An evaluation of nine genetic variants related to metabolism and mechanism of action of warfarin as applied to stable dose prediction

Abstract

Warfarin anticoagulation is complicated by the highly variable inter-individual response. Approximately 50% of the dose variability arises from clinical factors and variants in two genes, CYP2C9 (*2 and *3 variants) and VKORC1 -1173 C > T. We tested variants in five additional genes (EPHX1, PROC, APOE, CYP4F2, CALU and a new variant in VKORC1 in an attempt to further reduce the variability in predicted stable warfarin dose. Consecutive consenting outpatients requiring anticoagulation on stable warfarin dose (target INR 2-3) were genotyped; the association of SNP genotypes with stable warfarin dose was evaluated using the test of linear contrasts in analysis of variance (ANOVA). Study participants were 71 ± 13 years, 53% female, 85 ± 23 kg, body mass index 29 ± 7 kg/m(2). Genotypes were in Hardy-Weinberg equilibrium with the exception of VKORC1 -1639. Weekly stable dosages were 31.7 ± 13.9 mg/week; median: 30 mg/week, range: 11-70 mg/week. Significant associations with dose were seen for VKORC1 -1639 (P < 0.001), CYP2C9*2 (P = 0.005) and *3 (P = 0.003), the CYP4F2 SNP (P-trend = 0.00037), and VKORC1 3730 (p-trend = 0.042). In linear regression, age, sex, weight, and CYP2C9 *2 and *3 and VKORC1-1639 genotype explained 42% of variance. The addition of CYP4F2 genotype to the regression model increased the degree of variance explained to 47%. Addition of VKORC1 SNP -1639 to a model eliminated the association of VKORC1 3730 with warfarin dose (P-trend = 0.74), but -1639 remained highly significant. No impact on dose was observed for the other tested genetic variants.

Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement

“…34 In the white pediatric sample studied by Nowak-Göttl et al, the VKORC1 and CYP2C9 genotypes explained only a very small part of the warfarin dose variability (2.8% and 0.5%, respectively), 27 perhaps because of the small sample size (n ϭ 34). 28 In our study, the overall contribution of genetic factors (20.2%) to the interindividual variability in the warfarin maintenance dose was smaller than that reported in middle-aged adults (30%-40%) 6,7,9,10,12,13,[21][22][23] and similar to that found in the elderly (17.5%). 35 We did not find an association between warfarin maintenance dose and CYP4F2 genotype, probably because of the small size of the cohort.…”

“…10,12,20 Overall, genetic factors accounted for 30%-40% of the dose variability in white adults. 6,7,9,10,12,13,[21][22][23] Many studies have assessed genetic variants influencing the VKA response in adults. [4][5][6][7][8][9][10][11][12][13][14][15] In contrast, only a few small studies have investigated the effect of the VKORC1 and/or CYP2C9 genotype on VKA dose requirements in children.…”

Adherence in outpatients taking warfarin and its effect on anticoagulation control in Jordan

“…It is important to acknowledge other important factors that affect the INR within therapeutic range, in particular, genetic and environmental factors [9,20]. These factors can lead to inter-individual variability in body response to warfarin and effect on the anticoagulation control [21,22].…”

“…Out-of-range INR values can be a result of genetic predisposition, dietary modifications, drug interactions, and poor adherence [7][8][9]. Accordingly, it is important to evaluate patient adherence to warfarin because it is one of the modifiable factors and at the same time the evaluation can stimulate a better understanding of warfarin utilization and barriers to proper warfarin use.…”

Coleta, transporte e armazenamento de amostras para diagnóstico molecular

“…Já existem testes moleculares que consideram o fenótipo (ou informações clínicas) para o cálculo do risco de doenças ou da dose necessária de um fármaco para se obter um efeito clínico, como, por exemplo, a dose de warfarina para obtenção de determinada razão normalizada internacional (INR) do tempo de protrombina. A individualização das informações necessárias para cada teste e sua obtenção cuidadosa são essenciais para que o resultado do teste seja mais informativo e relevante para a condução clínica dos casos (6,14,20,21) .…”