臺灣博碩士論文加值系統

G6PD缺乏症是一種的性聯遺傳的先天疾病。患者因在日常生活中接觸某些食品 (如：蠶豆)、化學物質和部分藥物後，而出現急性溶血性貧血症狀。然而，已知有些藥物對G6PD缺乏患者會導致溶血，目前卻沒有標準方法可以測試該藥物的風險危害。
本研究共分析42種高風險、36種低風險和53種安全的藥物，利用ChemDIS系統找出高風險、低風險和安全藥物的交互作用網路，並找出重要生物標記。研究發現有風險藥物與人體蛋白質G6PD交互作用具有一致性，其他KMO、MHD2和NF-kB1也是關鍵蛋白質。而Beclin1和Diablo和細胞凋亡有關，是影響高風險藥物引起溶血的重要因素之一。由基因本體分析發現高風險藥物產生干擾素和宿主遭受到感染反應時相似；主要代謝路徑是經由清道夫接受器的結合和吸收配體產生作用。
以交互作用的蛋白質交互作用進行風險預測，發現高風險藥物精確度可達56%以上，有風險藥物精確度更可達80%以上；不論是高風險藥物或是有風險藥物，在保持一定精確度之下同時加入Beclin1和Diablo做預測，兩者的敏感度可提高至40 %以上，未來可做為藥物上市前的風險評估測試。

Glucose 6-phosphate dehydrogenase deficiency, an X-linked disorder, is the most common enzymatic disorder of red blood cells in humans. It can cause hemolysis after exposure to drugs with a high redox potential, fava beans, selected infections, or metabolic abnormalities. Several drugs have been found to be high risk of hemolytic anemia for G6PD deficiency patients. However, there is no standard method to evaluate drugs for their risks of hemolytic anemia. We propose to utilize ChemDIS system to study the interaction network of drugs and proteins and identify important biomarkers capable of predict corresponding risks. A total of 42 high-risk drugs, 36 low-risk drugs and 53 safe drugs were collected. Several proteins have been identified as important biomarkers such as G6PD, KMO, MHD2 and NF-kB1. The interaction networks of high-risk, low-risk and safe drugs were analyzed to find out the important biomarkers. This study identified G6PD, KMO, MHD2 and NF-kB1 as key biomarkers. Beclin1 and Diablo associated with apoptosis are also useful biomarkers that could be important factors for hemolysis of high-risk drugs. For the risk prediction of drugs using the identified biomarkers, this study found that the precision for high-risk drugs is 56%, the precision for risk drugs is over 80%. When Beclin1 and Diablo are combined for prediction, sensitivity can be improved to higher than 40%. The prediction methods could be used to screen drug hemolytic risk.

中文摘要 I
ABSTRACT II
目 錄 III
圖 目 錄 VI
表 目 錄 VII
附 錄 IX
第一章 緒論 1
第一節 G6PD缺乏症 1
一、疾病簡介 1
二、致病機轉 2
三、流行病學 4
四、分類 5
五、遺傳 6
六、臨床表徵 6
七、危險因素 7
八、檢驗和診斷 8
九、治療方式 9
第二節 研究目的 10
一、問題陳述 10
二、研究動機 12
第三節 文獻回顧 13
一、文獻探討 13
二、相關研究 14
第二章 研究方法 15
第一節 研究理論 15
一、系統藥理學 (Systems pharmacology) 15
二、預測毒理學 (Predictive toxicology) 16
第二節 資料收集 17
第三節 探勘軟體 18
第四節 研究設計 19
一、資料整理 19
二、實驗設計 20
三、藥物風險預測 23
第三章 研究結果 24
第一節 資料分析 24
一、排除品項 24
二、分析筆數 25
第二節 作用目標蛋白質分析 25
一、主要作用蛋白質 25
二、主要作用蛋白質綜合結果 29
三、其他重要蛋白質 29
第三節 基因本體分析 30
一、Biological process (BP) 31
二、Cellular component (CC) 35
三、Molecular function (MF) 37
第四節 作用路徑分析 40
一、作用路徑 (RACT) 40
一、作用路徑 (KEGG) 41
第五節 統整結果 42
第四章 討論 43
第一節 探討與溶血性貧血相關性 43
一、影響蛋白質 43
二、基因本體 44
第二節 其他發現 45
一、作用路徑 45
第三節 研究限制 46
第五章、藥物風險預測 47
第一節、預測資料分析 47
一、藥物風險預測的精準度 (Precision) 48
二、藥物風險預測的敏感度 (Sensitivity) 49
第二節、預測結果討論 49
一、高風險藥物預測分析 49
二、有風險藥物預測分析 49
第六章 結論 49
第一節 重要的研究發現 49
第二節 研究應用性 49
第三節 未來研究展望 49
參考文獻 49
附錄 49

1. Beutler E, Duparc S. Glucose-6-phosphate dehydrogenase deficiency and antimalarial drug development. The American Journal of Tropical Medicine and Hygiene. 2007;77: 779–789. doi:77/4/779 [pii]
2. Beutler E, T. G6PD Deficiency. Am Soc Hematol. 1994;84: 3613–36.
3. Frontiers C. Genetic basis of drug metabolism. The American Journal of Health-System Pharmacy. 2002;59: 2061–2070.
4. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371: 64–74. doi:10.1016/S0140-6736(08)60073-2
5. Mehta A, Mason PJ, Vulliamy TJ. Glucose-6-phosphate dehydrogenase de®ciency. Baillière''s Clinical Haematology. 2000;13: 21–38. doi:10.1053/beha.1999.0055
6. Mason PJ, Bautista M, Gilsanz F. G6PD deficiency : the genotype-phenotype association. BLOOD Reviews. 2007;21: 267–283. doi:10.1016/j.blre.2007.05.002
7. Mehta A, Mason PJ, Vulliamy TJ. Glucose-6-phosphate dehydrogenase deficiency. BaillieÁ re’s Clinical Haematology. 2000. pp. 21–38. doi:10.1053/beha.1999.0055
8. Heiden MG Vander, Cantley LC, Thompson CB, Mammalian P, Exhibit C, Metabolism A. Understanding the Warburg Effect : Cell Proliferation. Science. 2009;324: 1029–1034.
9. Pandolfil PP, Sonatil F, Rivil R, Mason P, Grosveld F, Luzzattol L. Targeted disruption of the housekeeping gene encoding glucose 6-phosphate dehydrogenase ( G6PD ): G6PD is dispensable for pentose synthesis but essential for defense against oxidative stress. The European Molecular Biology Organization Journal.1995;14: 5209–5215.
10. Article R. Glucose-6-phosphate dehydrogenase (G6PD) Deficiency. ranian Journal of Public Health. 2008;37: 1–18.
11. Chien Y, Lee N, Wu S, Liou J, Chen H. Glucose-6-phosphate dehydrogenase deficiency by population drift in Tawin. Southeast Asian Journal of Tropical Medicine andPublic Health. 2008;39: 154–161.
12. Ho H, Cheng M, Chiu DT. G6PD - An Old Bottle with New Wine. Chang Gung Medical Journal. 2005;28: 606–612.
13. 台大醫院基因醫學部新生兒篩檢中心 新生兒篩檢確認診斷就診說明書. 2016. pp. 6–7.
14. Glader B, Editors S, Schrier SL, Mahoney DH, Editor D, Landaw SA. Diagnosis and treatment of glucose-6-phosphate dehydrogenase deficiency. UpToDate. 2014. pp. 2012–2014.
15. G6PD Deficiency Association - Home. 2016Available: http://www.g6pd.org/
16. Liu M, Wu Y, Chen Y et al. Large-scale prediction of adverse drug reactions using chemical, biological, and phenotypic properties of drugs. Journal of the American Medical Informatics Association. 2012;19: e28–e35. doi:10.1136/amiajnl-2011-000699
17. Dart RC. Monitoring risk : Post marketing surveillance and signal detection. Drug and Alcohol Dependence. 2009;105: 26–32. doi:10.1016/j.drugalcdep.2009.08.011
18. Edwards IR, Aronson JK. Adverse drug reactions Adverse drug reactions : definitions , diagnosis , and management. Lancet. 2000;356: 1255–1259.
19. Benigni R. Predictive toxicology today: the transition from biological knowledge to practicable models. Expert Opinion on Drug Metabolism & Toxicology.2016;5255:1–4.doi:10.1080/17425255.2016.1206889
20. Chen, Hung-Yi Tsai, Pei-Yu Tang C-C. 蠶豆症慎用藥品 — 證據何在？. 藥學雜誌. 2012;28: 38–43.
21. 財團法人罕見疾病基金會. 2016. Available: http://www.tfrd.org.tw/tfrd/rare_a
22. Tung CW. ChemDIS: A chemical-disease inference system based on chemical-protein interactions. Journal of Cheminformatics. Springer International Publishing; 2015;7: 1–7. doi:10.1186/s13321-015-0077-3
23. Cappellini GF. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008. pp. 64–74.
24. Rowen L. Sequencing the Human Genome. Science. 1997;278: 605–607. doi:10.1126/science.278.5338.605
25. Youngster I, Arcavi L, Schechmaster R, Akayzen Y, Popliski H, Shimonov J, et al. Medications and Glucose-6-Phosphate Dehydrogenase Deficiency. Drug Safety. 2010;33: 713–726.
26. Yang Y, Li Z, Nan P, Zhang X. Drug-induced glucose-6-phosphate dehydrogenase deficiency-related hemolysis risk assessment. Journal ofComputational Biology. 2011;35: 189–192. doi:10.1016/j.compbiolchem.2011.04.010
27. Miller H, Han J. Geographic Data Mining and Knowledge Discovery An Overview. Geographic data mining and knowledge discovery. 2009;d: 1–26. doi:10.1201/9781420073980.ch1
28. Wu HF. Mining structural and physicochemical features for drug-induced glucose-6-phosphate dehydrogenase deficiency-related hemolysis. Master’s thesis, Graduate Institute of Pharmaceutical Science, Kaohsiung Medical University.2015
29. Bai JPF, Abernethy DR. Systems Pharmacology to Predict Drug Toxicity : Integration Across Levels of Biological Organization . Systems Pharmacology to Predict Toxicity. 2013;53: 451–73. doi:10.1146/annurev-pharmtox-011112-140248
30. Berger SI, Iyengar R. Role of systems pharmacology in understanding drug adverse events. Wiley Interdisciplinary Reviews: Systems Biology and Medicine. 2011;3: 129–135. doi:10.1002/wsbm.114.Role
31. Data Mining Concepts. 2016 .Available: https://msdn.microsoft.com/en-us/library/ms174949.aspx
32. Guengerich FP, Macdonald JS. Re V iews Applying Mechanisms of Chemical Toxicity to Predict Drug Safety. Chemical Research in Toxicology. 2007;20: 344–369.
33. Elyassi CAR, Rowshan MHH, Dds À. Perioperative Management of the Glucose-6- Phosphate Dehydrogenase Deficient Patient : A Review of Literature. Anesthesia Progress . 2009;3006: 86–91.
34. Tung C-W. ChemDIS. 2016. Available: http://cwtung.kmu.edu.tw/chemdis/#
35. STITCH: chemical association networks. 2016. Available: http://stitch1.embl.de/
36. Perrotta I, Carito V, Russo E, Tripepi S, Aquila S, Donato G. Macrophage Autophagy and Oxidative Stress : An Ultrastructural and Immunoelectron Microscopical Study. Oxidative Medicine and Cellular Longevity. 2011;2011: 1–8. doi:10.1155/2011/282739
37. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, et al. Identification of DIABLO , a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins. Cell Press. 2008;102: 43–53.
38. Ashburner M, Ca B, Ja B, Botstein D, Butler H, Jm C, et al. ontology : tool for the unification of biology . The NIH Public Access. Nature Genetics. 2000;25: 25–29. doi:10.1038/75556
39. Gene T, Consortium O. Gene Ontology Annotations and Resources.Nucleic Acids Research. 2013;41: 530–535. doi:10.1093/nar/gks1050
40. QuickGO . 2016. Available: https://www.ebi.ac.uk/QuickGO/
41. Alberati-giani D, Cesura AM, Broger C, Warren WD, Rver S, Malherbe P. Cloning and functional expression of human kynurenine 3-monooxygenase. Federation of European Biochemical Societies. 1997;410: 407–412.doi:10.1016/S0014-5793(97)00627-3
42. Han Q, Beerntsen BT, Li J. The tryptophan oxidation pathway in mosquitoes with emphasis on xanthurenic acid biosynthesis. Journal of Insect Physiology . 2007;53: 254–263. doi:10.1016/j.jinsphys.2006.09.004
43. Mercurio F, Manning AM. NF- k B as a primary regulator of the stress response. Oncogene. 1999;18: 6163–6171.
44. Weerd NA De, Samarajiwa SA, Hertzog PJ. Type I Interferon Receptors: Biochemistry and Biological Functions*. Journal of Biological Chemistry . 2007;282: 20053–57. doi:10.1074/jbc.R700006200
45. Nielsen MJ, M??ller HJ, Moestrup SK. Hemoglobin and Heme Scavenger Receptors 1. Antioxidants and Redox Signaling. 2010;12: 261–273.
46. Ulusu NN. Glucose-6-phosphate dehydrogenase deficiency and Alzheimer ’ s disease : Partners in crime ? The hypothesis. Medical Hypotheses . 2015;85: 219–223. doi:10.1016/j.mehy.2015.05.006
47. I LB, Leon M. Evidence of an Oxidative Challenge in the Alzheimer ’ s Brain. Neurochemical Research. 1994;19: 1131–1137.
48. Gaskin RS1, Estwick D PR. G6PD deficiency: its role in the high prevalence of hypertension and diabetes mellitus. Ethnicity and Disease. 2001;11: 749–54.
49. Wan G, Tsai S, Chiu DT. Decreased Blood Activity of Glucose-6-Phosphate Dehydrogenase Associates with Increased Risk for Diabetes Mellitus. Endocrine. 2002;19: 191–195.
50. Brumfield RT, Beerli P, Nickerson DA, Edwards S V. The utility of single nucleotide polymorphisms in inferences of population history. Trends in Ecology and Evolution.2003;18:249–256. doi:10.1016/S0169-5347(03)00018-1
51. Wang DG, Fan J, Siao C, Berno A, Young P, Sapolsky R, et al. Large-Scale Identification , Mapping , and Genotyping of Single-Nucleotide Polymorphisms in the Human Genome. Science. 1998;280: 1077–1083.