臺灣博碩士論文加值系統

簡介:
從心臟衰竭的病態生理學來看‚牽涉在其中的神經荷爾蒙機制都會跟心臟衰竭的產生有所關聯。在這當中‚跟腎素-血管張力素系統有關的基因變化都有可能是會引發心臟衰竭的候選基因。這個研究的目的是要找出那些基因的多形性會引起病人的心臟衰竭。
方法:
總共有123名心臟衰竭的病患 (有臨床症狀以及左心室的射出率小於45%),以及386名心臟收縮功能正常的受試者參與這次的研究。經由非簡約分析的多變數羅吉斯迴歸分析(non-parsimonious multivariable logistic regression)去估算全部受試者的propensity score。然後再依據受試者的propensity score加以分為實驗組還有對照組,然後分析這些受試者的基因多形性。在這個研究總夠探討T174M, M235T, G6-A, A-20C, G-152A, G-217A, 以及ACEI/D等七個基因多形性。

結果:
總共有93組配對完整的受試組接受最後的分析。配對的病患組還有對照組不管在年齡、性別、冠狀動脈疾病、心肌梗塞病史、高血壓、糖尿病、血中血脂濃度以及左心室質量等條件都沒有統計學上的差別。分析的結果發現到T174M CC跟心臟衰竭的產生有正相關(OR: 2.81, 95% CI: 1.20 to 6.61, p=0.018)。G-152A GG也會跟心臟衰竭的產生有正相關(OR: 6.25, 95% CI 1.54 to 25.4, p=0.010)。至於ACE I/D方面, ACE DD基因型跟ACE ID基因型相比之下有呈現正相關的趨勢但是並沒沒有統計學上面的差別(OR: 1.37, p=0.475)。ACE ID基因型跟ACE II基因型相比則有較大的機會會產生心臟衰竭(OR: 5.95, 95% CI: 2.16 to 16.4, p=0.001)。經由multiple partitioning tree的分析發現這些基因多形性並不會有交互作用的影響。

結論:
腎素-血管張力素系統的基因多形性有可能在心臟衰竭的發生過程中扮演重要的角色。經由這個配對完整的研究來探討腎素-血管張力素系統的基因多形性跟心臟衰竭的關係可以對於未來心臟衰竭的治療可以提供更加完整以及適切的治療。

Introduction: Considering the fundamental role of neurohormonal factors in the pathophysiology of systolic heart failure (sHF), variants of genes involved in the renin angiotensin system (RAS) are logical candidates. The objective of this study is to identify possible genetic polymorphisms of patients experiencing sHF.

Methods: A total of 123 patients with sHF (clinical symptoms and left ventricle ejection fraction < 45%) and 386 patients with good left ventricular (LV) contractility (ejection fraction >60%) were enrolled into this study. A non-parsimonious multivariable logistic regression model that incorporated potential risk factors was applied to calculate the propensity score for developing sHF. A 1:1 case-control selection process was made according to the rank of propensity. Seven genetic polymorphisms were then identified: T174M, M235T, G-6A, A-20C, G-152A, G-217A, and ACE I/D.

Results: Ninety-three patients (68 men and 25 women, age: 60+/-14) with sHF were enrolled. These patients were well-matched with 93 control subjects (71 men and 22 women, age: 62+/-12) relating to age, sex, presence of coronary heart disease, previous myocardial infarction, hypertension, diabetes mellitus, serum levels of high- and low-density lipoprotein cholesterol, triglycerides, and LV mass to serve as a control. T174M CC genotype was positively associated with sHF (OR: 2.81, 95% CI: 1.20 to 6.61, p=0.018). G-152A GG genotype was also positively associated with the presence of sHF (OR: 6.25, 95% CI 1.54 to 25.4, p=0.010). OR of ACE DD genotype for sHF, as compared with ACE II genotype was 1.37 (p=0.475), and OR for ID genotype compared with II genotype was 5.95 for sHF (95% CI: 2.16 to 16.4, p=0.001). Further classification through a multiple partitioning tree did not find any interaction among these polymorphisms.

Conclusions: Polymorphisms of the RAS may play an important role in the pathogenesis of sHF. Exploration of these RAS genes related to sHF by means of a well-matched case-control study may provide more targeted and tailored treatment of systolic heart failure.

目 錄
口試委員會審定書………………………………………………………………….i
誌謝………………………………………………………………………………….ii
中文摘要…………………………………………………………………………….iii
英文摘要…………………………………………………………………………….iv
第一章 續論………………………………………………………………………..1
第二章 研究方法………………………….………………………………………..6
2. 1 研究對象………………………….………………………………………6
2.2 受試者的病史以及實驗室檢查..…………………………………………7
2.3 心臟超音波檢查…………………..………………………………………7
2.4 冠狀動脈血管攝影…………..……………………………………………8
2.5 統計學方法…………………..……………………………………………8
2.6 選取病患組還有對照組…..………………………………………………9
第三章 研究材料與實驗方法…………………………………………………….10
3.1研究材料………………………………………………………………….10
3.2 決定高壓素原(angiotensinogen, AGT)的基因多形性 (exon2 region)………………11
3.3 決定高壓素原(angiotensinogen, AGT)的基因多形性 (promoter region)………....12
3.4決定血管收縮素轉化酵素基因嵌入/刪移多形性……………………....13
第四章 統計分析………………………………………………………………….15
第五章 結果……………………………………………………………………….16
5.1 受試者的基本資料………………………………………………………16
5.2 基因型的多形性…………………………………………………………17
第六章 討論……………………………………………………………………….18
第七章 結論……………………………………………………………………….22
參考文獻…………………………...………………………………………………23

圖 目 錄

圖一、心臟衰竭的病程與心血管疾病的關係…………………………...……........27
圖二、心臟衰竭與腎素-血管張力素系統的關係……………………………….…28
圖三、腎素-血管張力素系統中的各項作用因子…………..………………..….…29
圖四、血管收縮素原的基因多形性(exon2區域的T174M、M235T)………………….30
圖五、 血管收縮素原的基因多形性(promoter區域的G-6A、A-20C、G-152A、G-217A)…31
圖六、血管收縮素轉化酵素的基因多形性………………….……………………..32


表 目 錄

表一、使用propensity score配對前受試者的基本資料………………………..33
表二、使用propensity score配對前受試者的基因多形性分佈………………..34
表三、使用propensity score配對後受試者的基本資料………………………..35
表四、使用propensity score配對後受試者的基因多形性分佈………………..36
表五、經由propensity score配對分析後所得到的結果………………………..37
表六、使用傳統羅吉斯迴歸分析法分析後所得到的結果……………………..38
表七、以往血管收縮素轉化酵素的基因多形性與心臟衰竭的研究成果……..39

1.Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D''Agostino RB, Kannel WB, Murabito JM, Vasan RS, Benjamin EJ, Levy D. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106(24):3068-3072.
2.Bukharovich IF, Kukin M. Optimal medical therapy for heart failure. Prog Cardiovasc Dis. 2006;48(5):372-385.
3.Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V, Bauer EP, Klovekorn WP, Schaper J. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation. 2003;107(7):984-991.
4.Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med. 1987;316(23):1429-1435.
5.Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325(5):303-310.
6.Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med. 1991;325(5):293-302.
7.Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, Deedwania PC, Ney DE, Snavely DB, Chang PI. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997;349(9054):747-752.
8.Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667-1675.
9.Tsai CT, Lai LP, Kuo KT, Hwang JJ, Hsieh CS, Hsu KL, Tseng CD, Tseng YZ, Chiang FT, Lin JL. Angiotensin II activates signal transducer and activators of transcription 3 via Rac1 in atrial myocytes and fibroblasts: implication for the therapeutic effect of statin in atrial structural remodeling. Circulation. 2008;117(3):344-355.
10.Tsai CT, Wang DL, Chen WP, Hwang JJ, Hsieh CS, Hsu KL, Tseng CD, Lai LP, Tseng YZ, Chiang FT, Lin JL. Angiotensin II increases expression of alpha1C subunit of L-type calcium channel through a reactive oxygen species and cAMP response element-binding protein-dependent pathway in HL-1 myocytes. Circ Res. 2007;100(10):1476-1485.
11.Tsai CT, Hwang JJ, Ritchie MD, Moore JH, Chiang FT, Lai LP, Hsu KL, Tseng CD, Lin JL, Tseng YZ. Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction. Atherosclerosis. 2007;195(1):172-180.
12.Tsai CT, Lai LP, Lin JL, Chiang FT, Hwang JJ, Ritchie MD, Moore JH, Hsu KL, Tseng CD, Liau CS, Tseng YZ. Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation. 2004;109(13):1640-1646.
13.Wu SJ, Chiang FT, Chen WJ, Liu PH, Hsu KL, Hwang JJ, Lai LP, Lin JL, Tseng CD, Tseng YZ. Three single-nucleotide polymorphisms of the angiotensinogen gene and susceptibility to hypertension: single locus genotype vs. haplotype analysis. Physiol Genomics. 2004;17(2):79-86.
14.Schut AF, Bleumink GS, Stricker BH, Hofman A, Witteman JC, Pols HA, Deckers JW, Deinum J, van Duijn CM. Angiotensin converting enzyme insertion/deletion polymorphism and the risk of heart failure in hypertensive subjects. Eur Heart J. 2004;25(23):2143-2148.
15.Winkelmann BR, Russ AP, Nauck M, Klein B, Bohm BO, Maier V, Zotz R, Matheis G, Wolf A, Wieland H, Gross W, Galton DJ, Marz W. Angiotensinogen M235T polymorphism is associated with plasma angiotensinogen and cardiovascular disease. Am Heart J. 1999;137(4 Pt 1):698-705.
16.Ko YL, Ko YS, Wang SM, Chu PH, Teng MS, Cheng NJ, Chen WJ, Hsu TS, Kuo CT, Chiang CW, Lee YS. Angiotensinogen and angiotensin-I converting enzyme gene polymorphisms and the risk of coronary artery disease in Chinese. Hum Genet. 1997;100(2):210-214.
17.Danser AH, Schalekamp MA, Bax WA, van den Brink AM, Saxena PR, Riegger GA, Schunkert H. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation. 1995;92(6):1387-1388.
18.McNamara DM, Holubkov R, Postava L, Janosko K, MacGowan GA, Mathier M, Murali S, Feldman AM, London B. Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. J Am Coll Cardiol. 2004;44(10):2019-2026.
19.Wang Y, Ng MC, So WY, Tong PC, Ma RC, Chow CC, Cockram CS, Chan JC. Prognostic effect of insertion/deletion polymorphism of the ace gene on renal and cardiovascular clinical outcomes in Chinese patients with type 2 diabetes. Diabetes Care. 2005;28(2):348-354.
20.Henry WL, DeMaria A, Gramiak R, King DL, Kisslo JA, Popp RL, Sahn DJ, Schiller NB, Tajik A, Teichholz LE, Weyman AE. Report of the American Society of Echocardiography Committee on Nomenclature and Standards in Two-dimensional Echocardiography. Circulation. 1980;62(2):212-217.
21.Chiang FT, Hsu KL, Tseng CD, Hsiao WH, Lo HM, Chern TH, Tseng YZ. Molecular variant M235T of the angiotensinogen gene is associated with essential hypertension in Taiwanese. J Hypertens. 1997;15(6):607-611.
22.Chiang FT, Hsu KL, Chen WM, Tseng CD, Tseng YZ. Determination of angiotensin-converting enzyme gene polymorphisms: stepdown PCR increases detection of heterozygotes. Clin Chem. 1998;44(6 Pt 1):1353-1356.
23.Bleumink GS, Schut AF, Sturkenboom MC, Deckers JW, van Duijn CM, Stricker BH. Genetic polymorphisms and heart failure. Genet Med. 2004;6(6):465-474.
24.Mansson R, Joffe MM, Sun W, Hennessy S. On the estimation and use of propensity scores in case-control and case-cohort studies. Am J Epidemiol. 2007;166(3):332-339.
25.Ahmed A, Pitt B, Rahimtoola SH, Waagstein F, White M, Love TE, Braunwald E. Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG trial. Int J Cardiol. 2008;123(2):138-146.
26.Sui X, Gheorghiade M, Zannad F, Young JB, Ahmed A. A propensity matched study of the association of education and outcomes in chronic heart failure. Int J Cardiol. 2007.
27.Giamouzis G, Sui X, Love TE, Butler J, Young JB, Ahmed A. A propensity-matched study of the association of cardiothoracic ratio with morbidity and mortality in chronic heart failure. Am J Cardiol. 2008;101(3):343-347.
28.Ahmed A, Zannad F, Love TE, Tallaj J, Gheorghiade M, Ekundayo OJ, Pitt B. A propensity-matched study of the association of low serum potassium levels and mortality in chronic heart failure. Eur Heart J. 2007;28(11):1334-1343.
29.Ahmed A, Young JB, Love TE, Levesque R, Pitt B. A propensity-matched study of the effects of chronic diuretic therapy on mortality and hospitalization in older adults with heart failure. Int J Cardiol. 2008;125(2):246-253.
30.Sethi AA, Nordestgaard BG, Gronholdt ML, Steffensen R, Jensen G, Tybjaerg-Hansen A. Angiotensinogen single nucleotide polymorphisms, elevated blood pressure, and risk of cardiovascular disease. Hypertension. 2003;41(6):1202-1211.
31.Sato N, Katsuya T, Nakagawa T, Ishikawa K, Fu Y, Asai T, Fukuda M, Suzuki F, Nakamura Y, Higaki J, Ogihara T. Nine polymorphisms of angiotensinogen gene in the susceptibility to essential hypertension. Life Sci. 2000;68(3):259-272.
32.Pereira TV, Nunes AC, Rudnicki M, Yamada Y, Pereira AC, Krieger JE. Meta-analysis of the association of 4 angiotensinogen polymorphisms with essential hypertension: a role beyond M235T? Hypertension. 2008;51(3):778-783.
33.Liu Y, Jin W, Jiang ZW, Zhang KX, Sheng HH, Jin L, Sheng YY, Huang W, Yu JD. [Relationship between six single nucleotide polymorphisms of angiotensinogen gene and essential hypertension]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2004;21(2):116-119.
34.Huang W, Xie C, Zhou H, Yang T, Sun M. Association of the angiotensin-converting enzyme gene polymorphism with chronic heart failure in Chinese Han patients. Eur J Heart Fail. 2004;6(1):23-27.
35.van Berlo JH, Pinto YM. Polymorphisms in the RAS and cardiac function. Int J Biochem Cell Biol. 2003;35(6):932-943.
36.Covolo L, Gelatti U, Metra M, Donato F, Nodari S, Pezzali N, Dei Cas L, Nardi G. Angiotensin-converting-enzyme gene polymorphism and heart failure: a case-control study. Biomarkers. 2003;8(5):429-436.
37.Sanderson JE, Young RP, Yu CM, Chan S, Critchley JA, Woo KS. Lack of association between insertion/deletion polymorphism of the angiotensin-converting enzyme gene and end-stage heart failure due to ischemic or idiopathic dilate cardiomyopathy in the Chinese. Am J Cardiol. 1996;77(11):1008-1010.
38.Huang WY, Sun M, Zhou HY. [Effect of the polymorphism of the angiotensin-converting enzyme gene on the plasma angiotensin II levels and the risk of chronic heart failure]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2004;29(2):198-200.