Genetic Marker Predicts Greater Response to Warfarin           

            Too little blood thinner, and an embolism could be lethal. Too much, and the risk of internal bleeding could quickly become a crisis. So what is a physician to do in an emergency when there may be only minutes to assess the situation and make the right call?

            Warfarin is a text book example of a commonly prescribed drug with widely varying responses in patients. Complicating the issue even further are numerous drug interactions and secondary factors that can influence dosage. Calculating dosage is often a best guess situation based on a general algorithm, followed by adjusting the dosage depending on how the patient responds.

            While recent studies have identified CYP2C9*2 and CYP2C9*3 genetic variations that may account for some of the differences in response in patients of European and Asian descent, they do not fully account for the 20-fold variability in response seen in African Americans. In fact, none of the last three genome-wide studies included a significant number of African Americans as subjects.

            A missing piece of the puzzle has come to light in a study published in June in the highly regarded international medical journal, The Lancet.

“The genome -wide association study was the first of its kind, looking for genetic markers to better predict warfarin doses in African Americans,” Nita Limdi, Pharm.D, PhD, said. “We found a statistically significant association between a novel CYP2C single nucleotide polymorphisms on chromosome 10 called rs12777823 and reduced warfarin dose requirements in African-Americans who have this variation.

A first author of the study, Limdi is an associate professor in the Department of Neurology in the UAB School of Medicine where the largest number of participants in the 17-institution effort were enrolled in the study.

            “Our goal is to help more people arrive at their optimal dose more quickly,” Limdi said. “Taking information like this into account should improve the accuracy of the pharmacogenetic dosing algorithms. It’s also important to remember that not all African Americans have this variant and should not be under-dosed.”

            Along with Limdi, UAB authors of the study were Nianjun Liu, PhD, and Jelai Wang in the Section on Statistical Genetics.

Data analysis of findings suggest that individuals with one copy of the variant are likely to need a dosage reduction of 6.92 mg. per week and those with two copies would need a reduction of 9.34 mg. per week. While an association study is not direct proof of cause and effect, if confirmed by future studies, this finding should make a significant contribution toward improving accuracy in dosing.

            Approximately 25 million people are prescribed warfarin each year for the treatment and prevention of clots, but even with the best available dosing model, warfarin causes a third of US hospital visits related to drug side effects in patients over 65, with nearly two-thirds of those cases due to bleeding.

Ultimately, as the trend toward personalized medicine evolves and the cost of genotyping continues to decrease, in the not too distant future it is likely that physicians will be able to check for individual genetic variations before making their prescribing decisions. 

Limdi is working toward creating an infrastructure at UAB to incorporate genetic information into better informed clinical decisions in daily practice. She leads a project called PRIME, Pharmacogenomic Resource for Improving Medication Effectiveness, which identifies projects where adjusting treatment based on patient genotypes can dramatically improve a drug’s effectiveness.