臺灣博碩士論文加值系統

內皮一氧化氮合成酶基因298Asp基因性在台灣第二型糖尿病和糖尿病腎病變的高出現頻率

第二型糖尿病的病人常會合併一些大血管病變和小血管病變。而內皮細胞功能異常目前被認為和胰島素抗阻性、第二型糖尿病和動脈硬化的初期變化有關。一氧化氮（NO）異常是內皮細胞功能異常的主因之一，並導致血管舒張能力受損。內皮一氧化氮合成酶（eNOS）Glu298Asp的基因多型性已經被發現和冠狀動脈疾病、心肌梗塞、腦中風、本態性高血壓有關聯性。最近也有研究提出eNOS Glu298Asp基因多型性和胰島素抗阻性和第二型糖尿病的發生有關。但是eNOS基因的多型性和糖尿病血管併發症的相關性尚未有一致的結論。
為了研究eNOS Glu298Asp基因多型性和第二型糖尿病的發生與糖尿病血管併發症的關聯性，我們設計了這個研究。本篇研究共納入272位正常人為控制組和388位第二型糖尿病病人。糖尿病腎病變的診斷是由每天的尿蛋白多於500 mg以上來確定，再將糖尿病病人分為三組：1.糖尿病無腎病變組；2. 糖尿病腎病變─非洗腎組；3. 糖尿病腎病變─洗腎組。缺血性心臟病的診斷則為心電圖上依據Minnesota codes發現有明顯心肌缺血或心肌梗塞的變化，或是曾接受心導管或冠狀動脈繞道手術證實有冠狀動脈疾病者。糖尿病眼底病變則定義為在視網膜照相攝影，出現滲出物、出血、血管異常或新生血管。
我們的研究結果發現G╱T基因型的比例和T對偶基因的出現頻率在台灣第二型糖尿病的病人身上比正常控制組為高（24.7% vs 38.9%，p<0.001），但T╱T基因型的出現頻率在正常控制組和糖尿病組間則無明顯差異（13.7% vs 16.3%，p=ns）。
在第二型糖尿病族群中，我們針對腎病變、眼底病變、缺血性心臟病來和eNOS基因Glu298Asp多型性的相關性來做比較。這個基因多型性與糖尿病眼底病變、缺血性心臟病間並無關聯。G╱T, T╱T基因型的比例和T對偶基因的出現頻率在糖尿病腎病變─非洗腎組和糖尿病腎病變─洗腎組的出現頻率較高（p<0.001）。
本篇研究發現eNOS 298Asp的基因型在台灣第二型糖尿病與糖尿病腎病變的病人有較高的出現頻率，所以298Asp的基因型和第二型糖尿病與糖尿病腎病變有明顯的關聯。但與糖尿病人的眼底病變和缺血性心臟病則無關聯性。

Endothelial Nitric Oxide Synthase Gene 298Asp Genotype is More Frequent in Type 2 Diabetes and Diabetic Nephropathy in a Taiwanese Population

Type 2 diabetic patients often suffered from macrovascular and microvascular complications. Endothelial dysfunction is regarded as an early step of insulin resistance syndrome, type 2 diabetes, and atherosclerosis. Nitric oxide (NO) impairment is one of the major reasons of endothelial dysfunction and leads to impairment of vascular relaxation. The missense variant within exon 7 of eNOS gene (Glu298Asp) has been reported to be associated with coronary heart disease, myocardial infarction, stroke, and essential hypertension in some populations. It was also observed to be associated with type 2 diabetes and insulin resistance recently. However, the relationship between eNOS gene polymorphism and vascular complications of type 2 diabetes is still controversial.
To evaluate the association between eNOS gene polymorphism in exon 7 (Glu298Asp) and the occurrence of type 2 diabetes and diabetic vascular complications, we design this study. The study population included two hundred and seventy-two age-matched normal controls and three hundred and eighty-eight patients with type 2 diabetes. Diabetic nephropathy was defined as overt proteinuria (urine protein loss > 500 mg/day) with or without elevation of serum creatinine level. Patients with renal disease other than diabetic nephropathy were excluded. The diabetic patients with or without nephropathy were divided onto three groups: group 1, diabetes without nephropathy; group 2, diabetes with nephropathy-non-dialysis group; and group 3, diabetes with nephropathy-dialysis group. The definitions of ischemic heart disease (IHD) were presence of myoischemia or myocardial infarction in twelve leads electrocardiogram according to Minnesota codes, positive thallium myocardial perfusion scan or treadmill test, or ever received coronary artery bypass graft surgery. The diabetic retinopathy is defined as presence of exudates, hemorrhage, vascular abnormality or neovasculization.
The G/T genotype distribution and T allele frequency are significant higher in type 2 diabetic patients than control subjects (24.7% vs 38.9%, p<0.001). The allele frequency of T/T homozygote is not significant different between diabetes and control subjects (13.7% vs 16.3%, p= ns).
We analyzed the association between vascular complications of diabetes and gene polymorphisms in our patients, including nephropathy, retinopathy, and ischemic heart disease. There are no differences in genotype distribution and allele frequencies of eNOS Glu298Asp polymorphism in diabetic retinopathy or ischemic heart disease in type 2 diabetic subjects. Higher frequency of 298Asp polymorphism was found in diabetes with nephropathy-non-dialysis group and diabetes with nephropathy-dialysis group (p<0.001)
Our results indicate that the eNOS 298Asp polymorphism is more frequent in type 2 diabetes and diabetic nephropathy in a Taiwanese population, and the 298Asp polymorphism is significantly associated with type 2 diabetes and diabetic nephropathy. However, diabetic retinopathy and ischemic heart diseaseof type 2 diabetic were not associated with this eNOS variant in our observations.

目錄
�| 英文摘要 4
�| 中文摘要 9
�| 研究背景 13
�| 研究材料與方法 18
�| 實驗結果 23
�| 討論 27
�| 圖表 34
�| 參考文獻 46

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