VKORC1 Gene Variants Control Response to the Common Anti-Clotting Drug Warfarin

Allan E. Rettie, Ph.D. and Kenneth E. Thummel, Ph.D.
University of Washington
P30ES07033

Background: Warfarin is the most widely used anti-clotting drug in the United States with about 2 million people using the drug each day. Warfarin, also known as Coumadin®, is used to prevent blood clots after a heart attack, stroke, or major surgery. However the proper dose of the drug is very hard to determine and varies widely among individuals. Too much can lead to uncontrolled bleeding and too little doesn’t do enough to prevent clots. A patient’s race, age, sex, weight, and medical history are all used to determine initial dose, but it can take several months and many visits to the doctor to determine the best dose. Warfarin’s target is an enzyme known as vitamin K epoxide reductase, an enzyme that is a key component in the clotting process. Scientists and doctors speculated that small differences in the structure of the VKORC1 gene coding for the enzyme might be at least partially responsible for the individual variation.

Advance: Researchers at the University of Washington, funded by NIEHS, NHLBI, and NIGMS, have found several genetic variations, termed single nucleotide polymorphisms, of VKORC1. They examined 186 patients on stabilized doses of warfarin. They found genetic variations that appear to turn the expression of the gene up or down. They matched the gene sequencing results with the warfarin doses and determined that people with particular variations of the gene needed similar doses of warfarin.

Implications: These results suggest that individual genetic make-up could be a big factor in a person’s response to warfarin and therefore the correct dose. Racial differences also seem to be important in that Asian Americans generally had the low-dose genotype while African-Americans had the high-dose genotype. People of European descent generally fell in the middle. The authors conclude that genetic analysis of VKORC1 ”should be an essential component of prospective studies aimed at investigating the value of genotyping for warfarin therapy.”

Citation: Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005 Jun 2;352(22):2285-93.