PPARγ、NFKB1、NFKBIA基因多形性與缺血性中風之相關研究

Association of the peroxisome proliferator-activated receptor gamma、nuclear factor kappa b one、nuclear factor kappa b inhibitor alpha gene polymorphisms with ischemic stroke

邱惠雯(Hui-Wen Chiu)

指導教授 ： 邱弘毅

臺北醫學大學/公共衛生暨營養學院/公共衛生學研究所/碩士(2010年)

https://doi.org/10.6831/TMU.2010.00036

摘要

腦血管疾病是台灣十大死因的第三位，其中有70％為缺血性中風。缺血性中風的發生是因為血管內的血栓流經狹窄的腦血管中，阻塞了某部分腦細胞的血流，使腦細胞造成缺氧性壞死。缺血性中風中最主要的危險因子之一就是動脈粥狀硬化，動脈粥狀硬化不僅會造成血管內徑變窄，影響血流順暢，其粥狀硬化的斑塊也可能脫落形成血栓而阻塞腦部血流。過氧化體增生活化受體γ(peroxisome proliferator-activated receptorγ, PPARγ)在動脈粥狀硬化形成過程中扮演重要的角色，包括血管的重建、脂肪斑的形成、發炎反應以及血栓的形成等等的過程。另外，核因子κB (nuclear factor kappa b,NFκB)在發炎反應中扮演重要的轉譯因子，亦調控了許多誘發動脈硬化損傷相關的基因，例如：腫瘤壞死因子α(TNF-α)、單核球趨化蛋白-1 (MCP-1) 、介白素(IL-β)、血管黏附分子，因此在動脈粥狀硬化形成過程中，NFκB亦是一關鍵的因素。本研究目的為探討PPARγ、NFKB1、NFKBIA基因多形性以及傳統危險因子對缺血性中風的獨立與交互作用。

研究對象包括977位缺血性中風患者與977位經年齡、性別配對的對照族群。資料收集包括利用結構式問卷經標準化流程收集基本人口學、相關危險因子與疾病史等資料，以及利用禁食八小時靜脈血測量相關血液生化值資料。基因型的判定是使用聚合酶連鎖反應(polymerase chain reaction, PCR)與限制片段長度多形性方法(restriction fragment length polymorphism, RFLP)。使用邏輯斯迴歸模式分析PPARγ、NFKB1、NFKBIA基因多形性與缺血性中風的關係。

結果顯示抽菸、飲酒、高血壓、糖尿病、高血脂症、腹部肥胖等危險因子會增加罹患缺血性中風的風險。基因型部分的分析發現，PPARγC-681G、C-2821T基因多形性與缺血性中風的發生有相關性。相較於CC基因型，PPARγC-681G攜帶G對偶基因者有1.23倍的風險罹患缺血性中風；PPARγC-2821T攜帶C對偶基因者相較於TT基因型者有1.30倍的風險罹患缺血性中風。在調整年齡、性別與教育程度後，高血壓與PPARγC-681G、C-2821T對罹患缺血性中風的危險性存在加成協同作用的關係，而糖尿病與PPARγC-681G、C-2821T則是存在累乘協同作用，且達統計上顯著水準。再更進一步調整缺血性中風傳統危險因子之後，此趨勢仍然存在。而糖尿病與NFKB1 -94 ins/del對罹患缺血性中風的危險性存在累乘協同作用的關係。此外，PPARγC-2821T與NFKB1 -94 ins/del基因合併分析發現，在糖尿病的分層下，隨著攜帶PPARγC-2821T與NFKB1 -94ins/del危險基因數目的增加其罹患缺血性中風的危險性也隨之增加，且調整年齡、性別、教育程度與傳統危險因子後均達統計上顯著水準。

總結以上，本篇研究發現PPARγ基因多形性與缺血性中風的發生有相關性，而其風險與糖尿病存在累乘協同效應，而與高血壓存在加成協同效應。NFKB1 -94 ins/del與糖尿病則是對罹患缺血性中風的危險性存在累乘協同作用的關係。

關鍵字

過氧化體增生活化受體γ ； 核因子κB

並列摘要

Stroke is the third leading cause of death in Taiwan in 2008 and the major subtype of stroke is ischemic stroke. Atherosclerosis is the most important risk factor of ischemic stroke. The pathology of atherosclerosis is including inflammation, cell adhesion, endothelial dysfunction, thrombosis and platelets function.According to recent studies that peroxisome proliferator-activated receptor γ (PPARγ) modulate numerous cellular processes contributing to atherosclerosis. PPARγ was reported to involve in endothelia dysfunction, leucocyte chemotaxis and foam cell formation, plaque strbility and rupture. And the other important factor that influence atherosclerosis is nucluear factor kappa b (NFκB) which controls the transcription of many genes with an established role in atherosclerosis, such as cytokines, chemokines, adhesion molecules, acute phase proteins, regulators of apoptosis, and cell proliferation.

In order to examine this hypothesis, we investigated the relationship between gene polymorphisms of PPARγ, NFKB1, NFKBIA and the risk of developing ischemic stroke.

977 ischemic stroke patients and 977 controls were recruited in this study. 977 ischemic patients wrer reciuted from the department of neurology of Chi-Mei, Lotung Poh-Ai, Wan-Fang and TMU hospitals in Taiwan. 977 Stroke-free subjects from the regular health examination in Shin-Kong WHS Memories, TMU and Wan-Fang hospitals in Taipei were controls. Cases and controls were frequency matched by age and sex. We genotyped two SNPs of PPARγ (C-681G and C-2821T), one SNPs of NFKB1 (-94ins/del) and two SNPs of NFKBIA (rs696 and -826C/T) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. We collected conventional vascular risk factors and disease history from all subjects by trained research assistants using a questionnaire.Fasting glucose, lipid profile, CRP, and uric acid were from routine biochemistry tests. Logistic regression model was used to estimate the odds ratio (OR) and 95% confidence interval (CI).

Study subjects with the G allele of C-681G or C allele of C-2821T significantly increased the risk of ischemic stroke (OR=1.23, 95% CI : 1.04-1.50 and OR=1.30, 95% CI : 1.09-1.56, respectively). Moreover, we found the significant joint effect between PPARγ C-681G, C-2821T and hypertension, diabetes mellitus on the risk of ischemic stroke and also found the same effect between NFKB1 -94ins/del and diabetes mellitus. And combine C-2821T and NFKB1 -94ins/del, our results suggest that with diabetes mellitus, the risk of ischemic stroke will increase with the risk allele number you have.

In conclusion, our results provide the evidence of association between PPARγ gene polymorphisms and ischemic stroke in a Taiwanese population. Both C-681G G allele and C-2821T C allele of PPARγ gene significantly increased the risk of ischemic stroke. We also found a strong synergistic effect between the PPARγ, NFKB1gene and diabetes mellitus on the risk of ischemic stroke. Furthermore, our results indicated that there was interaction between the PPARγ and NFKB1 genes in predicting the risk of ischemic stroke.

並列關鍵字

PPARγ ； NFKB1 ； NFKBIA

參考文獻

GuangWang, Z. Zhang, et al. (2008). "Antidiabetic rosiglitazone reduces soluble intercellular adhesion molecule-1 level in type 2 diabetic patients with coronary artery disease." PPAR Research 2008.

行政院衛生署 2009統計年報

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