週邊白血球計數，CYP2J2與ABCA1基因變異在冠狀動脈疾病及第二型糖尿病危險因子之相關研究

Peripheral Leukocyte Counts and Genetic Variations of CYP2J2 and ABCA1 Genes in Association with Coronary Artery Disease and Risk Factors of Type 2 Diabetes Mellitus

蔡朝仁(Jack Chaur-Ren Tsai)

指導教授 ： 許勝雄

高雄醫學大學/醫學院/醫學研究所/博士(2008年)

https://doi.org/10.6832/KMU.2008.00035

摘要

中 文 摘 要
國人的主要死亡原因之一為心臟血管疾病及腦血管疾病。心臟血管疾病或腦血管疾病，從致病機轉的角度分析，與慢性次臨床性發炎及脂肪細胞激素作用有所關聯。代謝症候群視為多重代謝障礙群集發生在同一人身上，代謝症候群有較高之大小血管疾病之發生率及死亡率，但臨床報告上仍與多個因素有相關。研究指出週邊血液白血球數目與冠狀動脈嚴重程度，心臟血管疾病與腦血管疾病的死亡率等皆有相關，而且這些相關白血球數目在正常範圍內就可以發現其統計上的意義。顯示週邊血液白血球數目，的確是缺血性心臟病的一個重要危險因子。週邊血液的白血球包含有多型核白血球、單核球、淋巴球和其他白血球等組成。每一種白血球都有其特殊之抗發炎及免疫的功能，另外也有證據指出，各類的白血球在動脈硬化的慢性發炎中也有其扮演的角色。由於過去研究著重於總白血球數目與代謝症候群和動脈硬化等疾病之相關研究。但是在白血球或各分類白血球與動脈硬化的病理機轉仍不甚清楚，而且文獻上對於分析各分類白血球與缺血性動脈硬化疾病的報告仍然是相當的少。
有相當多之研究報告指出，脂肪細胞所分泌的細胞激素在調整胰島素敏感度的過程中，以及在引起心臟血管疾病，胰島素阻抗性、糖尿病、血脂不良、發炎、動脈硬化的致病機轉中扮演著重要的角色。然而脂肪細胞誘導胰島素阻抗性的機轉、以及脂肪細胞激素在糖尿病的致病成因仍然存在著許多的未知。
因此本研究假設1) 代謝症候群與國人缺血性冠狀動脈疾病有關，可以早期預測缺血性冠狀動脈疾病之發生。2)週邊血液白血球如各分類白血球與代謝症候群，及各組成成分和缺血性動脈硬化的血管疾病有關聯。3) 脂肪細胞激素與國人代謝症候群及心臟血管疾病之關係密切。
本研究乃針對假設，進行一橫切面相關性研究觀察，研究結果發現：
1. 冠狀動脈疾病很難早期診斷，病人是否合併代謝症候群不會影響冠狀動脈疾病發生率，但是國人糖尿病合併冠狀動脈疾病與白蛋白尿是否發生有關。
2. 週邊血液總白血球、中性球、單核球、及淋巴球數目在糖尿病合併心血管疾病病人有較無心血管疾病者顯著增加。
3. 週邊血液總白血球、中性球、單核球、及淋巴球數目與代謝症候群之血壓、血糖、血脂、及肥胖有關聯性。
4. 週邊血液總白血球、中性球、單核球、及淋巴球數目及代謝症候群與心臟血管疾病發生有密切關聯。
5. 前瞻性觀察研究更發現基礎週邊血液總白血球、中性球、單核球、及淋巴球數目及中性球與淋巴球的比例與糖尿病在4年內是否發生心臟血管疾病有關，為心臟血管疾病發生之危險因子。
6. 在基因方面，發現CYP2J2基因多型性變化與年齡層小於等於65歲與吸菸者對心臟血管疾病有顯著之關連。而ABCA 1 R219K多型性變化與心臟血管疾病與脂質代謝的情形，並沒有相關性。這樣的結果也發現在日本與美國最近的研究成果。
因此，研究之結果將可對冠狀動脈疾病之可能遺傳因素及機轉有進一步之探討，提供預防及治療冠狀動脈疾病之基礎研究資料。

關鍵字

動脈硬化 ； 發炎 ； 冠狀動脈疾病 ； 分子生物學 ； 傳統危險因子 ； 基因變異危險因子 ； 生化指標危險因子 ； 三磷酸苷酸轉運結合匣 ； 細胞色素酶P450 ； 白血球 ； 中性球 ； 單核球 ； 淋巴球 ； 基因多型性 ； 代謝症候群

並列摘要

Abstract
At the beginning of the 21st century, cardiovascular disease accounts for nearly half of all death in the developed world, it is the top one that ranks in the mortality in the western countries. In Taiwan, it ranks the number two in the mortality rate in 2004. By 2020, it is predicted that cardiovascular disease will claim 25 million lives annually and that coronary artery disease (CAD) will surpass infectious disease as the world’s number one leading cause of death and disability. As the trend is spreading and shifting to the developing countries. Specially in Taiwan, it is a red light to warn us to try every effort to combat this challenge of cardiovascular disease and to prevent it becoming worse.
There is increasing evidences that subclinical inflammation, metabolic syndrome, and adipocytokines play a central role in cardiovascular disease, obesity, glucose intolerance, type 2 diabetes mellitus (T2DM), and metabolic syndrome. The traditional risk factors are often congregated in a individual as metabolic syndrome, such as hyperstension, hyperglycemia, dyslipidemia, and obesity, and these risk factors make the atherosclerotic change to become worse and even ruptured of the blood vessels. Subjects with metabolic syndrome are known to have increased risk of cardiovascular disease, while the role of metabolic syndrome in the prediction of ischemic coronary artery disease still inconclusive.
There is a significant positive association between the white blood cells counts with the severity of carotid atherosclerosis, cardiovascular disease, and mortality from coronary heart and cerebrovascular diseases even within the normal range. The relationship between leukocyte counts and ischemic vascular diseases has been observed in prospective and retrospective cohort studies, as well as in case-control studies, and persists after adjustment for multiple risk factors, including smoking. There are so many abundant evidences that relative leukocytosis associated with high blood pressure, obesity, high serum triglycerides, and metabolic syndrome (MetS). Thus, there is a reason to believe that leukocyte is not simply a marker of chronic inflammation, but directly contributes to the pathogenesis of MetS and atherosclerosis.
The peripheral circulating white cells compose of polymorphonuclear cells, monocytes and lymphocytes, each cell possess unique biological function and contributes to inflammation and immune response. There are evidences indicate that all the differential white cells involved in the pathogenesis of chronic inflammation as the genesis of atherosclerosis. The causal relevance of the association between peripheral leukocyte and MetS or atherosclerosis, however, remains uncertain because it is not clear to what extent the association of the total or subtypes of leukocyte counts with atherosclerosis risk merely reflects the impacts of established risk factors, the extent of existing atherosclerosis, or both and relative few studies have examined counts of specific types of leukocyte in association with specific components of MetS and atherosclerosis.
Cytochrome P450 Epoxygenase (CYP 2J2) was found to influence the risk of the coronary artery disease. The procedures depend upon the CYP 2J2 gene expression which is relative to the productions of epoxyeicosatrienoic acid (EETs) and have been found the functions of anti-inflammation, anti-thrombotic, anti-oxidative, anti-apoptosistic effects and dilation of smooth muscle cells. There is also well known that the inflammation culprit is the lipoprotein metabolisms and genetic variations in gene regulating lipid metabolism affects the plasma lipid levels and correlated to the risk of cardiovascular disease. ATP-binding cassette transporter 1 (ABCA 1) have shown to affect the plasma HDL-C level. The contribution to us is promoting the “Efflux” of LDL-C from the intracellular and peripheral tissue and macrophage to apolipoprotein receptor and secretion with bile outside the human body.
The rationale of the present studies were 1) the components of metabolic syndrome are related to the ischemic coronary artery disease could be the indicator of presence of coronary artery disease. 2) the compartments of peripheral leukocyte, especially neutrophil, lymphocyte, and monocyte counts are related to the components of MetS and atherosclerotic diseases. 3) The percentage (%) of lymphocytes is the accessible prognosis maker in patients with CABG. 4) Genetic variations of CYP 2J2 and ABCA1 genes are related to the components of metabolic syndrome and cardiovascular disease. To clarify these, we conducted a cross-sectional observational study in Chinese with type 2 diabetes mellitus to observe the factors of chronic inflammation in the association with ischemic cardiovascular disease in a regional hospital.
Subjects with T2DM who enrolled in a diabetes disease management program were studied. The definition and criteria of MetS we used were modified from those outlined by the criteria of WHO and NCEP-ATP III.
The major findings are:
1) A considerable proportion of T2DM patients have silent CAD. A diabetic patient with incipient or overt nephropathy should be examined for the presence of CAD. The definition of metabolic syndrome may be modified for early detection of CAD in patients with T2DM.
2) Peripheral total and differential leukocyte counts are related to the risk of ischemic cardiovascular disease in patients with type 2 diabetes mellitus.
3) Peripheral total and differential leukocyte counts are related to the componenets of metabolic syndrome.
4) Peripheral toal and differential leukocyte counts are associated with risk of ischemic cardiovascular disease .
5) Peripheral total and differential leukocyte counts are related to the mortality of patients receiving coronary artery bypass surgery.
6) Genetic variations of CYP2J2 gene is associated with cardiovascular diseases in the age less than 65-year-old and smoking patients are increased the risk of the CAD.
In Conclusions：Our results show that the silent CAD in T2DM patients, the micro/macro albuminuria is the risk factor. And metabolic syndrome, peripheral total and differential leukocyte counts and leukocytes/lymphocytes ratio in T2DM patients and genetic variations of CYP 2J2 genetic polymorphisms in the age less than 65-year-old and smoking patients are increased the risk of cardiovascular disease. But the ABCA1 R219 genetic polymorphisms didn’t relate to the plasma HDL-C levels and severity of CAD in our study and the same result as Japanese’s.

並列關鍵字

Atherosclerosis ； Inflammation ； Coronary Artery Disease ； Molecular Biology ； Traditional Risk Factors ； Genetic Variations Risk Factors ； Biomarkers Risk Factor ； ABCA1s ； Cytochrome P450 Epoxygenase，CYP 2J2 ； White Blood Cell，WBC ； Neutrophil ； Monocyte ； Lymphocyte ； Genetic Polymorphism ； Metabolic Syndrome

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