依類型 族群 主題   
 
 
2007.06.01 ~ 2008.06.01
服用口服抗凝血劑病人的藥物基因體學研究 Pharmacogenomic Study on Patients taking Oral Anticoagulant : Warfarin
族群: 跨族群  
主題: 學術研究、醫療保健  
作者 劉翠蘭
學校系所 慈濟大學人類遺傳研究所
地點 全臺 全部  
研究內容

[ 摘要 ]
口服抗凝血劑(warfarin)被臨床廣泛使用在心血管疾病預防上。但因為其治療劑量因個人環境因素及基因因子差異性極大,且容易造成出血等併發症,而導致醫療上使用的不方便。口服抗凝血劑在個體間的反應差異性除了由一些臨床因子如年齡,性別,合併疾病及藥物決定以外,有大部份決定於基因多型性(genetic polymorphism)。至目前為止,關於口服抗凝血劑的藥物基因體學研究多關於CYP2C9及VKORC1這兩個決定口服抗凝血劑代謝及作用機轉的基因。大部份學者研究發現此兩個基因的多型性為主要決定個體對口服抗凝血劑反應的差異性及口服抗凝血劑造成的出血併發症。但是因為CYP2C9及VKORC1基因的多型性因種族差異性極大,況且東方人為容易出血體質且口服抗凝血劑維持劑量較白種人來得低,故研究東方人的口服抗凝血劑基因體學是必要的。
此計劃旨在探討目標一:決定口服抗凝血劑的基因多型性在東台灣漢族(Hans Taiwanese)和原住民族群(Taiwan aborigines)的不同;目標二:希望藉由基因多型性的分析及結合影響口服抗凝血劑反應的臨床因子建立給藥的數學模式以降低使用口服抗凝血劑引起的副作用。我們在東台灣針對正在服用抗凝血劑的台灣漢族及原住民族群進行一個回溯性的藥物基因體學研究。我們定序CYP2C9*3及VKORC1-1639G>A這兩個基因的多型性在東台灣族群的分佈。我們的研究發現台灣漢族及原住民族群的口服抗凝血劑使用量相同,且VKORC1-1639基因多型性的分佈及頻率在漢族及原住民族群間並沒有不同。在東台灣族群裡有大於80%的病患是VKORC1-1639AA基因型且此基因型的病患常須要較低的口服抗凝血劑使用量。在我們分析的病患裡並沒有發現CYP2C9*3基因多型性的存在。此研究的結論認為VKORC1-1639AA是導致較低的口服抗凝血劑使用量的主要原因,且此基因多型性的分佈及頻率在東台灣的漢族及原住民族群並沒有不同。

[ 英文摘要 ]
Warfarin is widely prescribed in our populations for secondary prevention of stroke and cardiovascular disorders. However, warfarin therapy is under-used because patients require different warfarin dosages to achieve the therapeutic level and high bleeding risk. The variability of warfarin response is largely genetically determined besides various clinical factors such as age, gender, concomitant disorders and concurrent medications. To date, the contribution of CYP2C9 and VKORC1 genetic polymorphism to the variable response of warfarin and bleeding events are well established by different groups in the world. But the frequency of genetic polymorphism is varied in different populations. The polymorphism of CYP2C9 and VKORC1 gene is quite different from Caucasian populations in Chinese population and also in Hans Taiwanese. Searching genetic polymorphisms that contributed to variability of warfarin response is necessary in our population due to warfarin maintenance dose is low and the expected bleeding risk are high in our population.
To evaluate the genetic factors related either to warfarin metabolism (CYP2C9) or to drug target (VKORC1) to variability in the response to warfarin treatment between Hans Taiwanese and Taiwanese aborigines in Eastern Taiwan. And we hope to establish a pharmacogenomics-based algorithm for warfarin dose determination. A retrospective study was conducted in patients who were receiving warfarin maintenance treatment in Eastern Taiwan’s population including Hans Taiwanese and Aboriginal Taiwanese. The CYP2C9*3 and VKORC1-1639G>A genetic polymorphism were genotyped. We documented that there was no significant difference of warfarin dosage requirement between Hans Taiwanese and Aboriginal Taiwanese along with similar frequency of VKORC1-1639 variant. Most of our patients (>80%) made up majority by VKORC1-1639AA genotype along with lower warfarin maintenance dose. No CYP2C9*3 allele was found in our recruited patients that contributed minor to variability of warfarin response. We concluded that frequency of the VKORC1-1639 genetic polymorphism is similar between Hans Taiwanese and Aboriginal Taiwanese. And the VKORC1-1639AA genotype is the dominant genetic factor along with lower warfarin dosage requirement in Eastern Taiwan’s population.