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Gattaca, LVADs, ISHLT: A War Far Strokes


J. Daniel Malone, BS MS3
Vincent G Valentine, MD

University of Texas Medical Branch
Galveston, TX, USA
vgvalent@utmb.edu



What could be more eye-catching than a pair like Uma Thurman and Ethan Hawke clutched together in Gattaca, haircuts perfect, clothing immaculate, and human features carved from perfection? As Vincent (Hawke) takes Irene's (Thurman) hand and places it over his heart, he says "but we do have one thing in common, only I don't have twenty or thirty years left in mine. Mine is already ten thousand beats overdue." Irene responds, "it's not possible." To which Vincent asserts, "they've got you looking for any flaw, that after a while that's all you see. For what it's worth, I'm here to tell you that it is possible. It is possible."

Gene-specific warfarin therapy is also the glamor hot topic in medicine, and it's not only possible, it's already here. Indeed, it paves the way for patient-specific warfarin dosing and stroke prevention for indications such as mechanical heart valves and left ventricular assist devices (LVADs). This approach totally changes the way doctors will prescribe medications and ultimately gives those like Vincent the means to soldier on and pursue the Irene of their dreams.

This innovative approach is based on two methods of altered warfarin processing. The CYP2C9 gene encodes the cytochrome P450 enzymes that metabolize warfarin. This gene effectively determines how long warfarin stays in its active form. The second major player is VKORC1, which encodes vitamin K epoxide reductase, an enzyme targeted by warfarin to alter coagulation. Einstein once said, "God does not play dice with the universe." Does this imply a grand design? If so, it's a complicated one. Still as Cowper writes, "variety's the spice of life, that gives it all its flavor." This intriguing and tasteful variety in genotypes is termed polymorphisms. The CYP2C9 gene has no less than thirty such variations, most commonly, CYP2C9*1. However, if you get a copy designated CYP2C9*2 or CYP2C9*3, you have reduced P450 enzyme activity, decreased warfarin metabolism, and increased sensitivity to warfarin. Similarly, the VKORC1 gene has a non-coding variant called -1639G>A. A copy of this polymorphism yields lower gene expression, less vitamin K epoxide reductase for warfarin to inhibit, and therefore less warfarin required for a given INR goal. Too much warfarin in such patients creates a warfarin surplus, one of which that the likes of Gordon Gekko would embrace to wreak havoc on a patient's coagulation cascade and drive the INR to dangerously high levels. So as Orwell states, "all animals are equal, but some animals are more equal than others."

By understanding the genes that affect warfarin dosing, doctors can tailor dose regimens based on the genotype of their patients. No more will patients and doctors wait in fear as recipients of an INR based off an educated guess for a starting warfarin dose. Instead, they'll embrace Peter Drucker's method and push forward with "the best way to predict the future is to create it." Similarly, we can create an understanding of genotypes to predict responses to not only warfarin dosing, but with any medication given to a patient in the future. Will genotyping be as routine as taking a patient's vital signs one day when meeting a patient for the first time? This concept begs the question: does this indicate a new dawn of human existence or simply a manifestation of predictions already alive and vibrant in the minds of our greatest artists? The future gets more predictable with genotype-based therapy, but the past is never too far away. Our youth embrace the future in the words of Imagine Dragons with "welcome to the new age" while the wiser generation echoes the past with a cautionary push towards a "brave new world."

For samples of dosing based on genotypes, the following website gives an algorithm:
http://www.warfarindosing.org/Source/Home.aspx.

A table reference for calculating warfarin doses based on genotypes is also given by the following table:

VKORC1
(-1639G>A)

CYP2C9

*1/*1

*1/*2

*1/*3

*2/*2

*2/*3

*3/*3

GG

5-7 mg

5-7 mg

3-4 mg

3-4 mg

3-4 mg

0.5-2 mg

AG

5-7 mg

3-4 mg

3-4 mg

3-4 mg

0.5-2 mg

0.5-2 mg

AA

3-4 mg

3-4 mg

0.5-2 mg

0.5-2 mg

0.5-2 mg

0.5-2 mg

Disclosure Statement: the authors have no conflicts of interest to report.


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