台灣族群中單核細胞趨化蛋白-1及 類胰島素生長因-1的基因多型性 與冠狀動脈疾病的相關性

In Taiwan the polymorphisms of MCP-1/ CCR-2 and IGF-1/IGFBP-3 associated with coronary artery disease

林秀玲(Hsiu-Ling Lin)

指導教授 ： 謝易修 ； 翁國昌

中山醫學大學/醫學院/生化暨生物科技研究所/博士(2013年)

https://doi.org/10.6834/CSMU.2013.00002

摘要

冠狀動脈疾病(Coronary artery disease，CAD)蟬聯近三年台灣十大死因的第二名，而造成冠狀動脈疾病的主要原因是動脈粥狀硬化(atherosclerosis)。這是一種慢性發炎過程，目前的研究發現，動脈粥狀硬化形成的過程和各種細胞激素(cytokines)與其接受體的活化有關，例如單核細胞趨化蛋白-1(Monocyte chemoattractant protein-1; MCP-1)、介白素-6 (Interleukin -6; IL-6)、介白素-1 beta (IL-1 beta)、類胰島素生長因子(Insulin-like growth factor-1; IGF-1) 以及其接受體IGFBP-3等，都曾被報導參與動脈粥狀硬化形成的過程。先前研究已證實MCP-1的蛋白表現量與冠狀動脈疾病的易感性以及臨床病理表現有相關；IGF-1 以及其接受體IGFBP-3的血清濃度大量表現可能會提高罹患冠狀動脈疾病的機率，因此，IGF-1相關的訊息傳遞因子被認為是新的冠狀動脈疾病危險因子之一。此外，近年來認為基因多型性(Gene polymorphisms)可以藉由影響不同基因的蛋白表現量進而改變許多疾病的易感性。因此，本篇研究主要希望探討在台灣族群中MCP-1與其接受體CCR-2以及IGF-1與其接受體IGFBP-3的基因多型性和冠狀動脈疾病之間的相關性。本實驗收集216位未罹患冠狀動脈疾病之對照組與392位罹患冠狀動脈疾病之實驗組，採用聚合酶連鎖反應-限制酶片段長度多型性 (polymerase chain reaction- restriction fragment length polymorphism，PCR-RFLP) 以及即時定量聚合酶連鎖反應(Real-time polymerase reaction chain) 分析實驗對象的MCP-1 -2518G/A基因型、CCR-2-V64I基因型、IGF-1 +1770基因型、IGF-1 +6093基因型以及IGFBP-3 -202基因型的分布，，探討各基因型分布與冠狀動脈疾病罹病率的關係。結果顯示MCP-1 -2518G/A基因型分布與冠狀動脈疾病的易感性有顯著相關性；其中，帶有G/G同型合子(OR =1.629; 95% CI = 1.003–2.644)或是至少帶有一個G等位基因(OR = 1.511; 95% CI = 1.006–2.270)的個體比帶有A/A同型合子的個體有更高的罹患冠狀動脈疾病風險。帶有至少一個A等位基因之CCR-2-V64I基因型也會顯著提升個體罹患冠狀動脈疾病的機率。在冠狀動脈疾病組別(CAD group)中，帶有G 等位基因的MCP-1 -2518基因型比較容易罹患心房顫動(atrial fibrillation，AF) (OR = 4.254; p<0.05)。而IGF-1 +1770 T/C和 C/C 基因型及 IGF+6093 G/A和A/A基因型患有冠狀動脈疾病的病人，會有顯著增高的收縮壓(p = 0.025; 0.023)以及舒張壓(p = 0.004; 0.006)。就IGF-1 +6093來看：含有基因型IGF-1 +6093 G/A和A/A的患有冠狀動脈疾病的病人罹患鬱血性心臟衰竭(congestive heart failure，CHF)的機率比含有基因型IGF-1 +6093 G/G的患有冠狀動脈疾病的病人提高1.695 倍。另外IGFBP-3 -202位置上含有至少一個突變的等位基因C的CAD組研究對象，如A/C或是 C/C，其罹患中風的風險會比在IGFBP-3 -202位置上含有A/A同型合子的CAD組研究對象降低 0.459倍 (95%, CI = 0.222 to 0.947)。
因此，我們發現在台灣人的族群中，MCP-1 -2518G/A基因型以及CCR-2-V64I基因型在冠狀動脈疾病的易感性中扮演著重要角色；而帶有G 等位基因的MCP-1 -2518G/A基因型在罹患冠狀動脈疾病的患者中可能會對心房顫動的病程發展扮演重要角色。而IGF-1 +1770 與增加冠狀動脈疾病的罹病率有顯著相關，在患有冠狀動脈疾病的病人中，IGF-1 +1770 以及IGF-1 +6093主要作用於血壓的改變而進一步在冠狀動脈疾病的形成過程中扮演一定的角色。而IGFBP-3-202在患有冠狀動脈疾病的病人中同時罹患中風的風險可能降低。之後若能更瞭解MCP-1以及其主要接受體CCR-2在冠狀動脈疾病中所扮演的角色以及更進一步了解IGF-1與 IGFBP-3在心血管方面詳細的作用機制後，MCP-/CCR-2或是IGF-1/ IGFBP-3可能可以作為新興的治療標的或者作為診斷冠狀動脈疾病的利器。

關鍵字

冠狀動脈疾病 ； 基因多行性 ； 細胞趨化蛋白-1 ； 類胰島素生長因-1

並列摘要

Coronary artery disease (CAD) was the second leading cause of death for the past three years in Taiwan. The major cause of CAD is coronary artery atherosclerosis, a chronic inflammatory disease. Prior research has demonstrated the association between cytokines and their receptors, such as monocyte chemoattractant protein-1 (MCP-1), Interleukin -6 (IL-6), and Interleukin -1 beta (IL-1 beta), Insulin-like growth factor-I (IGF-I), and Insulin-like growth factor binding protein III(IGFBP-3) which accumulate within the vessel walls of the coronary arteries during the initial phase of atherosclerosis. Previous studies suggested that increased serum MCP-1 levels associated with risk of CAD or other atherosclerotic vascular diseases. In addition, elevated circulating IGF-I and IGFBP-3 levels may contribute to increased CAD risk, Moreover, recent studies have demonstrated that polymorphisms in a gene influences its protein expression which in turn change the susceptibility to many diseases. Therefore, this study investigated the relationships among MCP-1, CCR-2, IGF-1 and IGFBP-3 genetic polymorphisms and CAD in the Taiwanese population. There 392 non-CAD controls and 216 patients with CAD, were recruited in this study and subjected to polymerase chain reaction -restriction fragment length polymorphism (PCR–RFLP) and real- time polymerase chain to evaluate the effects of MCP-12518G/A, CCR2-V64I, IGF-1+1770, IGF-1+6930 and IGFBP-3 -200 polymorphic variants on CAD. Results indicated a significant association between MCP-1 -2548 gene polymorphism and susceptibility to CAD. GG genotypes (OR =1.629; 95 % CI = 1.003–2.644), or individuals with at least one G allele (OR = 1.511; 95 % CI = 1.006–2.270), had a higher risk of CAD as compared with AA genotypes. And least one A allele of the V64I CCR2 gene polymorphism had significantly increased risk of CAD (OR = 1.486; 95 % CI = 1.026–2.154). G allele in MCP-1-2518 might contribute to higher prevalence of atrial fibrillation in CAD patients (OR = 4.254; p<0.05), it was also shown that a significant association with the IGF-I +1770 gene polymorphism and increased risk of CAD. Furthermore, CAD patients between with a minimum of one mutant C allele in IGF-I +1770 and one mutant A allele in IGF + 6093 gene polymorphism had significantly high blood pressure including systolic blood pressure (SBP; P = 0.025; 0.023) and diastolic blood pressure (DBP; P = 0.004; 0.006). What is more, CAD patients with IGF-I +6093 G/A gene polymorphism had a 1.695-fold elevated risk of congestive heart failure (CHF), compared to CAD patients with the G/G homozygote. Another of the IGFBP-3 −202 genetic polymorphism for the CAD group with a minimum of one mutant C allele, A/C or C/C, had a 0.459-fold (95%, CI = 0.222 to 0.947) significantly decreased risk of stroke, compared to A/A homozygote patients. In conclusion, MCP-1-2518G and CCR-2 64I gene polymorphisms represent important factors in determining susceptibility to CAD, and the contribution of MCP-1-2518 G allele could be through effects on AF in CAD patients. Polymorphism of IGF-I +1770 was associated with increased CAD risk. In CAD patients, the contributions of IGF-I +1770 and +6093 could be through the effect on blood pressure in CAD patients. The polymorphism of IGFBP-3 −202 may have an association with decreased stroke risk in CAD patients. With further investigation, confirm the role of MCP-1/CCR-2 and the regulatory mechanism of IGFI and IGFBP-3 in CAD might be potential candidates for the new therapy and practicable diagnosis of CAD.

並列關鍵字

MCP-1 ； CCR-2 ； IGF-1 ； IGFBP-3 ； polymorphisms

參考文獻

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