一項最新研究發(fā)現(xiàn)：影響血液凝固的基因發(fā)生變異，或許能夠說明為何醫(yī)生很難確定華法令的合適劑量，該藥是一種常見的抗凝劑。

醫(yī)生開出處方使用華法令（商品名包括Coumadin）來預(yù)防心臟病、腦卒中、或者大手術(shù)之后的有害的血液凝固。但是，合適的劑量范圍很大，很難進行預(yù)測。美國華盛頓大學醫(yī)學化學教授、高級發(fā)起人Allan E. Rettie博士指出：“在過多與過少之間的劑量窗口極小。”

研究人員檢測了服用華法令患者的基因背景，發(fā)現(xiàn)編碼CY2C9酶的基因出現(xiàn)變異，該酶負責華法令的新陳代謝，導(dǎo)致10%的患者對該藥的治療反應(yīng)不同。醫(yī)生并不常規(guī)檢測這些基因的變異。研究人員著眼于另外一種基因：維生素K環(huán)氧化物還原酶(VKORC1)，該基因編碼的蛋白有助于控制血液凝結(jié)，是華法令的關(guān)鍵的作用靶點。研究人員發(fā)現(xiàn)，變異并沒有基因上調(diào)或者下調(diào)，因此關(guān)于患者變異的信息能夠預(yù)測對華法令治療的反應(yīng)。除此之外，研究人員發(fā)現(xiàn)，特定人群特定變異的發(fā)生率較高。亞洲裔美國人一般為低劑量背景，非洲裔美國人一般為高劑量背景，歐洲裔美國人則處于中間水平。

第一作者Mark J. Rieder博士指出：“如果你試圖預(yù)測劑量，你需要知道更多的控制變異的基因。” 他是華盛頓大學基因科學系助理教授。這項研究發(fā)表在2005年6月2日的《新英格蘭醫(yī)學》。
 
Genetic Variation Affects Clotting
 
A new study has found that variations in a gene involved in blood clotting may account for the difficulty doctors have in deciding on the proper dose of warfarin, a common anticoagulant.

Warfarin (trade names include Coumadin) is prescribed by doctors to prevent harmful blood clotting after a heart attack, stroke, or major surgery. However, the proper dose can vary a lot and be hard to predict. “There is a narrow window between too much and too little,” explained senior author Allan E. Rettie, Ph.D., professor of medicinal chemistry at the University of Washington (Seattle, USA).

Researchers looked at the genetic background of people taking warfarin and found that variations in the gene encoding the CY2C9 enzyme that metabolizes warfarin account for about 10% of the difference in people’s response to the drug. Doctors do not routinely test for these variations. The researchers also focused on another gene: vitamin K epoxide reductase (VKORC1), which makes a protein that helps control clotting and is the key target of warfarin. They found that genetic variations did turn this gene up or down, so information about a patients’ variations could predict their response to warfarin. In addition, the researchers found that certain population groups tend to have a higher prevalence of a particular variation. Asian Americans tend to have a low-dose version, African-Americans have a high-dose version, and European Americans are in the middle.

“If you want to predict doses, you need to know more about the genes that control variability,” observed first author Mark J. Rieder, Ph.D., an assistant professor in the department of genome sciences at the University of Washington. The study was published in the June 2, 2005, issue of The New England Journal of Medicine.