Wednesday, November 20, 2019

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Warfarin: The Poster Child

In 2009, the FDA declared warfarin to be a “pharmacogenomic opportunity.” As one leading warfarin researcher had recently noted, “[W]arfarin is the ideal drug to test the hypothesis that pharmacogenetics can reduce drug toxicity: it is commonly prescribed, has a narrow therapeutic/toxic ratio, and is affected by common genetic polymorphisms.” Similarly, in January, 2009, after he stepped down from his post as director of the National Human Genome Research Institute under President George W. Bush and before his later elevation to director of the National Institutes of Health by President Barack Obama, Francis Collins noted that warfarin “has become a poster child for the future of pharmacogenomics.”

Warfarin, an anticoagulant, is among the most widely prescribed drugs in modern medicine. In 2004, more than 30 million prescriptions were written for the drug in the United States alone. Sales of warfarin in the U.S. were approximately $500 million in 2002. There was a 1.5-fold increase in warfarin prescriptions between 1999 and 2005, perhaps reflecting the demographic shift toward an aging population, which is typically a primary target of warfarin therapy. It is commonly prescribed to patients who are at risk of developing blood clots, such as persons with atrial fibrillation, recurrent strokes, deep venous thrombosis, pulmonary embolism, or those who have received heart valve replacements. It is difficult to calibrate the right dose for an individual patient because warfarin has a narrow therapeutic window of efficacy and a wide-range of inter-individual variability in response. Finding a correct dosage can be a delicate matter, involving the gradual upward titration of an initially low dose with regular monitoring of the coagulation rate using the “international normalized ratio” or INR (INR compares the blood's clotting ability at a given moment to a standardized measure) and adjusting the dosage until the appropriate rate of coagulation is obtained. Too much warfarin places a patient at risk of a potentially fatal hemorrhage while too little may increase a risk of blood clots and stroke. The complexity of warfarin dosing is indicated by the fact that warfarin is the second most common drug (after insulin) implicated in emergency room visits-- causing more than 43,000 emergency cases per year.

A variety of factors can influence individual response to warfarin, including dietary intake of green leafy vegetables, alcohol consumption, age, weight, and liver function. In addition, the current label lists approximately 130 specific drugs reported to interact with warfarin. For many years, researchers have also observed population-based variation in response to warfarin associated with different races or ethnicities, particularly “Asian” or “east Asian.” That is, studies have observed that on average, subjects identified as Asian may tend to have a different response to warfarin than subjects identified as belonging to different races, particularly “Caucasian.” Based on such observations, the FDA-approved label for Bristol Meyers' brand name warfarin, called Coumadin, states, “Asian patients may require lower initiation and maintenance doses of warfarin.” Race then has long been a part of the clinical conceptualization of warfarin response. It was widely assumed that a significant proportion of such variation was likely due to differing frequencies of certain alleles that affected drug response. In the absence specific information relating to such alleles, race was presumed to be a reasonable surrogate to finding the right dose of warfarin. As one 2005 study concluded, “Warfarin dose requirements vary across ethnic groups even when adjusted for confounding factors, suggesting that genetic variation contributes to interpatient variability.” As in the Albain et al. article, “other factors” here again created a space for geneticizing racial difference.

In the past decade great strides have been made toward identifying specific genetic variations that have a significant impact on individual response to warfarin. In particular, specific polymorphisms in the CYP2C9 gene and VKORC1 gene have been identified as accounting for 30%-50% of variation in individual response to warfarin. CYP2C9 affects pharmacokinetics, or what a body does to a drug. People with certain CYP2C9 alleles metabolize, or break down, warfarin more slowly than average; thus, they would need a lower dose of the medication. VKORC1, in contrast, involves pharmacodynamics, or what a drug does to a body. It affects the production of vitamin K, which is vital to blood clotting. Warfarin works, in part, by suppressing the production of vitamin K. Individuals with certain VKORC1 alleles might also need a lower dose of warfarin. Each person has two copies of each gene. Carriers of two CYP2C9 *1 alleles, known as the “wild type” or standard type, are extensive metabolizers of warfarin. The two most common relevant CYP2C9 variants are referred to as CYP2C9*2 and *3. The most common relevant VKORC1 variant is referred to as VKORC1 3673(-1639G> A). These variants have become particular targets for genetic testing.

With the proliferation of genetic data, one might think that race would cease to play a significant role in studies of warfarin response. Yet, as genetic studies have expanded, so has the use of race and related categories to assess variable frequencies of particular polymorphisms in specific population groups. Numerous studies have observed that some relevant CYP2C9 and VKORC1 alleles vary in frequency across certain ethnic or racial groups. Usually these studies employ such broad categories as “Asian,” “Caucasian” “Hispanic” or ““African-American,” but some studies are more nation specific, identifying allele frequencies and response, for example, in Swedes, Koreans, Iranians, Japanese, and Israelis.

Ironically, there seems to have been an increase in such racial, ethnic, or nation-specific studies of allele frequencies in recent years, as the significance of specific genetic variations has been more fully elaborated and characterized. In recent work on warfarin, racial categories have persisted, and even increased in use, alongside the production of specific genetic information. In studies of the impact of genetics on warfarin response, it seems to have become an unstated norm to characterize gene frequency with reference to whatever racial, ethnic, or national group on which the study happened to be performed.

For example, a report on warfarin and genetic testing issued in 2008 by the American Medical Association, the Critical Path Institute, and the Arizona Center for Education and Research on Therapeutics highlighted the significance CYP2C1 and VKORC1 but also emphasized for both that the “prevalence of gene variation differs depending on racial background,” stating, for example, that “[a]pproximately 37% of Caucasians, 14% of African-Americans and 89% of Asians carry at least one variant copy of VKORC1.” The Pharmacogneomics Knowledge Base (PharmGKB) lists studies of this VKORC1 variant finding a range of frequencies in European populations from 39% in “Swedish” to 54% in ““Spanish” with frequencies of 91% and 93% in “Chinese” and “Japanese” respectively. This begs the question of why one would care about frequencies across racial or ethnic groups when it is possible to test directly for the gene itself, regardless of race? Yet genes, it seems, somehow take on an added interest when connected with race, or perhaps vice versa. Far from withering away, race is persisting and even proliferating as genetic information increases.

Vernellia R. Randall
Founder and Editor
Professor Emerita of Law
The University of Dayton School of Law

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