口服抗凝血劑Warfarin （維他命K拮抗劑）與其代謝基因CYP2C9、VKORC1之相關研究

The Correlation Study between Oral Anticoagulants-Warfarin(Vitamin K Antagonist) and its Metabolic Genes (CYP2C9 and VKORC1)

蘇士銘(Shih-Ming Su)

指導教授 ： 顏銘宏

高雄醫學大學/藥學院/藥學系碩士在職專班/碩士(2015年)

摘要

研究背景：
鑑於近年來藥物基因學（pharmacogenomics）的進步，透過許多研究結果發現Warfarin最主要其代謝基因為CYP2C9及VKORC1（Vitamin K epoxide reductase complex 1；維他命K環氧化物還原酶）的多型性有關，在國內外都已經要求含Warfarin成份藥品仿單加刊警語注意事項，其中一項警語為CYP2C9和VKORC1酵素之基因多型性。本研究將會探討CYP2C9及VKORC1等代謝基因與Warfarin劑量、敏感度的差異，來探討檢驗CYP2C9和VKORC1這2種基因是否有醫療價值的存在。
研究方法：
本研究採用的研究方法為個案研究（case study），及病歷回顧（chart review）設計方式進行。地點為南部的一間區域教學醫院，研究對象為102年門診有在使用Warfarin的病患。我們在病患抽3㏄的血液去做CYP2C9及VKORC1的基因定序，並收集病患的相關資料等，回顧之前的檢驗數據（INR），再來比較不同的基因型態在劑量上、INR值是否具統計學上的差異。
研究結果：
本研究共收入了46位有在持續穩定使用Warfarin的病患，病患年齡平均57歲±12歲。病患的基因型態CYP2C9*1/*1有43位；CYP2C9*1/*3有3位； VKORC1 AA型態的有36位；VKORC1 AG型態的有10位。我們將不同基因型態的病患分成3組（*1/*1-AA；*1/*1-AG；*1/*3-AA） 來做分析比較，我們發現AA組跟AG組在年齡、BMI、每日劑量都不具統計上的意義，但在INR值的部分AG組的INR值檢驗出的平均INR值還要來的低（P=0.006）。 而*1/*1的平均INR值也是比*1/*3還要來的低（P=0.0005）。進一步我們分析了每日服用2.5 mg的病患，AG組的INR值也是比AA組還要來的低（P=0.0001），不過在*1/*1與*1*3的INR值就不具統計上的意義。
結論：
本研究證實CYP2C9及VKORC1的多型性分析與服用Warfarin時INR值檢測具有參考價值，但自費做基因定序的價格昂貴而導致推廣度低。在台灣CYP2C9及VKORC1有變種的機率跟國外比還不算高，CYP2C9及VKORC1的多型性雖然可以做為醫師在開立Warfarin時的參考，但並不能當作最主要的依據，還是得依病人的實際情況來作劑量上的調整。

關鍵字

藥物基因學 ； Warfarin ； CYP2C9 ； VKORC1 ； INR

並列摘要

Background:
According to the improvement of pharmacogenomics in the medical field nowadays, the main metabolism genes was discovered to be CYP2C9 and VKORC1 (Vitamin K epoxide reductase complex 1) in Warfarin
This research aimed for the question that whether there was a medical value in these two metabolism genes by observing patients’ degree of differences in the sensitivity between these two genes when having taken Warfarin.

Method:
The methodologies of case study and chart review were applied in this research. The research was taken place in a regional educational hospital in the South of Taiwan (R.O.C).
There was the amount of 3 ml blood drawn from each patients to test genome sequencing of CYP2C9 and VKORC1. After this data was collected, the INR was reviewed. Afterwards, whether there was any differences appeared in the statistic about the types of genes in the amount of dose and INR was studied.

Result:
The research samples were 46 patients whose ages averaged 59 ±12 and constantly took Warfarin in 2013. The patients genotype number of CYP2C9*1/*1 were 43 ; CYP2C9*1*3 were 3 ; VKORC1 AA were 36 ; VKORC1 AG were 10, respectively.
We were divided into 3 groups (*1/*1-AA, *1/*1-AG, and *1/*3-AA) based on different types of patients’ genes. We discovered there was no statistical significance between AA and AG group in age , BMI and daily dose. But AG group average INR were lower than AA group (P=0.006).
Furthermore, *1/*1 group average INR were also lower than *1/*3 group (P=0.0005)
Then we analyzed AA and AG whose daily dose is 2.5 mg. AG group average were also lower then AA group. But there were no statistical significance in *1/*1 and *1/*3 group.

Conclusion:
The result of this research had demonstrated that analyzing the polymorphisms of CYP2C9 and VKORC1, along with the INR in Warfarin had the medical value. Yet, it was only the value of being reference resources when a doctor gives Warfarin on a prescription. However, taking the test of genome sequencing costs a lot that in turn, becomes unpopular in Taiwan. The abnormal CYP2C9 and VKORC1 were not often discovered in Taiwan compared to its in other country. It was suggested that giving such prescription, Warfarin, the dose given should be in accordance with each patient’s actual overall conditions.

並列關鍵字

Pharmacogenomics ； Warfarin ； CYP2C9 ； VKORC1 ； INR

參考文獻

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