Novel Associations of VKORC1 Variants with Higher Acenocoumarol Requirements

Abstract

BackgroundAlgorithms combining both clinical and genetic data have been developed to improve oral anticoagulant therapy. Three polymorphisms in two genes, VKORC1 and CYP2C9, are the main coumarin dose determinants and no additional polymorphisms of any relevant pharmacogenetic importance have been identified.ObjectivesTo identify new genetic variations in VKORC1 with relevance for oral anticoagulant therapy.Methods and Results3949 consecutive patients taking acenocoumarol were genotyped for the VKORC1 rs9923231 and CY2C9* polymorphisms. Of these, 145 patients with a dose outside the expected range for the genetic profile determined by these polymorphisms were selected. Clinical factors explained the phenotype in 88 patients. In the remaining 57 patients, all with higher doses than expected, we sequenced the VKORC1 gene and genetic changes were identified in 14 patients. Four patients carried VKORC1 variants previously related to high coumarin doses (L128R, N = 1 and D36Y, N = 3).Three polymorphisms were also detected: rs17878544 (N = 5), rs55894764 (N = 4) and rs7200749 (N = 2) which was in linkage disequilibrium with rs17878544. Finally, 2 patients had lost the rs9923231/rs9934438 linkage. The prevalence of these variations was higher in these patients than in the whole sample. Multivariate linear regression analysis revealed that only D36Y and rs55894764 variants significantly affect the dose, although the improvement in the prediction model is small (from 39% to 40%).ConclusionOur strategy identified novel associations of VKORC1 variants with higher acenocoumarol doses albeit with a low effect size. Further studies are necessary to test their influence on the VKORC1 function and the cost/benefit of their inclusion in pharmacogenetic algorithms.

Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

“…The CYP4F2 V433M (rs2108622) gene polymorphism was not finally entered into our pharmacogenetic algorithm, despite previous reports of its association with a higher VKA dose requirement [50,51] and its inclusion in other pharmacogenetic algorithms [25,26]. Our finding is consistent with published evidence of the very low influence of this gene polymorphism on ACN dose variability (1-2%) [26,51,52].…”

“…An additional 3.9% of dose variability was explained by including a new gene polymorphism of APOE, but not by incorporating other potential gene candidates that have been little studied, such as CYP4F2, CYP2C19, ABCB1, and GGCX. Novel polymorphisms of VKORC1, that is, rs61742245 and rs55894764 variants [52][53][54][55], have been associated with a slightly higher stable ACN requirement and produced an improvement of ≈1% in one prediction model [52]. Given that the loss of rs9923231/rs9934438 linkage has been described in some patients, the determination of rs9934438 may provide a better dose adjustment in these cases [52].…”

“…Novel polymorphisms of VKORC1, that is, rs61742245 and rs55894764 variants [52][53][54][55], have been associated with a slightly higher stable ACN requirement and produced an improvement of ≈1% in one prediction model [52]. Given that the loss of rs9923231/rs9934438 linkage has been described in some patients, the determination of rs9934438 may provide a better dose adjustment in these cases [52]. The novel CYP2C9*57 haplotype, which was detected in one out of 309 oral anticoagulated patients (0.3%), showed VKA hypersensitivity because of a slower warfarin and ACN metabolism, mandating a dose reduction, and it was associated with multiple bleeding episodes and an increased percentage of INRs above 3.0 [56].…”

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

“…25 In fact, the CYP2C9*3 allele have a twofold higher risk of major bleeding in warfarin users. 26 At the same time, VKORC1 rs9923231 and rs9934438, which are in linkage disequilibrium, 27 have an increased incidence of major haemorrhagic complications during anticoagulant treatment.…”

Genotype-phenotype correlations in patients treated with acenocoumarol / Corelaţii genotip-fenotip la pacienţii trataţi cu acenocumarol

“…), acute intercurrent pathologies (fever, sepsis, acute decompensated heart failure, diarrhea, etc. ), and concomitant medication (6,7).…”