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Gene Marker May Predict Doses Of Important Anticoagulant

Ruzanna Harutyunyan's picture

A particular gene marker may help predict a patient’s safest and most effective dose of warfarin, the most widely prescribed anticoagulant in North America, according to a new study led by Ohio State University Medical Center researchers.

The findings explain why African-Americans often require higher doses of the drug than do Caucasians and Asians.

Doctors use warfarin to prevent life-threatening blood clots in people recovering from surgery and from many disorders, including heart attacks and stroke. Achieving the correct drug dose is critical. If it is too high, side effects such as blood in the urine or severe bleeding may occur; if too low, clots may form.

Genetic tests are now available to help determine the right dose of warfarin. Many of these tests detect one among five DNA biomarkers in a gene called VKORC1 that is involved in clotting and is targeted by warfarin. However, it is not known which of the five affects the function of the gene and is therefore essential to measure, or whether two or more cooperate in the effect.

This study, led by Wolfgang Sadee, director of Ohio State’s pharmacogenomics program and professor of pharmacology, answers that question. The findings are reported in the August 15 issue of the journal Blood.

It shows that one of the biomarkers, called -1639 G>A, does in fact influence the gene’s role in clotting and in warfarin’s effectiveness. Individuals lacking the marker require higher warfarin doses to inhibit clot formation with equal effect.

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“These findings indicate that we can use this functional biomarker with confidence to determine stable warfarin doses for patients, which should lower the risks of adverse drug effects across ethnic populations,” says principal investigator Danxin Wang, a research scientist in Sadee’s laboratory.

Optimum warfarin doses are usually determined using a trial-and-error process that takes two to six weeks and requires regular monitoring of blood-clotting ability. Drug-related bleeding and other adverse side effects usually happen during this period, Sadee says.

Genetic tests designed to more quickly determine warfarin doses focus on two genes, with VKORC1 playing the stronger role in influencing the steady-state warfarin dose. The gene does this by producing a protein that plays a vital role in blood clotting. The protein is also targeted by warfarin.

The tests detect variations in the gene’s DNA called single nucleotide polymorphisms, or SNPs (pronounced “snips”). The gene can have up to five different SNPs at one time.

This study by Sadee and his colleagues shows that the presence or absence one of these five SNPs, the biomarker -1639 G>A, can fully account for the differences in activity of the VKORC1 protein that are often seen between patients. That is, the presence of this marker causes the gene to make less of its protein, which means less warfarin is needed to inhibit clotting.

But when the marker is absent – as it is in about 90 percent of all African Americans – the gene makes more of the protein, requiring higher warfarin doses.

“African Americans are known to need a higher dose of warfarin and Asians and Caucasians need lower doses,” says Wang. “Now we have a basis for understanding why this is the case.”

Sadee notes that, overall, “This study highlights the importance of identifying genetic biomarkers that reflect a marker gene’s variability and the molecular mechanisms that underlie that gene’s activity.”