腎素-血管收縮素系統基因多型性與舒張性心衰竭

Renin-Angiotensin System Gene Polymorphisms and Diastolic Heart Failure

吳卓鍇(Cho-Kai Wu)

指導教授 ： 江福田

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2007年)

https://doi.org/10.6342/NTU.2007.02375

摘要

心臟衰竭是許多心臟疾病末期的表徵，同時也是全球統計上名列前茅的死因。至於心臟的舒張性功能障礙指的是左心室在舒張期的膨脹，填充，舒張出現了異常。統計上心衰竭的病人有1/2~1/3屬於舒張性心衰竭(diastolic heart failure)，每年的死亡率約為5~8% [Aurigemma-2004]，但臨床上對於診斷或者是治療往往都因沒有治療終點而輕忽。
導致舒張性心衰竭的原因包括心肌舒張不良，心肌硬化增加，心包膜疾病，心肌疾病，以及各種激素，收縮素的影響….等等[Brad-2003]。在各種致病因中，可以在臨床上用藥物來調節的便是腎素-血管激素系統。腎素 - 血管收縮素系統是我們體內調控血壓的系統，除了可以讓鈉和水分留在體內，也可以讓細胞增生，血管增厚。研究報告顯示，它也和高血壓病患產生心臟肥大[Brilla-1990]，心臟衰竭[Webber-1993]，心肌梗塞[Hanatani-1995]，心肌症[Urata-1993]，以及心房振顫[Goette-2000]有關。
實驗證明，腎素血管激素系統和SERCA(sarcoplasmic reticulum calcium ATP-ase pump)的調節有關，而血管收縮素阻斷劑更可以透過調控SERCA的多寡影響到心臟的舒張功能。臨床上腎素血管收縮素系統基因的多型性證明和心肌局部的SERCA濃度相關。因此，我們假設腎素-血管收縮素系統基因可能是舒張性心衰竭的易感受基因(susceptible gene)，進一步希望能分析藥物對基因型的影響。
我們用臨床症狀，以及心臟超音波的表徵來定義出舒張性心衰竭的病患。抽取病人的去氧核醣核酸 (DNA)，並檢測血管收縮素轉化酵素基因的插入/缺失(ACE gene insertion/deletion)多型性、血管收縮素原 (angiotensinogen)的T174M、M235T、G-6A、A-20C、G-152A、G-217A等六處基因的多型性，以及血管收縮素II的第一型接受器基因 (angiotensin II type I receptor)的A1166C多型性。研究這些基因是否與舒張性心衰竭有關，並且使用組合多基因型方法 (Composite Haplotype Method)來做haplotypes的分析，希望能找到相關的基因，進而評估基因對於藥物的反應。
此研究包括148位舒張性心衰竭的患者以及148位對照組，對照組和實驗組根據性別、年齡採用一對一的方式選取，單基因座的分析發現血管收縮素轉化酵素基因的插入/缺失多型性以及血管收縮素II的第一型接受器基因的A1166C多型性會增加患病的感受性，勝算比 (Odds Ratios)分別為2.37 (95%信賴區間為1.33至4.22,P=0.003)以及4.44 (95%信賴區間為1.81至10.9, P=0.001)。在血管收縮素原的多基因座單套型 (Multilocus haplotype)分析中發現有兩種基因單套型在舒張性心衰竭和對照組有顯著的差異。擁有G-A-A-A-T-C以及A-G-A-G-C-C這兩種單倍型對於舒張性心衰竭的感受性較高，其P值分別為<0.005以及<0.05。
我們證實了腎素-血管收縮素系統基因多型性與舒張性心衰竭的關聯，也提供未來利用腎素-血管收縮素阻斷劑來治療舒張性心衰竭臨床實驗的一個很好的依據。

關鍵字

舒張性心衰竭 ； 基因 ； 多型性 ； 腎素 ； 血管收縮素 ； 接受器

並列摘要

Objectives: We analysis the renin-angiotensin system(RAS) genes and determine the association between single locus RAS genes polymorphisms, and multilocus AGT gene polymorphisms and gene-gene interaction with diastolic heart failure(DHF).
Background: DHF refers to an abnormality of diastolic distensibility, filling, or relaxation of the left ventricle. Pathology leading to DHF include impaired relaxation, increased passive stiffness, endocardial and pericardial disorders, microvacular flow and neurohormonal regulation. Among them, the association of RAS system and diastolic dysfunction are already established. There are many reports demonstrating the association of RAS system genes polymorphisms with congestive heart failure, but to what extent they affect DHF remains uncertain. We hypothesized that RAS gene might be the susceptible gene for DHF and conducted a case-control study with this regard.
Method: The definition of DHF is according to guidelines from the ACC and AHA which include typical symptoms and signs of heart failure, normal left ventricle(LV) ejection fraction, evidence of LV impaired relaxation under echocardiography. Exclusion criteria include coronary artery disease, significant valvular heart disease, cardiomyopathy, pericardial disease and renal insufficiency. A total of 148 patients with DHF and 148 controls were included. The controls were matched to cases on a 1-to-1 basis with regard to age, gender, diabetes mellitus, hypertension. The ACE gene insertion/deletion polymorphism, the T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene and the A1166C polymorphisms of the angiotensin II type I receptor gene were genotyped. Differences in allele frequencies and genotype distributions between the DHF and control group patients were compared using the χ2 test or the Fisher exact test. Mutilocus haplotypes analysis and gene-gene interaction analysis were performed by composite haplotype method of Zaykin et al.
Results In single-locus analysis, ACE gene DD genotype, the angiotensin II type I receptor A1166C gene CC genotype were significantly associated with higher incidence of DHF. The odds ratio for DHF were 2.37 (95% CI 1.33 to 4.22, p=0.003) with ACE DD genotype, 4.44 (95% CI 1.81 to 10.9, p=0.001) with 1166CC plus 1166AC genotype. In addition, two angiotensinogen gene haplotype frequencies (GAAATC, AGAGCC) were significantly different between DHF group and the controls. There were obvious gene-gene interaction between ACE I/D and AGT A-20C, T174M in determing DHF.
Conclusions This study confirmed an association of RAS gene polymorphisms with DHF. ACE DD and AT1R 1166 AC/CC genotypes conferred risk for DHF. We first demonstrate that AGT haplotype is associated with DHF.

並列關鍵字

Haplotypes ； Diastolic heart failure ； genetic ； polymorphism ； angiotensinogen ； angiotensin-converting enzyme ； receptors ； angiotensin II

參考文獻

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