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系統識別號 U0026-2310201716241500
論文名稱(中文) 台灣族群中單一核苷酸多形性與自體免疫關節疾病之疾病易感受性及疾病嚴重程度之關聯性研究
論文名稱(英文) Single-nucleotide polymorphisms associated with susceptibility and disease severity of autoimmune articular diseases in Taiwanese populations
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 106
學期 1
出版年 106
研究生(中文) 陳偉喬
研究生(英文) Wei-Chiao Chen
學號 S68011053
學位類別 博士
語文別 英文
論文頁數 93頁
口試委員 指導教授-黃金鼎
共同指導教授-張偉嶠
口試委員-賴明德
口試委員-張惠華
口試委員-魏正宗
口試委員-王紋璋
中文關鍵字 僵直性脊椎炎  類風溼性關節炎  單一核苷酸基因多形性  巴斯僵直性脊椎炎健康綜合評分 
英文關鍵字 Ankylosing spondylitis  Rheumatoid arthritis  Polymorphism  Bath AS Global (BAS-G)  PLD4  CSF2  rs657075  rs2841277  rs4672495 
學科別分類
中文摘要 人體之免疫系統在對抗有害抗原上扮演相當重要的角色,然而免疫系統的紊亂與失調則可能導致疾病的產生,例如自體免疫疾病。自體免疫疾病主要是由於免疫系統對於自身正常組織進行攻擊破壞而產生的疾病,到目前為止已有超過八十種以上的自體免疫疾病被發現。僵直性脊椎炎 (ankylosing spondylitis,縮寫AS) 與類風濕性關節炎 (rheumatoid arthritis,縮寫RA) 是自體免疫疾病中兩個較常見的發炎性關節疾病。僵直性脊椎炎是一種血清陰性脊椎關節病變的自體免疫疾病,其主要的發炎部位為脊椎與骶髂關節,而其他較常見的侵犯部位為周邊關節。雖然在過去的研究中已發現超過二十五個基因座區域與僵直性脊椎炎的發病相關,但是僵直性脊椎炎的致病成因仍然尚未被釐清。類風濕性關節炎是一種慢性發炎的自體免疫疾病,其發病過程中會伴隨著長期的慢性發炎及疼痛,進而對於發炎的關節造成破壞,嚴重時則可能導致手部正常功能的喪失。
之前以國外族群所進行的全基因組關聯研究 (genome-wide association studies,縮寫GWASs) 發現相當多與類風濕性關節炎相關的單一核苷酸多形性 (single-nucleotide polymorphisms,縮寫SNPs) 位點,其中有部分位點尚未在台灣族群中進行過探討。此外,過去有關自體免疫疾病的研究發現,某些自體免疫疾病間具有部分共同的相關基因。之前研究指出,類風濕性關節炎與其他的自體免疫疾病具有部分共同的易感受性基因,其中包含僵直性脊椎炎。因此我們想探討先前於日本族群中以全基因組關聯研究統合分析所得到與類風濕性關節炎相關的位點,是否與台灣族群中的僵直性脊椎炎具相關性。另外,我們也選擇了十五個在過去的全基因組關聯研究中分別與類風濕性關節炎和僵直性脊椎炎具有相關性的基因多形性位點,探討這些位點是否於台灣族群中與類風濕性關節炎具有相關性。
在僵直性脊椎炎的研究中,我們由中山醫學大學附設醫院納入了475名病例,並以台灣人體資料庫中所釋出的16,036名健康民眾作為對照組進行分析。雖然分析結果未發現與僵直性脊椎炎易感受性相關的位點,但我們發現,rs657075 (CSF2) 與巴斯僵直性脊椎炎健康綜合評分 (Bath Ankylosing Spondylitis Global,縮寫BAS-G) 之分數具相關性,攜帶rs657075 AA基因型的患者有較高的巴斯僵直性脊椎炎健康綜合評分數值。此相關性對性別、年齡及疾病持續時間進行校正後仍然顯著;另外,根據人類白血球抗原B27 (縮寫HLA-B27) 進行分組分析後,此相關性仍然顯著。利用生物資訊學研究方法,我們發現rs657075基因多形性會影響ACSL6基因的表現量。
另一方面,在類風濕性關節炎的研究中,我們於台中榮民總醫院納入334名病例,並仍以台灣人體資料庫中所釋出的16,036名健康民眾作為對照組進行分析。我們發現,相較於攜帶rs2841277 (PLD4) TT基因型者,攜帶rs2841277 C對偶基因型者 (CC與CT) 罹患類風濕性關節炎的風險較低 (勝算比 (OR) 為0.6,P值為3.0 x 10-6)。此外,我們發現,相較攜帶rs4672495 GT與TT基因型患者,攜帶rs4672495 GG基因型患者的疾病嚴重度較低 (勝算比為0.09,P值為5.6 x 10-3)。我們藉由生物資訊學研究方法發現rs2841277會影響LINC00638及AHNAK2基因的表現量,而rs4672495會影響B3GNT2基因的表現量。
因此總結所得之結果,我們的研究指出於日本族群中所得與類風濕性關節炎易感受性相關之單一核苷酸多形性位點rs657075 (CSF2),會與台灣族群中僵直性脊椎炎患者的巴斯僵直性脊椎炎健康綜合評分 (BSA-G) 之數值具有相關性。另一方面,我們的研究也驗證rs2841277 (PLD4) 於台灣族群中與類風濕性關節炎的易感受性具有相關性;另外也發現與僵直性脊椎炎相關之單一核苷酸多形性位點rs4672495,會與類風濕性關節炎的疾病嚴重程度具有相關性。
英文摘要 The immune system plays an essential part in the host defense against harmful antigens. Dysregulation of the immune system can result in disorders, such as autoimmune diseases. Autoimmune disorders arise from improper destruction of normal tissue by the immune system. There are more than eighty types of autoimmune diseases. The ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are two common inflammatory arthritis in autoimmune diseases. Ankylosing spondylitis is a systemic autoimmune disease mainly affecting the lumbar spine and sacroiliac joints, and exhibits peripheral inflammatory arthropathy. More than 25 loci have been identified as associated with AS. But, the cause of AS is still unclear. Rheumatoid arthritis is one of the most common autoimmune diseases, can lead to long-term joint damage, chronic pain, and loss of motor function in the hands. Many single-nucleotide polymorphisms (SNPs) were reported by genome-wide association studies (GWASs) of RA, but some of them have not been examined in a Taiwanese population. Previous studies reported that autoimmune diseases share many genetic factors. Accumulating evidences indicated that RA may share some common genetic factors with other autoimmune disorders, such as AS. Therefore, we examined if the RA susceptibility polymorphisms from GWAS meta-analysis are also associated with the pathogenesis of AS. On the other hand, for 15 SNPs reported in previous RA and AS GWASs, we investigated their association with RA in a Taiwanese population.
In the AS study, we enrolled 475 AS patients from Chung Shan Medical University Hospital and 16,036 healthy subjects from a Taiwanese biobank as controls. Although none of SNPs were associated with the susceptibility to AS, the AS disease index Bath AS Global (BAS-G) clinical phenotype was significantly correlated to the genotypes of rs657075 (CSF2). The significance remains after gender/age/disease duration adjustment and after group categorization by human leukocyte antigen-B 27 (HLA-B27) genotype. We further investigated the possible functions of rs657075 through bioinformatics approaches. Results revealed that polymorphism of rs657075 is able to influence the expression of acyl-CoA synthetase long-chain family member 6 (ACSL6). In the RA study, we investigated the association with RA in a Taiwanese population which based on 334 RA patients recruited from the Taichung Veterans General Hospital and 16,036 healthy subjects from the Taiwan Biobank (TWB) project. We observed that subjects having minor allele C at rs2841277 (phospholipase D family, member 4 (PLD4)) have lower susceptibility of RA, compare to those having genotype TT (Odd ratio (OR) = 0.6, p = 3.0 x 10-6). Among the RA patients, we observed that subjects having GG at rs4672495 have a lower proportion of severe RA, compared to other subjects (OR = 0.09, p = 5.6 x 10-3). Results of a bioinformatics approach showed that rs2841277 is able to influence expression of LINC00638 and AHNAK2 and rs4672495 is able to influence the expression of B3GNT2.
In summary, our study indicated that rs657075 (CSF2) is strongly associated with the AS disease index Bath AS Global (BAS-G) clinical phenotype. This study also replicated an association of rs2841277 with RA susceptibility and showed an AS-associated SNP, rs4672495, is associated with RA activity in the Taiwanese population.
論文目次 Abstract…………………………………………………………………………………………………………………I
中文摘要…………………………………………………………………………………………………………………IV
致謝…………………………………………………………………………………………………………………………VII
Contests……………………………………………………………………………………………………………IX
Contests of Tables…………………………………………………………………………………XII
Contests of Figures………………………………………………………………………………XV
Chapter 1. Introduction………………………………………………………………………………………………1
1.1 Autoimmune diseases……………………………………………………………………………………1
1.2 Ankylosing spondylitis (AS)………………………………………………………………2
1.3 Rheumatoid arthritis (RA) …………………………………………………………………4
1.4 Autoimmune diseases share genetic factors…………………………5
1.5 Purpose of study……………………………………………………………………………………………6
Chapter 2. Materials and Methods………………………………………………………………………8
2.1.1 Study subjects for ankylosing spondylitis study………………8
2.1.2 Study subjects for rheumatoid arthritis study……………………9
2.1.3 Study subjects for treatment response study………………………10
2.2 Candidate single-nucleotide polymorphisms (SNPs)………………10
2.3 DNA extraction…………………………………………………………………………………………………………11
2.4 Genotyping……………………………………………………………………………………………………………………11
2.5 SNP annotation data query……………………………………………………………………………12
2.6 Statistical analysis…………………………………………………………………………………………13
2.6.1 Statistical analysis for ankylosing spondylitis……………13
2.6.2 Statistical analysis for rheumatoid arthritis…………………14
2.6.3 Statistical analysis for treatment response study………15
Chapter 3. Results…………………………………………………………………………………………………………16
3.1.1 Sample characteristics for AS study……………………………………………16
3.1.2 Association between RA-associated polymorphisms and susceptibility to AS……………………………………………………………………………………………………16
3.1.3 rs657075 is associated with the disease activity index of AS……………………………………………………………………………………………………………………………17
3.1.4 Association between RA-associated polymorphisms and inflammatory biochemical parameters of AS……………………………………………17
3.1.5 Studies for tissue expression quantitative trail loci (eQTLs) of rs657075………………………………………………………………………………………………………18
3.2.1 Sample characteristics for RA study……………………………………………18
3.2.2 SNP rs2841277 is associated with RA susceptibility……19
3.2.3 SNP rs4672495 is associated with RA activity……………………20
3.2.4 Association of polymorphisms with autoantibodies…………21
3.2.5 Studies of tissue expression quantitative trait loci (eQTLs) of rs2841277 and rs4672495………………………………………………………………21
3.3.1 Sample characteristics of AS patients treated with biological agents……………………………………………………………………………………………………………21
3.3.2 Association of polymorphisms with treatment response of biological agents in AS patients……………………………………………………………22
3.3.3 Sample characteristics of RA patients treated with biological agents……………………………………………………………………………………………………………23
3.3.4 Association between polymorphisms and treatment response of biological agents in RA patients……………………………………23
3.3.5 SNP rs2841277 is associated with treatment response of TNF inhibitors in RA patients……………………………………………………………………24
Chapter 4 Discussion……………………………………………………………………………………………………26
Chapter 5 Conclusion……………………………………………………………………………………………………34
Chapter 6 Reference………………………………………………………………………………………………………35
Chapter 7 Tables and Figures………………………………………………………………………………49
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