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標題: | 風濕疾病基因與流行病學之研究 The genetic and epidemiology study of the rheumatic diseases |
作者: | Hsin-Hui Yu 俞欣慧 |
指導教授: | 江伯倫(Bor-Luen Chiang) |
關鍵字: | 紅斑性狼瘡,幼年型類風濕性關節炎,自體免疫,基因,高血脂症,statin, systemic lupus erythematous,juvenile idiopathic arthritis,autoimmune,gene,hyperlipidemia,statin, |
出版年 : | 2016 |
學位: | 博士 |
摘要: | 兒童風濕疾病以紅斑性狼瘡(systemic lupus erythematosus,簡稱SLE)與幼年型特異性關節炎(juvenile idiopathic arthritis,簡稱JIA)最常見且最重要,紅斑性狼瘡臨床表現多變化,幾乎全身器官都會受影響,以皮膚、黏膜、腎炎、血液、關節、神經病變、漿膜組織發炎為特徵。幼年型特異性關節炎是兒童最常見的關節炎,定義為16歲以下孩童之慢性關節炎超過6星期,JIA分成七個分型:系統型、少關節型、類風濕因子陰性多關節型、類風濕因子陽性多關節型、肌腱附著點相關性關節炎、乾癬型、與未分類型。自體免疫的致病機轉包括基因與環境因素造成免疫失調,紅斑性狼瘡之免疫失調包括過度細胞凋亡呈現核抗原活化抗原呈現細胞,過度活化自體反應T細胞與B細胞產生大量自體抗體,尤其是抗核抗體與抗DNA抗體為疾病特徵、另外合併補體低下與免疫複合體清除不良,產生組織發炎與器官傷害。在幼年型特異性關節炎之致病幾轉方面,對關節抗原呈自體反應之T細胞被活化與發炎性細胞激素上升,造成關節滑液囊發炎腫脹,關節炎的晚期才可見到軟骨與硬骨破壞,關節外則以眼睛之葡萄膜炎為主要疾病表現;而系統型關節炎被認為是自體發炎疾病,可見吞噬球與中性球大量活化與發炎性細胞激素上升,除關節炎外,也產生全身系統性發炎反應(發燒、皮疹、肝脾腫大)。
我們進行兒童風濕疾病之基因多型性的研究,我們提出假說:TH1與TH2免疫反應相關之細胞激素基因與SLE發病或狼瘡腎炎之發生有關,我們選取參與TH1與TH2免疫反應的細胞激素基因包括IL12、IFNG、IL18、IL4、IL5、IL10、IL13和TH2反應之重要轉錄因子signal transducer and activator of transcription 6, IL-4 induced (STAT6)基因的核苷酸變異(single nucleotide polymorphism簡稱SNP),我們收錄110位紅斑性狼瘡病患與138位健康受試者,利用GenomeLab SNPstream 基因型分析平台分析位在8個細胞激素基因上的20個SNP,我們研究的結果發現IL4與STAT6基因交互作用與SLE發病顯著相關,IL18基因多型性則與狼瘡性腎炎相關,推測TH1與TH2參與狼瘡發病之不同時期或不同表現,尚需進一步大規模研究確認基因功能變異造成之疾病機轉,釐清細胞激素基因變異對於細胞激素與免疫反應不平衡、抗體製造的影響,對於SLE致病機轉會更有所貢獻。 過去的研究顯示statin類藥物具降血脂與抗發炎之能力,而狼瘡病人有高比例合併高血脂症、動脈粥狀硬化與心血管疾病,而心血管疾病是紅斑性狼瘡病人重要合併症與造成死亡的原因,過去的隨機對照臨床試驗結果顯示狼瘡病人接受降血脂藥物statin治療一到三年可降低發炎指標C反應蛋白,但並無顯著心血管疾病保護效果,我們推測可能與觀察期間太短且病人數量低有關,我們提出假說statin使用可減少紅斑性狼瘡病人合併高血脂症者之死亡率(mortality)或心血管疾病併發症。利用1997到2008年健保資料庫針對SLE進行全國性世代研究長達12年之追蹤,我們觀察4095位紅斑性狼瘡病人合併高血脂症之患者以Cox proportional hazard model多變項分析,發現statin使用尤其是高劑量statin (>365 cumulative defined daily dose 簡稱cDDD)可顯著減少死亡之風險比(hazard ratio簡稱HR) 0.44 (95%信賴區間CI 0.32-0.60)、心血管疾病 (HR 0.20, 95%CI 0.13-0.31)、腦血管疾病(HR 0.14, 95%CI 0.08-0.25)、末期腎病變(HR 0.22, 95%CI 0.16-0.29)的風險,保護效果與statin劑量有顯著相關,此外抗瘧疾藥物hydroxychloroquine與statin合併使用顯著減少死亡(HR 0.38, 95%CI 0.28-0.53),statin的保護效果除了在兒童(非心血管疾病高風險族群)與平均住院次數每年小於0.7次(輕度病患)的次族群不顯著之外,在各種分層分析下結果是一致的,本研究結果需醫院資料驗證假說。 我們第三個研究目的是找出台灣為幼年型特異性關節炎與JIA相關葡萄膜炎之疾病特徵,世界各國報告JIA的之發生率(incidence)為每年每十萬人口2.6至23人,盛行率(prevalence)為每十萬人口15.7至140人,發生率與盛行率差異很大與疾病本身的多樣性與總族不同有關,目前缺乏亞洲或華人之大規模流行病學研究,我們利用健保資料庫在1999年到2009年間總共有2636位JIA之16歲以下兒童納入研究,JIA平均年發生率為每十萬孩童4.93人,盛行率為每十萬孩童33.8人,4.7%JIA病患併發葡萄膜炎(uveitis),JIA相關葡萄膜炎之年發生率10萬孩童0.25人且有緩慢上升的趨勢,研究結論台灣為JIA低發生率與盛行率之國家,疾病特色為具有高比例的男性與肌腱附著點相關性關節炎(ERA),另外ERA與葡萄膜炎有高度相關性,葡萄膜炎在關節炎之前發生為葡萄膜炎有併發白內障與青光眼之危險因子,並無JIA葡萄膜炎並無失明個案發生。希望我們的研究可落實JIA葡萄膜炎之篩檢與追蹤,並提供眼科醫師對於不明原因之葡萄膜炎應長期追蹤之依據。 上述研究讓我們對於兒童風濕疾病有本土資料與更進一步的瞭解,未來需要大規模研究來了解華人自體免疫疾病之基因變異性,並進一步研究基因表現改變造成免疫細胞功能改變。未來將用醫院資料確認statin使用是否在特定高風險族群(例如CRP升高之病患)可減緩發炎、疾病活性、動脈粥狀硬化、與心血管疾病之發生;藥物機轉方面研究statin與抗瘧疾藥物hydroxychloroquine對於抗發炎與心血管保護之加成作用,期望我們的研究可為自體免疫疾病治療提供新的方向。 Systemic lupus erythematous (SLE) and juvenile idiopathic arthritis (JIA) are the most important autoimmune diseases in children. The multifactorial etiology with interaction of genetic factors and environmental factors is essential in the pathogenesis. SLE is characterized by grossly immune dysregulation including nuclear antigen release due to abnormal apoptosis, over-reactive antigen presenting cells with type I interferon production, polyclonal T and B cells activation, autoantibodies overproduction, impaired immune complex clearance, then inflammation and damage in multiple organ systems. JIA collectively refers to a group of chronic arthritis of at least six weeks duration in children or adolescents under the age of 16. Seven subtypes of JIA are defined as systemic JIA, oligoarticular JIA, rheumatoid factor (RF)-negative polyarticular JIA, RF-positive polyarticular JIA, enthesitis-related arthritis (ERA), psoriatic arthritis, and undifferentiated JIA. Auto-reactive T cells activation in response to synovial antigen exposure and inflammatory response involved the synovial tissues of joints (arthritis), and less frequently the eye (uveitis), are the key features in the pathogenesis of JIA. On the other hand, systemic JIA is considered to be an auto-inflammatory disease. Highly activated phagocytes and neutrophils in innate immune system cause systemic inflammatory symptoms of fever, skin rash, hepato-splenomegaly, and arthritis. We hypothesized that the single nucleotide polymorphisms (SNPs) of cytokine genes contributed to the development of SLE. We investigated 20 SNPs derived from the 8 genes encoding TH1 and TH2 cytokines: IL12, IFNG, IL18, IL4, IL5, IL10, IL13 and a transcriptional factor related to the TH2 pathway (signal transducer and activator of transcription 6, interleukin-4 induced [STAT6]) in 110 SLE patients and 138 healthy controls, using GenomeLab SNPstream platform for genotyping. Our results showed that IL4 haplotype, and gene–gene interaction between IL4 and STAT6 conferred a significantly increased risk for SLE. IL18 gene polymorphism carried increased risk for lupus nephritis. Research has shown that statins have anti-inflammatory and lipid-lowering effect. Dyslipidemia, atherosclerosis, cardiovascular diseases are common in patients with SLE. Cardiovascular diseases have emerged as a major cause of morbidity and mortality in patients with SLE. We hypothesized that statin therapy could reduce mortality and cardiovascular diseases in patients with SLE and hyperlipidemia. We identified 4095 patients with SLE and hyperlipidemia from the Taiwan National Health Insurance Research Database (NHIRD) from year 1997 to 2008. We compared the risk of all-cause mortality, coronary artery diseases, cerebrovascular disease and end-stage renal disease among SLE patients with and without using lipid-lowering medications in Cox regression hazard analysis. We observed that statins use in SLE patients with hyperlipidemia was associated with reduced mortality and morbidity. High dose statins users had more significant reduced risk of outcomes, which could be explained by the dose-dependently lipid-lowering and anti-inflammatory properties of statins. The additive effect of hydroxychloroquine and statins in reducing mortality was observed, and the mechanisms most likely involve the common effects of inflammation and lipid levels. On the other hand, the reported incidence and prevalence of JIA vary widely across the world. There has been no large-scale epidemiologic study involving long-term follow-up of JIA and JIA-associated uveitis in Asia. We identified 2636 cases of JIA from NHIRD from year 1999 to 2009. The average incidence of JIA and JIA-associated uveitis was 4.93 and 0.25 per 100,000 person-years, respectively. The average prevalence of JIA was 33.8 per 100,000 population. Higher percentage of males in patients with ERA and the strong association between ERA and uveitis are unique for children with JIA in Taiwan. Uveitis diagnosed before arthritis is an important risk factor for complications. The screening protocols of uveitis are not standardized among hospitals in Taiwan. This study may facilitate the optimization of guidelines for the screening and follow-up of JIA patients with uveitis in Taiwan. Further large-scale study with validation is required in SLE and JIA cohort to clarify whether genetic polymorphism leads to altered cytokine production and the involved inflammatory mechanism underlying the pathogenesis of autoimmune diseases. We will further explore the high-risk group beneficial for statin therapy (such as patients with elevated CRP), and the mechanism of statins and hydroxychloroquine in the process of atherosclerosis, inflammation and vascular protection. Advances in our understanding of the signaling pathway downstream endothelial dysfunction would lead to the development of novel targeted treatments for autoimmune diseases. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51148 |
DOI: | 10.6342/NTU201600166 |
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顯示於系所單位: | 臨床醫學研究所 |
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