Genotype and Risk of Major Bleeding During Warfarin Treatment

Kawai, Vivian; Cunningham, Andrew; Vear, Susan I.; Driest, Sara L. Van; Oginni, Abimbola; Xu, Hua; Jiang, Min; Li, Chun; Denny, Joshua C.; Shaffer, Christian M.; Bowton, Erica; Gage, Brian F.; Ray, Wayne A.; Roden, Dan M.; Stein, C. Michael

doi:10.2217/pgs.14.153

Cited by 51 publications

(45 citation statements)

References 42 publications

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“…This association was not significant in African-Americans, likely due to a lack of statistical power (only 1 TT homozygous subject). The finding of decreased INR variability associated with the T allele of this CYP4F2 variant is concordant with findings in recent studies of genetic risk factors for major bleeding in patients receiving warfarin that suggested a lower risk of bleeding in subjects bearing the minor T allele [13, 15]. …”

Section: Discussionsupporting

confidence: 89%

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Genetic determinants of variability in warfarin response after the dose-titration phase

Iwuchukwu

Ramirez

Shi

et al. 2016

Pharmacogenetics and Genomics

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Objectives Genetic factors contribute substantially to variability in warfarin dose requirements and are important in the dose-titration phase; their effects on the stability of anticoagulation later in therapy are not known. Methods Using de-identified electronic medical records linked to a DNA-biobank, we studied 140 African-Americans and 943 European-Americans after the warfarin dose-titration phase. We genotyped 12 SNPs in genes (CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, CALU) associated with altered warfarin dose-requirements and tested their associations with INR variability (INRVAR) and percent time in therapeutic range (TTR) in European-Americans and African-Americans. Results One allele copy of rs2108622 in CYP4F2 was associated with a 15 percent (95% CI, 1, 26, p = 0.03) decrease in median INRVAR in European-Americans. In African-Americans, GGCX variants rs11676382 and rs699664 were associated with 4.16 (95% CI, 1.45, 11.97, p = 0.009) and 1.50 (95% CI, 1.07, 2.08, p = 0.02) fold changes in median INRVAR per variant allele copy respectively; rs11676382 was also significantly associated with a 23.19 (95%CI, 5.89, 40.48, p = 0.01) percent decrease in TTR. The total variation in INRVAR explained by both clinical factors and rs2108622 was 5.2% for European-Americans. In African-Americans, the inclusion of GGCX variants rs11676382 and rs699664, and CYP2C9*8 variant rs7900194 explained approximately 29% of the variation in INRVAR. Conclusions The stability of anticoagulation after the warfarin dose-titration phase is differentially affected by variants in CYP4F2 in European-Americans and GGCX loci in African-Americans.

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Section: Discussionsupporting

confidence: 89%

“…For example, the risk of bleeding or thrombosis was increased long after the initial 2 week dose-titration phase in patients with genotypes associated with altered warfarin sensitivity [12, 13]. The mechanisms whereby genotype might affect complications of warfarin therapy beyond the dose-titration phase are not known.…”

Section: Introductionmentioning

confidence: 99%

Genetic determinants of variability in warfarin response after the dose-titration phase

Iwuchukwu

Ramirez

Shi

et al. 2016

Pharmacogenetics and Genomics

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“…Although older people are more likely to bleed [36], the bleeding events are likely to be mainly due to the incorrect warfarin dose since there is a high percentage of subjects with supratherapeutic INR (i.e., 88%). The higher number of CYP2C9*3 alleles in uncontrolled patients is in line with recent studies that indicated an increased bleeding risk of CYP2C9*3 carriers [37,38]. However, CYP2C9 alleles (*2 and *3) are not associated with the therapeutic warfarin doses future science group Research Article Karaca, Bozkurt, Cesuroglu et al in our controlled patients.…”

Section: Discussionsupporting

confidence: 87%

International Warfarin Genotype-Guided Dosing Algorithms in the Turkish Population and Their Preventive Effects on Major and Life-Threatening Hemorrhagic Events

Karaca

Bozkurt

Cesuroğlu³

et al. 2015

Pharmacogenomics

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“…Tomek et al [38] showed that anticoagulated Caucasian patients carriers of 3 variant alleles of the genes CYP2C9 and VKORC1 exhibited a significantly higher risk of major bleeding during the initiation and maintenance phases of warfarin therapy. Kawai et al [39] showed that the CYP2C9∗3 allele could double the risk of major bleeding among patients administered warfarin for 30 or more days. However, the authors did not find any association with VKORC1 variants and the study population largely consisted of Caucasians, although it also included Afro-Americans and others ethnic groups.…”

Section: Discussionmentioning

confidence: 99%

VKORC1 and CYP2C9 polymorphisms related to adverse events in case-control cohort of anticoagulated patients

et al. 2016

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Vitamin K antagonists (VKAs) are highly effective but have a narrow therapeutic index and require routine monitoring of the INR. The primary aim of pharmacogenetics (PGx) is to optimize patient care, achieving drug treatments that are personalized according to the genetic profile of each patient. The best-characterized genes involved in VKA PGx involve pharmacokinetics (VKORC1) and pharmacodynamics (CYP2C9) of VKA metabolism. The role of these genes in clinical outcomes (bleeding and thrombosis) during oral anticoagulant (OAC) therapy is controversial. The aim of the present study was to evaluate any potential association between genotype VKORC1 and CYP2C9 and adverse events (hemorrhagic and/or thrombotic), during initiation and long-term VKA treatment, in Caucasian patients. Furthermore, we aimed to determine if the concomitant prescription of other selected drugs affected the association between genotype and adverse events.We performed a retrospective, matched case-control study to determine associations between multiple gene variants, drug intake, and any major adverse effects in anticoagulated patients, monitored in 2 Italian anticoagulation clinics.Our results show that anticoagulated patients have a high risk of adverse events if they are carriers of 1 or more genetic polymorphisms in the VKORC1 (rs9923231) and CYP2C9 (rs1799853 and rs1057910) genes.Information on CYP2C9 and VKORC1 variants may be useful to identify individualized oral anticoagulant treatment for each patient, improve management and quality of VKA anticoagulation control, and monitor drug surveillance in pharmacovigilance programs.

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Genotype and Risk of Major Bleeding During Warfarin Treatment

Cited by 51 publications

References 42 publications

Genetic determinants of variability in warfarin response after the dose-titration phase

Genetic determinants of variability in warfarin response after the dose-titration phase

International Warfarin Genotype-Guided Dosing Algorithms in the Turkish Population and Their Preventive Effects on Major and Life-Threatening Hemorrhagic Events

VKORC1 and CYP2C9 polymorphisms related to adverse events in case-control cohort of anticoagulated patients

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