依民國九十六年衛生署統計之十大死亡原因，心臟疾病高居第二位。而冠狀動脈硬化是引發心血管疾病之主要因素。過去的研究中多著重於脂質及生活型態與心血管疾病之相關性。在動脈硬化病變的形成過程中，內膜的增生常見於病灶中，而IL-1β則可能在這個過程中扮演重要的角色。介白素-1β(interleukin-1β，IL-1β)是一種抗發炎反應的細胞激素，可以調節免疫系統並參與反應許多證據顯示IL-1β在粥狀動脈硬化形成過程中具有保護作用。同時在許多流行病學危險因子當中，高血壓、心血管疾病、糖尿病以及心肌梗塞等疾病有重要的相關性。本篇研究的主要目的是想瞭解IL-1β基因的基因型性與心肌梗塞發生之間的關聯。本實驗使用病例-控制試驗的方法，研究的病人數目共有183人，其中49人為AMI病患組，對照組中有58人為一般的健康人，無心肌梗塞病史(ⅡA)，另外128位為不具有傳統心血管疾病危險因數的病人((ⅡB)。我們利用分析PCR-AvaⅠ-digested DNA片段的方法來偵測IL-1β基因在promoter位置的基因多型性。結果顯示急性心肌梗塞患者之具有傳統心血管疾病危險因數之對照組ⅡA，其IL-1β C/C 同型合子與急性心肌梗塞具有明顯統計上的意義(p=0.02)，但對照組ⅡB與急性心肌梗塞則無顯著差異(0.551)。因此我門認為台灣人族群中具有心血管疾病危險因子者，IL-1β
Promoter基因多型性與急性心肌梗塞有關。

Heart disease was ranked on fourth among ten leading causes of death in 1999 in Taiwan. The significance of elevated serum cholesterol levels，and cigarette smoking as risk factors for the development of coronary heart disease has been well documented in numerous studies. Neointimal hyperplasia， mainly the proliferation of smooth muscle cells and accumulation of macrophage-derived foam cells and interleukin-1β might play a central role in the process of atherosclerosis. Among several etiological risk factor，hypertension，cardiac disease，diabetes and myocardial infarction。IL-1β (interleukin-1β) is a cytokine with anti- inflammatory and evidence suggests a potential role for IL-1β in atherosclerosis . For discriminating the association between The aim of this study was to examine whether polymorphism of the IL-1βgene is associated with the risk of AMI. Therefore，we performed a case-control study from 183 patients .The study population comprised of 49 AMI patients (AMI)，58 healthy individuals with AMI disease history (control ⅡA)，76 personnel don'' have any conventional cardiovascular disease risk factors (control ⅡB). IL-1β gene polymorphism was performed by analyzing AvoⅠ-digested DNA fragment obtained by polymerase chain reaction (PCR). An association of the IL-1βC/C genetype of control group ⅡA to the AMI onset was found (p=0.02)，but not in control group ⅡB (0.551)。In conclusions，our result suggest that IL-1β polymorphism was associated with acutr myocardial infarction among Taiwansecohot with convestional cardiovascular disease risk factors,

縮寫表……………………………
貳、 中英文摘要……………………..1
參、 緒論……………………………..3
肆、 研究動機…………………………20
伍、 實驗材料與方法………………..22
陸、 結果 …………………………….27
柒、 討論 …………………………….29
捌、 參考文獻…………………………33
玖、 圖表………………………………43

1.Opie, L. H. (2007). Acute myocardial infarction and diabetes. Lancet. 370: 634-5.
2.El-Menyar, A. A., M. M. Gomaa, et al. (2006). "Obesity: a risk factor for acute myocardial infarction with angiographically patent epicardial coronary vessels in an adolescent." Med Princ Pract 15(6): 449-52.
3.行政院衛生署 (2007)‧民國九十六年台灣地區主要死亡原因。
4.蔡岡廷，邱千芳，蘇世斌，李聰明:年輕人的急性心肌梗塞之一的病例報告。基層醫學2006，21(10):6。
5.Ehtisham, A., M. I. Chimowitz, et al. (2005). "Systemic risk factors associated with progression of atherosclerosis from the coronary to the carotid arteries." J Stroke Cerebrovasc Dis 14(4): 182-5.
6.Lusis AJ.2000.Atherosclerosis.Nature 407:233-41
7.Liuzzo, G. (2001). "Atherosclerosis: an inflammatory disease." Rays 26(4): 221-30.
8.Maxwell, S. R. and G. Y. Lip (1997). "Free radicals and antioxidants in cardiovascular disease." Br J Clin Pharmacol 44(4): 307-17.
9.Huang ,H., W. Mai, et al (2008). "The oxidation ratio of LDL :a predictor for coronary artery disease. " Dis Markers 24(6):341-9.
10.Keaney, J. F., Jr. (2000). "Atherosclerosis: from lesion formation to plaque activation and endothelial dysfunction." Mol Aspects Med 21(4-5): 99-166.
11.Corrado, E. and S. Novo (2005). "Role of inflammation and infection in vascular disease." Acta Chir Belg 105(6): 567-79.
12.Jairath N. Coronary heart disease and risk factor management: A nursing perspective. 1st ed. Philadelphia: W.B. Saunders Company; 1999.
13.Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990''s. Nature 1993;362(29):801-809.
14.Benditt EP. The origin of atherosclerosis. Sci Am 1977;236(2):74-85.
15.Velican C, Velican D. Natural history of coronary atherosclerosis. 1st ed. Boca Raton: CRC Press; 1989.
16.Fuster V, Badimon L, Badimon JJ and Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:242-250.
17.Friedman M. Pathogenesis of coronary atherosclerosis disease. 1st ed. New York: McGraw-Hill; 1969.
18.Glagov S, Zarins C, Gidden DP and Ku DN. Hemodynamics and atherosclerosis. Arch Pathol Lab Med 1988;112:1018-1031.
19. Davies MJ. A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation 1990;82(3)(Suppl II):3846.
20.Harpaz, D., S. Behar, et al. (2004). "Family history of coronary artery disease and prognosis after first acute myocardial infarction in a national survey." Cardiology 102(3): 140-6.
21.Huang, H., W. Mai, et al. (2008). "The oxidation ratio of LDL: a predictor for coronary artery disease." Dis Markers 24(6): 341-9.
22.Washio, M. and R. Hayashi (2004). "Past history of obesity (overweight by WHO criteria) is associated with an increased risk of nonfatal acute myocardial infarction: a case-control study in Japan." Circ J 68(1): 41-6.
23.DiLeo, M. V., J. A. Kellum, et al. (2009). "A simple mathematical model of cytokine capture using a hemoadsorption device." Ann Biomed Eng 37(1): 222-9.
24.Grau, A. J., M. Aulmann, et al. (2001). "Increased cytokine release by leucocytes in survivors of stroke at young age." Eur J Clin Invest 31(11): 999-1006.
25.Saadeddin, S. M., M. A. Habbab, et al. (2002). "Markers of inflammation and coronary artery disease." Med Sci Monit 8(1): RA5-12.
26.Mazurek, T., L. Zhang, et al. (2003). "Human epicardial adipose tissue is a source of inflammatory mediators." Circulation 108(20): 2460-6.
27.Ehara, S., T. Naruko, et al. (2008). "Small coronary calcium deposits and elevated plasma levels of oxidized low density lipoprotein are characteristic of acute myocardial infarction." J Atheroscler Thromb 15(2): 75-81.
28.Pepys, M. B. and A. Berger (2001). "The renaissance of C reactive protein." Bmj 322(7277): 4-5.
29.Lindahl, B., H. Toss, et al. (2000). "Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease." N Engl J Med 343(16): 1139-47.
30.Halil, M., B. Yavuz, et al. (2008). "Novel cardiovascular risk factors in the elderly and their correlation with the Framingham risk score." J Cardiovasc Med (Hagerstown) 9(7): 683-7.

31.de Ferranti, S. D. and N. Rifai (2007). "C-reactive protein: a nontraditional serum marker of cardiovascular risk." Cardiovasc Pathol 16(1): 14-21.
32.Zwaka, T. P., V. Hombach, et al. (2001). "C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis." Circulation 103(9): 1194-7.
33.Bautista, L. E., I. A. Arenas, et al. (2002). "Total plasma homocysteine level and risk of cardiovascular disease: a meta-analysis of prospective cohort studies." J Clin Epidemiol 55(9): 882-7.
34.Splaver, A., G. A. Lamas, et al. (2004). "Homocysteine and cardiovascular disease: biological mechanisms, observational epidemiology, and the need for randomized trials." Am Heart J 148(1): 34-40.
35.Nygard, O., J. E. Nordrehaug, et al. (1997). "Plasma homocysteine levels and mortality in patients with coronary artery disease." N Engl J Med 337(4): 230-6.
36.Russell, J. C. and S. D. Proctor (2006). "Small animal models of cardiovascular disease: tools for the study of the roles of metabolic syndrome, dyslipidemia, and atherosclerosis." Cardiovasc Pathol 15(6): 318-30.
37.Benson, V., A. C. McMahon, et al. (2007). "ICAM-1 in acute myocardial infarction: a potential therapeutic target." Curr Mol Med 7(2): 219-27.
38.Hansson, G. K., P. Libby, et al. (2002). "Innate and adaptive immunity in the pathogenesis of atherosclerosis." Circ Res 91(4): 281-91.
39.Satoh, M., Y. Ishikawa, et al. (2008). "Association between oxidative DNA damage and telomere shortening in circulating endothelial progenitor cells obtained from metabolic syndrome patients with coronary artery disease." Atherosclerosis 198(2): 347-53.
40.Libby, P. (2002). "Inflammation in atherosclerosis." Nature 420(6917): 868-74.
41.Ross, R. (1999). "Atherosclerosis--an inflammatory disease." N Engl J Med 340(2): 115-26.
42.Hegyi, L., J. N. Skepper, et al. (1996). "Foam cell apoptosis and the development of the lipid core of human atherosclerosis." J Pathol 180(4): 423-9.
43.Shah, P. K. (2003). "Pathophysiology of plaque rupture and the concept of plaque stabilization." Cardiol Clin 21(3): 303-14, v.
44.Tang, Z. H., N. P. Wang, et al. (2007). "[Roles of shear stress in atherogenesis]." Sheng Li Ke Xue Jin Zhan 38(1): 37-42.
45.Chien, S. (2008). "Role of shear stress direction in endothelial mechanotransduction." Mol Cell Biomech 5(1): 1-8.
46.Corrado, E. and S. Novo (2005). "Role of inflammation and infection in vascular disease." Acta Chir Belg 105(6): 567-79.
47.Brown, M. D., T. M. Wick, et al. (2001). "Activation of vascular endothelial cell adhesion molecule expression by sickle blood cells." Pediatr Pathol Mol Med 20(1): 47-72.
48.Maier, W., L. A. Altwegg, et al. (2005). "Inflammatory markers at the site of ruptured plaque in acute myocardial infarction: locally increased interleukin-6 and serum amyloid A but decreased C-reactive protein." Circulation 111(11): 1355-61.
49.Ginsburg, I. (2002). "The role of bacteriolysis in the pathophysiology of inflammation, infection and post-infectious sequelae." Apmis 110(11): 753-70.
50.Hanada, T. and A. Yoshimura (2002). "Regulation of cytokine signaling and inflammation." Cytokine Growth Factor Rev 13(4-5): 413-21.
51.Calixto, J. B., M. F. Otuki, et al. (2003). "Anti-inflammatory compounds of plant origin. Part I. Action on arachidonic acid pathway, nitric oxide and nuclear factor kappa B (NF-kappaB)." Planta Med 69(11): 973-83.
52.Calixto, J. B., M. M. Campos, et al. (2004). "Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules." Planta Med 70(2): 93-103.
53.Jialal, I., S. Devaraj, et al. (2002). "Oxidative stress, inflammation, and diabetic vasculopathies: the role of alpha tocopherol therapy." Free Radic Res 36(12): 1331-6.
54.. Laude, K., V. Richard, et al. (2004). "Coronary endothelial cells: a target of ischemia reperfusion and its treatment?" Arch Mal Coeur Vaiss 97(3): 250-4.
55.Berk, B. C., J. I. Abe, et al. (2001). "Endothelial atheroprotective and anti-inflammatory mechanisms." Ann N Y Acad Sci 947: 93-109; discussion 109-11.
56.Platanias, L. C. and N. J. Vogelzang (1990). "Interleukin-1: biology, pathophysiology, and clinical prospects." Am J Med 89(5): 621-9.
57.El-Omar, E. M. (2001). "The importance of interleukin 1beta in Helicobacter pylori associated disease." Gut 48(6): 743-7.
58.Pomianek, M. J., C. K. Colton, et al. (1996). "Synthesis of tumor necrosis factor alpha and interleukin-1 receptor antagonist, but not interleukin-1, by human mononuclear cells is enhanced by exposure of whole blood to shear stress." Asaio J 42(1): 52-9.
59.Gogusev, J., S. Barbey, et al. (1996). "Regulation of TNF-alpha and IL-1 gene expression during TPA-induced differentiation of "Malignant histiocytosis" DEL cell line t(5;6) (q35:p21)." Anticancer Res 16(1): 455-60.
60.Calcagni, E. and I. Elenkov (2006). "Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases." Ann N Y Acad Sci 1069: 62-76.
61.Dinarello, C. A. (1996). "Biologic basis for interleukin-1 in disease." Blood 87(6): 2095-147.
62.Mastruzzo, C., N. Crimi, et al. (2002). "Role of oxidative stress in pulmonary fibrosis." Monaldi Arch Chest Dis 57(3-4): 173-6.
63.Berger, M., S. Budhu, et al. (2002). "Different G(i)-coupled chemoattractant receptors signal qualitatively different functions in human neutrophils." J Leukoc Biol 71(5): 798-806.
64.Cavanaugh, P. F., Jr., M. P. Meredith, et al. (1998). "Coordinate production of PGE2 and IL-1 beta in the gingival crevicular fluid of adults with periodontitis: its relationship to alveolar bone loss and disruption by twice daily treatment with ketorolac tromethamine oral rinse." J Periodontal Res 33(2): 75-82.
65.Raivich, G., M. Bohatschek, et al. (2003). "Lymphocyte infiltration in the injured brain: role of proinflammatory cytokines." J Neurosci Res 72(6): 726-33.
66..Dinarello, C. A. (1996). "Cytokines as mediators in the pathogenesis of septic shock." Curr Top Microbiol Immunol 216: 133-65.
67.Bromander, A., J. Holmgren, et al. (1991). "Cholera toxin stimulates IL-1 production and enhances antigen presentation by macrophages in vitro." J Immunol 146(9): 2908-14.
68.Tong, L., R. Balazs, et al. (2008). "Interleukin-1 beta impairs brain derived neurotrophic factor-induced signal transduction." Neurobiol Aging 29(9): 1380-93.
69.Nakamura, C., Y. Fukutomi, et al. (1997). "Dharmendra antigen but not integral M. leprae is an efficient inducer of immunostimulant cytokine production by human monocytes, and M. leprae lipids inhibit the cytokine production." Int J Lepr Other Mycobact Dis 65(1): 63-72.
70.Fantuzzi, G., D. A. Reed, et al. (1999). "IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor." J Clin Invest 104(6): 761-7.
71..Balkwill, F. R. (1989). "Tumour necrosis factor." Br Med Bull 45(2): 389-400.
72.Tseng, L. H., P. J. Chen, et al. (2001). "Single nucleotide polymorphisms in intron 2 of the human interleukin-1 receptor antagonist (IL-1Ra) gene: further definition of the IL-1 beta and IL-1Ra polymorphisms in North American Caucasians and Taiwanese Chinese." Tissue Antigens 57(4): 318-24.
73.DeGraba, T. J. (1998). "The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy." Neurology 51(3 Suppl 3): S62-8.
74.Rothwell, N., S. Allan, et al. (1997). "The role of interleukin 1 in acute neurodegeneration and stroke: pathophysiological and therapeutic implications." J Clin Invest 100(11): 2648-52.
75.Rothwell, N. J. and G. N. Luheshi (2000). "Interleukin 1 in the brain: biology, pathology and therapeutic target." Trends Neurosci 23(12): 618-25.
76.Dinarello, C. A. (1996). "Cytokines as mediators in the pathogenesis of septic shock." Curr Top Microbiol Immunol 216: 133-65.
77.Stevenson, F. T., F. Torrano, et al. (1992). "Interleukin 1: the patterns of translation and intracellular distribution support alternative secretory mechanisms." J Cell Physiol 152(2): 223-31.
78.Kato, Z., J. Jee, et al. (2003). "The structure and binding mode of interleukin-18." Nat Struct Biol 10(11): 966-71.
79.Zhang, D. L., H. M. Zheng, et al. (2005). "Association of polymorphisms of IL and CD14 genes with acute severe pancreatitis and septic shock." World J Gastroenterol 11(28): 4409-13.
80.Huang, D., R. Pirskanen, et al. (1998). "Polymorphisms in IL-1beta and IL-1 receptor antagonist genes are associated with myasthenia gravis." J Neuroimmunol 81(1-2): 76-81.
81.Pociot, F., J. Molvig, et al. (1992). "A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro." Eur J Clin Invest 22(6): 396-402.
82.Chen, Y. L., Y. L. Huang, et al. (2006). "Differential regulation of ARE-mediated TNFalpha and IL-1beta mRNA stability by lipopolysaccharide in RAW264.7 cells." Biochem Biophys Res Commun 346(1): 160-8.
83.Robert, A., E. Saperas, et al. (1991). "Gastric cytoprotection by intracisternal interleukin-1 beta in the rat." Biochem Biophys Res Commun 174(3): 1117-24.
84.El-Omar, E. M., M. Carrington, et al. (2000). "Interleukin-1 polymorphisms associated with increased risk of gastric cancer." Nature 404(6776): 398-402.
85.Mazuski, J. E., K. Tolman, et al. (1997). "Effects of cytokine antagonists on the hepatic acute-phase response." J Surg Res 68(2): 161-9.
86.Wang, C., M. W. Wang, et al. (2005). "Evodiamine induced human melanoma A375-S2 cell death partially through interleukin 1 mediated pathway." Biol Pharm Bull 28(6): 984-9.
87.Wiegmann, K., R. Schwandner, et al. (1999). "Requirement of FADD for tumor necrosis factor-induced activation of acid sphingomyelinase." J Biol Chem 274(9): 5267-70.
88.Mabuchi, T., K. Kitagawa, et al. (2000). "Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats." Stroke 31(7): 1735-43.
89.Jin, Z. and W. S. El-Deiry (2006). "Distinct signaling pathways in TRAIL- versus tumor necrosis factor-induced apoptosis." Mol Cell Biol 26(21): 8136-48.
90..Wang, L. X., M. Ideishi, et al. (2001). "Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia/reperfusion-induced myocardial injury." Hypertens Res 24(2): 179-87.
91.Camargo, M. C., R. Mera, et al. (2006). "Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms and gastric cancer: a meta-analysis." Cancer Epidemiol Biomarkers Prev 15(9): 1674-87.
92.Beales, I. L. and J. Calam (1998). "Interleukin 1 beta and tumour necrosis factor alpha inhibit acid secretion in cultured rabbit parietal cells by multiple pathways." Gut 42(2): 227-34.
93.Al-Moundhri, M. S., M. Al-Nabhani, et al. (2006). "Interleukin-1beta gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms and gastric cancer risk in an Omani Arab population." Gastric Cancer 9(4): 284-90.
94.Machado, J. C., P. Pharoah, et al. (2001). "Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma." Gastroenterology 121(4): 823-9.
95.Elhage, R., A. Maret, et al. (1998). "Differential effects of interleukin-1 receptor antagonist and tumor necrosis factor binding protein on fatty-streak formation in apolipoprotein E-deficient mice." Circulation 97(3): 242-4.
96.Aziz, A. (2006). "A study on immunopathogenetic mechanisms of atherosclerotic process caused by chronic infection of Chlamydia pneumoniae in rats (Ratus novergicus)." Acta Med Indones 38(4): 206-12.
97.Mrak, R. E. and W. S. Griffin (2000). "Interleukin-1 and the immunogenetics of Alzheimer disease." J Neuropathol Exp Neurol 59(6): 471-6.
98.Minster, R. L., S. T. DeKosky, et al. (2000). "Genetic association studies of interleukin-1 (IL-1A and IL-1B) and interleukin-1 receptor antagonist genes and the risk of Alzheimer''s disease." Ann Neurol 48(5): 817-9.
99.Schubert, P., T. Morino, et al. (2000). "Cascading glia reactions: a common pathomechanism and its differentiated control by cyclic nucleotide signaling." Ann N Y Acad Sci 903: 24-33.
100.Witkin, S. S., S. Gerber, et al. (2002). "Influence of interleukin-1 receptor antagonist gene polymorphism on disease." Clin Infect Dis 34(2): 204-9.
101.IKimya, Y., C. Akdis, et al. (1997). "Plasma interleukin-1alpha, interleukin-1beta and interleukin-1 receptor antagonist levels in pre-eclampsia." Eur J Obstet Gynecol Reprod Biol 73(1): 17-21.
102.Bortolami, M., A. Kotsafti, et al. (2008). "Fas / FasL system, IL-1beta expression and apoptosis in chronic HBV and HCV liver disease." J Viral Hepat 15(7): 515-22.
103.Manzoli, A., F. Andreotti, et al. (1999). "Allelic polymorphism of the interleukin-1 receptor antagonist gene in patients with acute or stable presentation of ischemic heart disease." Cardiologia 44(9): 825-30.
104.Byrne, C. E., A. Fitzgerald, et al. (2004). "Elevated white cell count in acute coronary syndromes: relationship to variants in inflammatory and thrombotic genes." BMC Med Genet 5: 13.
105.Chou, H. T., C. H. Tsai, et al. (2005). "Lack of association of genetic polymorphisms in the interleukin-1beta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 genes with risk of rheumatic heart disease in Taiwan Chinese." Int Heart J 46(3): 397-406.
106.Li, B., Y. H. Liao, et al. (2006). "Effects of carvedilol on cardiac cytokines expression and remodeling in rat with acute myocardial infarction." Int J Cardiol 111(2): 247-55.
107.Oda, K., N. Tanaka, et al. (2007). "Polymorphisms in pro- and anti-inflammatory cytokine genes and susceptibility to atherosclerosis: a pathological study of 1503 consecutive autopsy cases." Hum Mol Genet 16(6): 592-9.
108.Arman, A., O. Soylu, et al. (2008). "Interleukin-1 receptor antagonist gene VNTR polymorphism is associated with coronary artery disease." Arq Bras Cardiol 91(5): 293-8.
109.Geismar, K., C. Enevold, et al. (2008). "Involvement of Interleukin-1 Genotypes in the Association of Coronary Heart Disease With Periodontitis." J Periodontol 79(12): 2322-2330.

110.Carter, K. W., J. Hung, et al. (2008). "Association of Interleukin-1 gene polymorphisms with central obesity and metabolic syndrome in a coronary heart disease population." Hum Genet 124(3): 199-206.

111.Lin, R. C. and B. J. Morris (2002). "Association analysis of polymorphisms at the interleukin-1 locus in essential hypertension." Am J Med Genet 107(4): 311-6.