血液多重抗藥性-1訊息核醣核酸、微型核醣核酸-27a以及-451之表現影響僵直性脊椎炎的發展與藥物療效

Expressions of Whole Blood Multi-Drug Resistance 1 mRNA, MicroRNA-27a, and -451 Affect Ankylosing Apondylitis Development and Therapeutic Efficacy of Drugs

林玟君(Wen-Chun Lin)

指導教授 ： 翁瑞宏

中山醫學大學/健康管理學院/公共衛生學系碩士班/碩士(2016年)

摘要

僵直性脊椎炎 (ankylosing spondylitis；AS) 是一種血清陰性脊椎關節病變 (seronegative spondyloarthropathy) 之自體免疫疾病。多重抗藥性 (multidrug resistance 1；MDR1) 基因之產物 – p-醣蛋白 (p-glycoprotein；P-gp) 為藥物進入標的部位的主要傳輸者之一，並且已知在自體免疫疾病之抗藥性中扮演關鍵的角色。進一步地，微型核醣核酸 (microRNAs；miRNAs)-27a與miR-451亦可能調節MDR1表現。已經觀察到僵直性脊椎炎病患相較於健康對照具有較低的miR-27a表現，miR-451在全身紅斑性狼瘡 (systemic lupus erythematosus) 與類風濕性關節炎 (rheumatoid arthritis) 患者中也被觀察到相較於健康對照具有較高的表現。然而，對於MDR1 mRNA、miR-27a和miR-451表現與僵直性脊椎炎之相關研究則是缺乏。因此，我們設計了一項以醫院為基礎的病例對照研究以評估MDR1 mRNA、miR-27a和miR-451表現對於僵直性脊椎炎發展之影響以及藥物療效。總計有150名僵直性脊椎炎病例與150名經由年齡以及性別配對的健康對照被納入本研究，利用即時定量聚合酶鏈鎖反應 (real-time polymerase chain reaction) 來測量血液中MDR1 mRNA、miR-27a與miR-451之表現。結果顯示，MDR1 mRNA高度表現是僵直性脊椎炎發生之危險因子 (vs. 低度表現; 危險對比值 [odds ratio, OR] = 2.45, 95%信賴區間 [confidence interval, C.I.] = 1.46-4.12)，而miR-27a高度表現是保護因子 (vs. 低度表現; OR = 0.44, 95% C.I. = 0.27-0.72)。進一步地，疾病調節抗風濕藥物 (disease-modifly antirheumatic drugs [DMARDs]; sulfasalazine) 的療效在具有MDR1 mRNA高度表現的僵直性脊椎炎患者是明顯較差的 (vs. 低度表現; OR = 5.14, 95% C.I. = 0.99-26.82)，而DMARDs的療效在具有miR-27a高度表現的患者是顯著較佳的 (vs. 低度表現; OR = 0.25, 95% C.I. = 0.06-0.97)。我們的結果建議，MDR1 mRNA與miR-27a表現有潛力成為僵直性脊椎炎的生物標記，而MDR1 mRNA表現量的分析將有助於預測使用DMARD的療效。

關鍵字

僵直性脊椎炎 ； 多重抗藥性-1 訊息核醣核酸 ； 微型核醣核酸-27a ； 微型核醣核酸-451 ； 藥物療效

並列摘要

Ankylosing spondylitis (AS) is an autoimmune disease of seronegative spondyloarthropathy. The product of multidrug resistance 1 (MDR1) gene, p-glycoprotein, is one of the major transporters responsible for the entry of drugs into target sites. P-glycoprotein is also known to act as a pivotal role in the drug resistance of autoimmune disease. Further, microRNAs (miRNAs) -27a and miR-451 might also regulate MDR1 expression. Patients with AS were observed to have a lower miR-27a expression than healthy controls; miR-451 was also seen to have a higher expression in patients with systemic lupus erythematosus and rheumatoid arthritis than healthy controls. However, there is a lack of study towards the relationships of MDR1 mRNA, miR-27a, and miR-451 expressions with AS. Therefore, we designed a hospital-based case-control study to evaluate the influences of MDR1 mRNA, miR-27a, and miR-451 expressions on the AS development and therapeutic efficacies of drugs. A total of 150 AS patients and 150 age and gender-matched healthy controls were recruited into this study. Real-time polymerase chain reaction was applied to measure the MDR1 mRNA, miR-27a, and miR-451 expressions in blood. Results showed that higher MDR1 mRNA expression was a risk factor for AS occurrence (vs. lower expression; odds ratio [OR] = 2.45, 95% confidence interval [C.I.] = 1.46-4.12), while higher miR-27a expression was a protective factor (vs. lower expression; OR = 0.44, 95% C.I. = 0.27-0.72). Further, the efficacy of disease-modifying anti-rheumatic drug (DMARDs; sulfasalazine) therapy in AS patients with higher MDR1 mRNA expression was obviously worse (vs. lower expression; OR = 5.14, 95% C.I. = 0.99-26.82); while efficacy of DMARDs therapy in patients with higher miR-27a expression was significantly better (vs. lower expression; OR = 0.25, 95% C.I. = 0.06-0.97). Our data suggest that the expressions of MDR1 mRNA and miR-27a are useful disease biomarkers of AS. Furthermore, the expression of MDR1 mRNA may be a potential biomarker for predicting therapeutic efficacy of DMARDs.

並列關鍵字

ankylosing spondylitis ； MDR1 mRNA ； miR-27 ； miR-451 ； therapeutic efficacy of drugs

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