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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 陳沛隆(Pei-Lung Chen) | |
| dc.contributor.author | Siao-Jyuan Jhan | en |
| dc.contributor.author | 詹曉娟 | zh_TW |
| dc.date.accessioned | 2022-11-25T05:35:32Z | - |
| dc.date.available | 2023-10-30 | |
| dc.date.copyright | 2021-11-09 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-10-28 | |
| dc.identifier.citation | 1. Hegele, R.A., et al., The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. The lancet Diabetes endocrinology, 2014. 2(8): p. 655-666. 2. Laufs, U., et al., Clinical review on triglycerides. European heart journal, 2020. 41(1): p. 99-109c. 3. Lewis, G.F., C. Xiao, and R.A. Hegele, Hypertriglyceridemia in the genomic era: a new paradigm. Endocrine reviews, 2015. 36(1): p. 131-147. 4. Dron, J.S., et al., Severe hypertriglyceridemia is primarily polygenic. Journal of clinical lipidology, 2019. 13(1): p. 80-88. 5. Brahm, A.J. and R.A. Hegele, Chylomicronaemia—current diagnosis and future therapies. Nature Reviews Endocrinology, 2015. 11(6): p. 352-362. 6. Brahm, A. and R.A. Hegele, Hypertriglyceridemia. Nutrients, 2013. 5(3): p. 981-1001. 7. G Nordestgaard, B. and J. J Freiberg, Clinical relevance of non-fasting and postprandial hypertriglyceridemia and remnant cholesterol. 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Journal of clinical lipidology, 2018. 12(4): p. 920-927. e4. 19. Iacocca, M.A., J.S. Dron, and R.A. Hegele, Progress in finding pathogenic DNA copy number variations in dyslipidemia. Current opinion in lipidology, 2019. 30(2): p. 63-70. 20. Surendran, R.P., et al., Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. Journal of internal medicine, 2012. 272(2): p. 185-196. 21. Dron, J.S. and R.A. Hegele, Genetics of hypertriglyceridemia. Frontiers in Endocrinology, 2020. 11. 22. Dron, J.S. and R.A. Hegele, Genetics of lipid and lipoprotein disorders and traits. Current genetic medicine reports, 2016. 4(3): p. 130-141. 23. Zhang, Z., et al., Association of genetic loci with blood lipids in the Chinese population. PLoS One, 2011. 6(11): p. e27305. 24. Wolska, A., et al., Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism. Atherosclerosis, 2017. 267: p. 49-60. 25. Tudorache, I.F., V.G. Trusca, and A.V. Gafencu, Apolipoprotein E-a multifunctional protein with implications in various pathologies as a result of its structural features. Computational and structural biotechnology journal, 2017. 15: p. 359-365. 26. Bennet, A.M., et al., Association of apolipoprotein E genotypes with lipid levels and coronary risk. Jama, 2007. 298(11): p. 1300-1311. 27. Gautier, T., et al., Human apolipoprotein CI accounts for the ability of plasma high density lipoproteins to inhibit the cholesteryl ester transfer protein activity. Journal of Biological Chemistry, 2000. 275(48): p. 37504-37509. 28. Pillois, X., et al., Constitutive inhibition of plasma CETP by apolipoprotein C1 is blunted in dyslipidemic patients with coronary artery disease [S]. Journal of lipid research, 2012. 53(6): p. 1200-1209. 29. Allan, C. and J. Taylor, Expression of a novel human apolipoprotein (apoC-IV) causes hypertriglyceridemia in transgenic mice. Journal of lipid research, 1996. 37(7): p. 1510-1518. 30. Kim, E., et al., Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor γ complex and correlates with liver steatosis. Journal of hepatology, 2008. 49(5): p. 787-798. 31. Yamamura, T., et al., Familial type I hyperlipoproteinemia caused by apolipoprotein C-II deficiency. Atherosclerosis, 1979. 34(1): p. 53-65. 32. Johansen, C.T., et al., An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia. Arteriosclerosis, thrombosis, and vascular biology, 2011. 31(8): p. 1916-1926. 33. Perez-Martinez, P., et al., Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states. The American journal of clinical nutrition, 2009. 89(1): p. 391-399. 34. Dron, J.S. and R.A. Hegele, Genetics of triglycerides and the risk of atherosclerosis. Current atherosclerosis reports, 2017. 19(7): p. 31. 35. Fuior, E.V. and A.V. Gafencu, Apolipoprotein C1: its pleiotropic effects in lipid metabolism and beyond. International journal of molecular sciences, 2019. 20(23): p. 5939. 36. Richards, S., et al., Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine, 2015. 17(5): p. 405-423. 37. Jaganathan, K., et al., Predicting splicing from primary sequence with deep learning. Cell, 2019. 176(3): p. 535-548. e24. 38. Gill, P.K., J.S. Dron, and R.A. Hegele, Genetics of hypertriglyceridemia and atherosclerosis. Current Opinion in Cardiology, 2021. 39. Richardson, K., et al., Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site. The American Journal of Human Genetics, 2013. 92(1): p. 5-14. 40. Caussy, C., et al., Multiple microRNA regulation of lipoprotein lipase gene abolished by 3′ UTR polymorphisms in a triglyceride-lowering haplotype harboring p. Ser474Ter. Atherosclerosis, 2016. 246: p. 280-286. 41. Dron, J.S. and R.A. Hegele, Genetics of hypertriglyceridemia. Frontiers in Endocrinology, 2020. 11: p. 455. 42. Marais, A.D., Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology, 2019. 51(2): p. 165-176. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82085 | - |
| dc.description.abstract | "高三酸甘油酯血症是心血管和代謝疾病中常見的一種表型，其遺傳變異異常複雜。家族性乳糜微粒血症(familial chylomicronemia syndrome, FCS)導致的三酸甘油酯數值嚴重升高是由LPL、APOC2、APOA5、LMF1和GPIHBP1基因中的同型合子(homozygous)或雙等位基因功能喪失變異(biallelic loss-of-function variants)所引起。相比之下，多因素乳糜微粒血症(multifactorial chylomicronemia, MCM)則是由兩種不同類型的遺傳變異引起(1)罕見的雜合變異(heterozygous variants)在家族性乳糜微粒血症的五個基因中具有可變外顯率(variable penetrance)(2)常見變異點位(common variants)，其個別單核苷酸多型性(Single Nucleotide Polymorphism, SNP)小效應積累使得三酸甘油脂升高，其複雜的遺傳變異因素造成臨床上分子檢測極大的困難與挑戰。有鑑於此，本研究建立次世代定序平台篩檢高三酸甘油酯血症之變異類型及釐清複雜的遺傳因素，在次世代定序與傳統的定序方法相較之下，能夠同時讀取上百萬條DNA序列，所以可以大量降低成本，且快速幫助病患確立基因變異找出原因，了解本土病患的基因變異分佈情形，則未來應考慮包括(1)評估特定類型的高三酸甘油酯血症遺傳易感性是否影響醫療決策或長期結果(2)探討其它遺傳因素，包括全基因組多基因評分、新基因或基因與基因-環境之間的相互作用，以擴展我們對高三酸甘油酯血症的了解。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T05:35:32Z (GMT). No. of bitstreams: 1 U0001-2610202117364000.pdf: 3199569 bytes, checksum: 0a89567abcc3dfd107555e057190fe65 (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 口試委員會審定書…………………………………………………………………i 致謝…………………………………………………………………………………ii 中文摘要……………………………………………………………………………iii 英文摘要……………………………………………………………………………iv 第一章 研究背景與動機 1-1高三酸甘油脂血症之疾病介紹 ………………………………… 1-2 1-2 高三酸甘油脂血症之基因概論……………………………………2-3 1-3 研究動機……………………………………………………………4-6 第二章 研究方法 2-1研究對象………………………………………………………………7 2-1-1納入條件 ………………………………………………………7 2-1-2排除條件 ………………………………………………………7 2-2次世代定序檢測………………………………………………………7 2-2-1 DNA的萃取 …………………………………………………7-9 2-2-2次世代定序原理 ………………………………………………9 2-2-3定序輸出與分析 …………………………………………9-10 2-2-4基因檢測平台(探針設計)……………………………………10 2-2-5桑格定序法(Sanger sequencing)………………………10-11 2-3黃金標準檢測法分析 ………………………………………………11 第三章 結果 3-1次世代定序分析結果 ………………………………………… 12-14 3-1-1案例結果分析…………………………………………… 15-21 第四章 討論 4-1 基因檢測變異點位分析…………………………………………22-23 4-2 基因變異型別分析………………………………………………24 第五章 結論 ………………………………………………………………25 第六章 文獻……………………………………………………………………26-28 附錄………………………………………………………………………………29-30 表目錄 表一、高三酸甘油血酯症基因檢測平台…………………………………………10 表二、基因變異型別分析…………………………………………………………12 表三、APOE基因的基因型…………………………………………………………14 表四、APOE基因型頻率………………………………………………………………25 表五、APOE對偶基因頻率……………………………………………………………25 表六、內含子單核苷酸多型性列表(已報導)………………………………………29 表七、25名嚴重高甘油三酯血症患者的致病或可能致病基因的變異點位………31-32 表八、62名重度高甘油三酯血症患者不確定意義的基因變異點位………………33-36 圖目錄 圖一、根據2014年遺傳統計數據重新定義高三酸甘油酯血症………………2 圖二、基因功能 …………………………………………………………………3 圖三、遺傳決定因素 ……………………………………………………………5 圖四、APOA1-APOC3-APOA4-APOA5基因簇………………………………………6 圖五、APOA1-APOC3-APOA4-APOA5基因簇 ………………………………6 圖六、嚴重高三酸甘油酯血症患者和不同血統的對照遺傳譜………………13 圖七、APOE 基因型占比 ………………………………………………………14 圖八、高三酸甘油酯血症分析結果……………………………………………14 圖九、案例一家族譜 ……………………………………………………………15 圖十、案例一IGV檢視基因變異………………………………………………16 圖十一、案例一桑格定序結果 …………………………………………………16 圖十二、案例二家族譜 …………………………………………………………17 圖十三、案例二IGV檢視基因變異 ……………………………………………17 圖十四、案例三家族譜 …………………………………………………………18 圖十五、案例三IGV檢視基因變異(1)…………………………………………19 圖十六、案例三IGV檢視基因變異(2) ………………………………………19 圖十七、案例四家族譜 …………………………………………………………20 圖十八、案例四IGV檢視基因變異(1) ………………………………………21 圖十九、案例四IGV檢視基因變異(2) ………………………………………22 圖二十、台灣的高三酸甘油酯血症患者中發現的LPL基因變異點位…………22 | |
| dc.language.iso | zh-TW | |
| dc.subject | 多因素乳糜微粒血症 | zh_TW |
| dc.subject | 高三酸甘油酯血症 | zh_TW |
| dc.subject | 次世代定序 | zh_TW |
| dc.subject | 基因檢測 | zh_TW |
| dc.subject | 遺傳決定因素 | zh_TW |
| dc.subject | 單基因 | zh_TW |
| dc.subject | 多基因 | zh_TW |
| dc.subject | 家族性乳糜微粒血症 | zh_TW |
| dc.subject | genetic determinants | en |
| dc.subject | multifactorial chylomicronemia (MCM) | en |
| dc.subject | familial chylomicronemia syndrome(FCS) | en |
| dc.subject | Hypertriglyceridemia | en |
| dc.subject | Next-generation sequencing | en |
| dc.subject | genetic testing | en |
| dc.subject | single genes | en |
| dc.title | 應用次世代定序技術建立高三酸甘油脂血症基因檢測平台 | zh_TW |
| dc.title | Next-Generation sequencing to establish the genetic testing platform for hypertriglyceridemia | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 楊偉勳(Hsin-Tsai Liu),蘇大成(Chih-Yang Tseng) | |
| dc.subject.keyword | 高三酸甘油酯血症,次世代定序,基因檢測,遺傳決定因素,單基因,多基因,家族性乳糜微粒血症,多因素乳糜微粒血症, | zh_TW |
| dc.subject.keyword | Hypertriglyceridemia,Next-generation sequencing,genetic testing,single genes,genetic determinants,familial chylomicronemia syndrome(FCS),multifactorial chylomicronemia (MCM), | en |
| dc.relation.page | 36 | |
| dc.identifier.doi | 10.6342/NTU202104255 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-10-28 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| dc.date.embargo-lift | 2023-10-30 | - |
| Appears in Collections: | 分子醫學研究所 | |
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|---|---|---|---|
| U0001-2610202117364000.pdf Access limited in NTU ip range | 3.12 MB | Adobe PDF |
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