Genetic polymorphisms and major bleeding risk during vitamin K antagonists treatment: The BLEEDS case-cohort.

Major bleeding occurs annually in 1%-3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk. To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma-glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit-1 (VKORC1). A case-cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow-up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression. Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2-TT carriership was associated with a 1.6-fold (95% CI 0.9-2.8) increased risk of major bleeding compared with CC-alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2-TT, and VKORC1-AA was associated with a 4.0-fold (95%CI 1.4-11.4) increased risk, while carriers of both CYP4F2-TT and VKORC1-AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5-29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively). CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.

Camilleri E ，Ghobreyal M ，Bos MHA ，Reitsma PH ，Van Der Meer FJM ，Swen JJ ，Cannegieter SC ，van Rein N ... -  《-》

Bleeding predictors in patients following venous thromboembolism treated with vitamin K antagonists: Association with increased number of single nucleotide polymorphisms.

Single nucleotide polymorphisms (SNP) in genes encoding proteins involved in metabolism and action of vitamin K antagonists (VKA) affect anticoagulation stability. We investigated how those polymorphisms influence bleeding rates in patients following venous thromboembolism (VTE). In 324 patients following unprovoked VTE, 143 (44%) on warfarin and 181 (56%) on acenocoumarol, we recorded bleeds within the preceding 24 months. We assessed eight SNP, including those in cytochrome P450 isoform 2C9 (CYP2C9) and isoform 4F2 (CYP4F2), vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX), apolipoprotein E (APOE) and multidrug resistance gene 1 (MDR1). Within 48 months before enrolment, bleeding events occurred in 80 (25%) patients, including 14 (4%) major bleeds. Patients with bleeds had 16.2% lower median time in therapeutic range (TTR) and were more often carriers of CYP2C9*3 variant (26 [33%] vs. 19 [8%], p < 0.001) compared with the remainder. Bleeding occurred more frequently in patients with ≥4 SNP compared with the remainder (27 [34%] vs. 47 [19%], p = 0.009) with no intergroup differences of TTR. Number of SNP was one of the predictors of any bleeding. The regression model for major bleeding including factors such as CYP2C9*3 c. 1075 C, VKORC1 c. -1639 A and APOE c. 388 C showed good predictive ability (area under the curve - 0.79). In VTE patients on the maintenance treatment with VKA, bleeding episodes are associated with CYP2C9 gene variations and increased number of SNP of genes involved in the action and metabolism of VKA.

Bryk AH ，Wypasek E ，Plens K ，Awsiuk M ，Undas A ... -  《-》

Genetic determinants of acenocoumarol and warfarin maintenance dose requirements in Slavic population: a potential role of CYP4F2 and GGCX polymorphisms.

VKORC1 and cytochrome CYP2C9 genetic variants contribute largely to inter-individual variations in vitamin K antagonists (VKAs) dose requirements. Cytochrome P450 4F2 isoform (CYP4F2), gamma-glutamyl carboxylase (GGCX) and apolipoprotein E (APOE) polymorphisms have been suggested to be of minor significance. We sought to assess the impact of those polymorphisms on dose requirements in Central-Eastern European cohort of 479 patients receiving acenocoumarol (n=260) or warfarin (n=219). There were no differences between the acenocoumarol and warfarin groups with regard to the gender, age, body mass index and international normalized ratio. The VKORC1 c.-1639A allele carriers required a lower dose of acenocoumarol and warfarin than the non-carriers (28.0 [21.0-35.0] vs. 42.0 [28.0-56.0] mg/week, p<0.0001; 35.0 [28.0-52.0] vs. 52.0 [35.0-70.0] mg/week, p=0.0001, respectively). Carriers of 2 and/or 3 variant alleles for CYP2C9 also required a lower dose of warfarin as compared with 1 1 carriers (35.0 [31.5-52.5] vs. 43.8 [35.0-60.2] mg/week, p=0.02; 35.0 [23.5-35.0] vs. 43.8 [35.0-60.2] mg/week, p<0.0001, respectively). Similarly, possession of G allele of GGCX c.2084+45 polymorphism was associated with lower warfarin dose (35.0 [26.3-39.2] vs. 45.5 [35.0-65.1] mg/week, p=0.03). No effect of CYP2C9*2,-*3 and GGCX c.2084+45G>C polymorphisms on acenocoumarol dosage was observed. Interestingly, carriers of CYP4F2 c.1297A variant required a higher dose of acenocoumarol and warfarin than non-carriers (43.8 [35.0-60.2] vs. 35.0 [35.0-52.5] mg/week, p=0.01; 35.0 [28.0-52.5] vs. 28.0 [28.0-42.0] mg/week, p=0.05). We have shown for the first time, that besides VKORC1 and CYP2C9 genetic variants, the CYP4F2 c.1297A and GGCX c.2084+45G have a moderate effect on VKAs dose requirements in Slavic population from Central-Eastern Europe.

Wypasek E ，Branicka A ，Awsiuk M ，Sadowski J ，Undas A ... -  《-》

Long-term outcomes of elderly patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists.

Essentials The long-term effects of VKORC1 and CYP2C9 variants on clinical outcomes remains unclear. We followed 774 patients ≥65 years with venous thromboembolism for a median duration of 30 months. Patients with CYP2C9 variants are at increased risk of death and non-major bleeding. Patients with genetic variants have a slightly lower anticoagulation quality only. Background The long-term effect of polymorphisms of the vitamin K-epoxide reductase (VKORC1) and the cytochrome P450 enzyme gene (CYP2C9) on clinical outcomes remains unclear. Objectives We examined the association between CYP2C9/VKORC1 variants and long-term clinical outcomes in a prospective cohort study of elderly patients treated with vitamin K antagonists for venous thromboembolism (VTE). Methods We followed 774 consecutive patients aged ≥ 65 years with acute VTE from nine Swiss hospitals for a median duration of 30 months. The median duration of initial anticoagulant treatment was 9.4 months. The primary outcome was the time to any clinical event (i.e. the composite endpoint of overall mortality, major and non-major bleeding, and recurrent VTE. Results Overall, 604 (78%) patients had a CYP2C9 or VKORC1 variant. Three hundred and thirty-four patients (43.2%) had any clinical event, 119 (15.4%) died, 100 (12.9%) had major and 167 (21.6%) non-major bleeding, and 100 had (12.9%) recurrent VTE. After adjustment, CYP2C9 (but not VKORC1) variants were associated with any clinical event (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.08-1.66), death (HR, 1.74; 95% CI, 1.19-2.52) and clinically relevant non-major bleeding (sub-hazard ratio [SHR], 1.39; 95% CI, 1.02-1.89), but not with major bleeding (SHR, 1.03; 95% CI, 0.69-1.55) or recurrent VTE (SHR, 0.95; 95% CI, 0.62-1.44). Patients with genetic variants had a slightly lower anticoagulation quality. Conclusions CYP2C9 was associated with long-term overall mortality and non-major bleeding. Although genetic variants were associated with a slightly lower anticoagulation quality, there was no relationship between genetic variants and major bleeding or VTE recurrence.

Nagler M ，Angelillo-Scherrer A ，Méan M ，Limacher A ，Abbal C ，Righini M ，Beer JH ，Osterwalder J ，Frauchiger B ，Aschwanden M ，Matter CM ，Kucher N ，Cornuz J ，Banyai M ，Husmann M ，Staub D ，Mazzolai L ，Hugli O ，Rodondi N ，Aujesky D ... -  《-》

Effect of CYP2C9, VKORC1, CYP4F2, and GGCX gene variants and patient characteristics on acenocoumarol maintenance dose: Proposal for a dosing algorithm for Moroccan patients.

Elkhazraji A ，Bouaiti EA ，Boulahyaoui H ，Nahmtchougli CP ，Zahid H ，Bensaid M ，Ibrahimi A ，Messaoudi N ... -  《-》