K Epoxide reductase Complex Subunit 1 (VKORC1): The Key Protein of the Vitmin K Cycle. Antioxid. Redox Signal. 2006;8:247-252.

K. L . Berkner, K. W. Runge. The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis.J Thromb Haemost. 2004;2:2118-2132.

Kalofoutis C, Piperi C, Kalofoutis A, Harris F, Phoenix D, Singh J. Type II diabetes mellitus and cardiovascular risk factors: Current therapeutic approaches. Exp Clin Cardiol. 2007;12(1):17-28.

Kari Bente Foss Haug, Mohammad N Sharikabad, Marianne K Kringen,Sigrid Narum, Stine T Sjaatil, Per Wiik Johansen, Peter Kierulf,Ingebjørg Seljeflot, Harald Arnesen and Odd Brørs. Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction. Thrombosis Journal. 2008;6(7):1-7.

Keating FK, Whitaker DA, Kabbani SS, Ricci MA, Sobel BE, Schneider DJ.
Relation of augmented platelet reactivity to the magnitude of distribution of atherosclerosis. Am J Cardiol. 2004;94:725–728.




Kevin W. Hallgren, Wen Qian, Anna V. Yakubenko, Kurt W. Runge, and Kathleen L. Berkner. r-VKORC1 expression in factor IX BHK cells increases factor IX carboxylation but is limited by saturation of another carboxylation component or by a shift in the rate limiting step. Biochemistry. 2006;45(17):5587–5598.

Khaw KT, Barrett-Connor CE. Family history of stroke as an independent predictor of ischemic heart disease in men and stroke in women. Am J Epidemiol. 1986;17:1239-1242.

Kong AP, Choi KC, Cockram CS, Ho CS, Chan MH, Ozaki R, Wong GW, Ko GT, So WY, Tong PC, Lam CW, Lau JT, Chow FC, Chan JC. Independent associations of alanine aminotransferase (ALT) levels with cardiovascular risk factor clustering in Chinese adolescents. J Hepatol. 2008 Jul;49(1):115-22.

Koshi Nakamura, MD; Federica Barzi, PhD; Tai-Hing Lam, MD; Rachel Huxley, DPhil; Valery L. Feigin, MD; Hirotsugu Ueshima, MD; Jean Woo, MD; Dongfeng Gu, MD; Takayoshi Ohkubo, MD; Carlene M.M. Lawes, PhD; Il Suh, MD; Mark Woodward, PhD; for the Asia Pacific Cohort Studies Collaboration.
Cigarette Smoking, Systolic Blood Pressure, and Cardiovascular Diseases in the Asia-Pacific Region. Stroke. 2008;39:1694-1702.

Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. J Am Med Assoc. 2002:288:2709 –2716.

Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature. 2004;427:541–4.

Lim HS, Blann AD, Lip GY. Soluble CD40 ligand, soluble P-selectin, interleukin-6, and tissue factor in diabetes mellitus: relationships to cardiovascular disease and risk factor intervention. Circulation. 2004;109:2524–2528.

Lisa K. Jennings. Role of platelets in atherothrombosis. Am J Cardiol. 2009;103[suppl]:4A-10A.

Loebstein, R., Yonath, H., Peleg, D., Almog, S., Rotenberg, M., Lubetsky, A., Roitelman, J., Harats, D., Halkin, H. and Ezra, D. Interindividual variability in sensitivity to warfarin—nature or nurture? Clin. Pharmacol. Ther. 2001;70:159-164.
Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G.
Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386:78–81.

M. Teichert, L.E. Visser, R.H.N. van Schaik, A. Hofman, A.G. Uitterlinden, P.A.G. M. De Smet, J.C.M. Witteman and B.H.Ch. Stricker. Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1) Polymorphism and Aortic Calcification: The Rotterdam Study. Arterioscler. Thromb. Vasc. Biol. 2008;28:771-776.

MacMahon S, Rodgers A. The epidemiological association between blood pressure and stroke: implications for primary and secondary prevention. Hypertens Res. 1994;17(suppl 1):S23-S32.

Marianne Zeller, PhD; Philippe Gabriel Steg, MD, PhD; Jack Ravisy, MD; Luc Lorgis, MD; Yves Laurent, MD; Pierre Sicard, PhD; Luc Janin-Manificat, MD; Jean-Claude Beer, MD; Hamid Makki, MD; Anne-Cécile Lagrost, MSc; Luc Rochette, PharmD, PhD; Yves Cottin, MD, PhD; for the RICO Survey Working Group. Relation Between Body Mass Index, Waist Circumference, and Death After Acute Myocardial Infarction. Circulation. 2008;118:482-490.

Mark J. Rieder, Alexander P. Reiner, M.P.H.,Brian F. Gage, M.Sc., Deborah A. Nickerson, Charles S. Eby, Howard L. McLeod, P David K. Blough, Kenneth E. Thummel, David L. Veenstra, and Allan E. Rettie. Effect of VKORC1 Haplotypes on Transcriptional Regulation and Warfarin Dose. NEJM. 2005;352:2285-2293.

Markatos Christos N, Grouzi Elissavet, Politou Marianna, Gialeraki Argyri, Merkouri Efrosyni, Panagou Ioannis, Spiliotopoulou Ioanna, Travlou Anthi. VKORC1 and CYP2C9 allelic variants influence acenocoumarol dose requirements in Greek patients . Pharmacogenomics. 2008;9(11):1631-1638.

Masatoshi Matsumoto, MD; Shizukiyo Ishikawa, MD; Eiji Kajii, MD
Association of Adiponectin With Cerebrovascular Disease: A Nested Case–Control Study. Stroke. 2008;39:000-000.





Matteo Monamia, Gianluca Bardinib, Caterina Lamannaa, Laura Palab, Barbara Crescib, Paolo Francesconic, Eva Buiattic, Carlo M. Rotellab and Edoardo Mannuccia, Gianluca Bardini, Caterina Lamanna, Laura Pala, Barbara Cresci, Barbara Cresci, Eva Buiatti, Carlo M. Rotella and Edoardo Mannucci. Liver enzymes and risk of diabetes and cardiovascular disease: Results of the Firenze Bagno a Ripoli (FIBAR) study. Metabolism Clinical and Experimental. 2008;57:387–392

Monica Schenone, Barbara C. Furie, Bruce Furie. The blood coagulation cascade.
Current Opinion in Hematology. 2004;11:272-277.

Nadeem Wajih, David C. Sane, Susan M. Hutson, and Reidar Wallin
Engineering of a Recombinant Vitamin K-dependent -Carboxylation System with Enhanced r -Carboxyglutamic Acid Forming Capacity. J Biol Chem. 2005;280:10540–10547.

Nadeem Wajih, SusanMHutson, and Reidar Wallin Disulfide-dependent Protein Folding Is Linked to Operation of the Vitamin K Cycle in the Endoplasmic Reticulum: A PROTEIN DISULFIDE ISOMERASE-VKORC1 REDOX ENZYME COMPLEX APPEARS TO BE RESPONSIBLE FOR VITAMIN K1 2,3-EPOXIDE REDUCTION. J Biol Chem. 2007;282:2626-2635.

National heart, lung and blood institute,National Institutes of Health.
2007 NHLBI Morbidity and Mortality Chart Book.

P. A. Wolf, R. B. D''Agostino, W. B. Kannel, R. Bonita and A. J. Belanger
Cigarette smoking as a risk factor for stroke. The Framingham Study. JAMA.
1988;259:1025-1029.

Pei-Hsuan Chu, Teng-Yi Huang, Jason Williams, and D. W. Stafford
Purified vitamin K epoxide reductase alone is sufficient for conversion of vitamin K epoxide to vitamin K and vitamin K to vitamin KH2. PNAS. 2006;103:19308-19313.

Per Harmsen, Georg Lappas, Annika Rosengren and Lars Wilhelmsen
Long-Term Risk Factors for Stroke: Twenty-Eight Years of Follow-Up of 7457 Middle-Aged Men in Goteborg, Sweden. Stroke. 2006;37:1663-1667.

Peter Libby. Inflammation in atherosclerosis. NATURE. 2002;420:868-874.

P. Gupte, D. Amarapurkar and S. Agal et al., Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol. 2004; 19 (8): 854–858.

RB D''Agostino, PA Wolf, AJ Belanger and WB Kannel. Stroke risk profile: adjustment for antihypertensive medication: The Framingham Study. Stroke.
1994;25:40-43.

R. LEMMENS, S . ABBOUD, L . VANHEES, A. GORIS and V. THI JS
Lack of association between variants in the VKORC1 gene and cerebrovascular or coronary heart disease. J Thromb Haemost. 2008;6:2220–3.

Ralph L. Sacco, MD, MS, Chair; Emelia J. Benjamin, MD, ScM; Joseph P. Broderick, MD; Mark Dyken, MD; J. Donald Easton, MD; William M. Feinberg, MD; Larry B. Goldstein, MD; Philip B. Gorelick, MD, MPH; George Howard, DrPH; Steven J. Kittner, MD, MPH; Teri A. Manolio, MD, MHS; Jack P. Whisnant, MD; Philip A. Wolf, MD. Risk Factors. Stroke. 1997;18:1507-1517.


Rina Kimura , Kotaro Miyashita , Yoshihiro Kokubo , Yasuhisa Akaiwa , Ryoichi Otsubo , Kazuyuki Nagatsuka , Toshiho Otsuki , Akira Okayama , Kazuo Minematsu , Hiroaki Naritomi , Shigenori Honda , Hitonobu Tomoike , Toshiyuki Miyata
Genotypes of vitamin K epoxide reductase, γ-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients.
Thrombosis Research. 2007;120:181–186.

Roger K. Schindhelm, Jacqueline M. Dekker, Giel Nijpels, Lex M. Bouter, Coen D.A. Stehouwer, Robert J. Heine, Michaela Diamant. Alanine aminotransferase predicts coronary heart disease events: A 10-year follow-up of the Hoorn Study. Atherosclerosis 191 (2007) 391–396

Rost, S., Fregin, A., Hunerberg, M., Bevans, C. G., Muller, C. R., and Oldenburg, J.
Site-directed mutagenesis of coumarin-type anticoagulant-sensitive VKORC1: Evidence that highly conserved amino acids define structural requirements for enzymatic activity and inhibition by warfarin. Thromb. Haemostasis. 2005;94:780-786.

Russell Ross. Atherosclerosis - an Inflammatory disease. NEJM. 1999;340:115-126.

Salim Yusuf, Steven Hawken, Stephanie Ôunpuu, Leonelo Bautista, Maria Grazia Franzosi, Patrick Commerford, Chim C Lang, Zvonko Rumboldt,
Churchill L Onen, Liu Lisheng, Supachai Tanomsup, Paul Wangai Jr, Fahad Razak, Arya M Sharma, Sonia S Anand, on behalf of the INTERHEART
Study Investigators. Obesity and the risk of myocardial infarction in 27 000 participants from 52 countries: a case-control study. Lancet. 2005;366:1640–49.

Seung-Han Suk, Ralph L. Sacco, Bernadette Boden-Albala, Jian F. Cheun, John G. Pittman, Mitchell S. Elkind, and Myunghee C. Paik
Abdominal Obesity and Risk of Ischemic Stroke: The Northern Manhattan Stroke Study. Stroke. 2003;34:1586-1592.

Shinozaki K, Naritomi H, Shimizu T, Suzuki M, Ikebuchi M, Sawada T, Harano Y.
Role of insulin resistance associated with compensatory hyperinsulinemia in ischemic stroke. Stroke. 1996;27:37-43.

Spreafico M, Lodigiani C, van Leeuwen Y, Pizzotti D, Rota LL, Rosendaal F, Mannucci PM, Peyvandi F. Effect of CYP2C9 and VKORC1 on INR variation and dose requirement during initial phase of anticoagulant therapy. Pharmacogenomics.
2008;9(9):1237-1250.

Spreafico Marta, Lodigiani C, van Leeuwen Y, Pizzotti D, Rota LL, Rosendaal F, Mannucci PM, Peyvandi F. Effects of CYP2C9 and VKORC1 on INR variations and dose requirements during initial phase of anticoagulant therapy. Pharmacogenomics.
2008;9(9):1237-50.

Stéphanie Debette and Sudha Seshadri. Genetics of Atherothrombotic and Lacunar Stroke. Circ Cardiovasc Genet. 2009;2:191-198.

Takahashi, H., Wilkinson, G.R., Caraco, Y., Muszkat, M., Kim, R.B.,
Kashima, T., Kimura, S. and Echizen, H. Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients.
Clin. Pharmacol. Ther. 2003;73:253–263.





Toshiyuki Horiuchi, Hirohito Kazama, Atsushi Araki, Junichiro Inoue, Takayuki Hosoi, Tsuneko Onouchi, Shouichi Mizuno, Hideki Ito1, and Hajime Orimo
Impaired gamma carboxylation of osteocalcin in elderly women with type II diabetes mellitus: relationship between increase in undercarboxylated osteocalcin levels and low bone mineral density. J Bone Miner Metab. 2004;22:236–240.

Tschoepe D, Roesen P, Kaufmann L, Schauseil S, Kehrel B, Ostermann H, Gries FA.
Evidence for abnormal platelet glycoprotein expression in diabetes mellitus.
Eur J Clin Invest. 1990;20:166–170.

Viveca M. Bhat, MD; John W. Cole, MD, MS; John D. Sorkin, MD, PhD; Marcella A. Wozniak, MD, PhD; Ann M. Malarcher, PhD; Wayne H. Giles, MD, MS; Barney J. Stern, MD; Steven J. Kittner, MD, MPH. Dose-Response Relationship Between Cigarette Smoking and Risk of Ischemic Stroke in Young Women. Stroke. 2008;39:2439-2443.

Wang TL, Li HL, Tjong WY, Chen QS, Wu GS, Zhu HT, Hou ZS, Xu S, Ma SJ, Wu M, Tai S. Genetic factors contribute to patient-specific warfarin dose for Han Chinese.
Clin Chim Acta. 2008;396(1-2):76-79.

Wannamethee SG, Lowe GD, Shaper AG, Rumley A, Lennon L, Whincup PH.
The metabolic syndrome and insulin resistance: relationship to haemostatic and inflammatory markers in older non-diabetic men. Atherosclerosis. 2005;181:101–108.


Watzka M, Nebel A, El Mokhtari NE, Ivandic B, Müller J, Schreiber S, Oldenburg J.
Functional promoter polymorphism in the VKORC1 gene is no major genetic determinant for coronary heart disease in Northern Germans. J Thromb Haemost.
2007;97:998-1002.

Xie, H.G., Kim, R.B., Wood, A.J. and Stein, C.M.
Molecular basis of ethnic differences in drug disposition and response.
Annu. Rev. Pharmacol. Toxicol. 2001;41:815–850.

Yan B, Parsons M, Mckay S, Campbell D, Infeld B, Czajko R, Davis SM.
When to measure lipid profile after stroke? A prospective serial study.
Cerebrovascular Disease. 2005;19:234-238.

Yan-Mei Sun, Da-Yun Jin, Rodney M. Camire and Darrel W. Stafford
Vitamin K epoxide reductase significantly improves carboxylation in a cell line overexpressing factor X. Blood. 2005;106:3811-3815.

Yan-Mei Sun, Da-Yun Jin, Rodney M. Camire, Darrel W. Stafford.
Vitamin K epoxide reductase significantly improves carboxylation in a cell line overexpressing factor X. Blood. 2005;106:3811-3815.

Yibo Wang, Weili Zhang, Yuhui Zhang, Yuejin Yang, Lizhong Sun, Shengshou Hu, Jilin Chen, Channa Zhang, Yi Zheng, Yisong Zhen, Kai Sun, Chunyan Fu, Tao Yang, Jianwei Wang, Jing Sun, Haiying Wu, Wayne C. Glasgow and Rutai Hui
VKORC1 Haplotypes Are Associated With Arterial Vascular Diseases (Stroke, Coronary Heart Disease, and Aortic Dissection). Circulation. 2006;113:1615-1621.

Ying Zhang, James M. Galloway, Thomas K. Welty, David O. Wiebers, Jack P. Whisnant, Richard B. Devereux, Jorge R. Kizer, Barbara V. Howard, Linda D.
Incidence and Risk Factors for Stroke in American Indians: The Strong Heart Study.
Circulation. 2008;118:1577-1584.
Yutaka Kiyohara, MD; Isao Kato, MD; Hiromitsu Iwamoto, MD; Keizo Nakayama, MD Masatoshi Fujishima, MD. The impact of alcohol and hypertension on stroke incidence in a general Japanese population: the Hisayama study. Stroke. 1995;26:368-372.

Zaverio M. Ruggeri. Platelets in atherothrombosis. NATURE MEDICINE
2002;8:1227-1234.

Zhang X, Patel A, Horibe H, Wu Z, Barzi F, Rodgers A, MacMahon S, Woodward M and sia Pacific SC. Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. international journal of epidemiology. 2003;32:563-572.

Website of American heart association
http://www.americanheart.org/

Website of American Stroke Association
http://www.strokeassociation.org/

Website of Framingham heart study
http://www.framinghamheartstudy.org/

內政部統計年報-戶政司網頁
15歲以上人口教育程度(http://sowf.moi.gov.tw/stat/year/list.htm)

胡漢華 醫師. 腦中風的分類與診斷.

陳震寰,陳宜民.第18章 心臟血管疾病的預防,預防醫學. 巨流出版
2003; 初版第一刷.

廖建彰, 李采娟,林瑞雄, 宋鴻樟. 2000年台灣腦中風盛行率與發生率的城鄉差異.台灣衛誌. 2006;25:223-230.