A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk.
BACKGROUND
A C1173T polymorphism in intron 1 of the VKORC1 gene has been claimed to determine the interindividual variability in the response to vitamin K antagonist therapy (VKA), but it is unknown whether it also influences bleeding risk. We aimed to confirm the relationship between C1173T status and phenprocoumon or acenocoumarol use, and to examine the risk of severe bleeding for the various genotypes.


RESULTS
We studied this in a case-control study of 110 patients who bled during VKA therapy and 220 control patients free of bleeding under the same therapy. To achieve the same target INR, CT genotype and TT genotype control patients required less phenprocoumon (CC genotype 2.9 mg/d [95% confidence interval (CI): 2.6-3.2], CT genotype 2.6 mg/d [95% CI: 2.1-3.1], TT genotype 1.4 mg/d [95 % CI: 1.1-1.7]) or acenocoumarol (CC genotype 3.2 mg/d [95% CI: 2.9-3.5], CT genotype 2.3 mg/d [95% CI: 2.1-2.5], TT genotype 1.7 mg/d [95% CI: 1.3-2.1]) than CC genotype control patients. Compared with CC genotype individuals, carriers of at least one T allele had an increased risk of bleeding in the phenprocoumon users (crude odds ratio = 2.6, 95% CI: 1.2-5.7), but not in acenocoumarol users (crude odds ratio = 1.2, 95% CI: 0.6-2.3).


CONCLUSIONS
These findings encourage taking further steps towards the evaluation of the use of VKORC1 genetic testing for bleeding prevention in individuals who receive VKA therapy.
Reitsma
Pieter H
PH
Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. p.h.reitsma@amc.uva.nl
van der Heijden
Jeroen F
JF
Groot
Angelique P
AP
Rosendaal
Frits R
FR
Büller
Harry R
HR
D000074:Acenocoumarol / Q000009:adverse effects / Q000627:therapeutic use; D000925:Anticoagulants / Q000494:pharmacology*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced* / Q000235:genetics*; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000502:physiology*; D010644:Phenprocoumon / Q000009:adverse effects / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014812:Vitamin K / Q000627:therapeutic use; D064417:Vitamin K Epoxide Reductases
D000925:Anticoagulants; D014812:Vitamin K; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol; D010644:Phenprocoumon