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The warfarin dose requirement and therapeutic response of a 42-year-old African–American male with genotype CYP2C9 *11/*11, VKORC1 -1639GG and CYP4F2 433Val/Val anticoagulated for ischemic stroke is described herein. Warfarin was dosed according to the institution’s personalized medicine program recommendations of a 10 mg mini-load dose, followed by dose decreases to 4–6 mg/day through discharge. Stable international normalized ratio was achieved after eight doses, with good overall long-term maintenance of therapeutic international normalized ratio over several years with warfarin doses of 3.1–4.3 mg/day. This case report sheds further light on the clinical impact of CYP2C9 *11/*11 on warfarin dose requirements, short- and long-term treatment response and practical considerations for warfarin management in suspected carriers of rare variant CYP2C9 alleles.

Aim: This study was conducted to investigate the effects of VKORC1, CYP2C9, CYP4F2 and EPHX1 and nongenetic factors on warfarin maintenance dose in a very elderly, frail Han-Chinese population. Materials & methods: 16 variants of VKORC1, CYP2C9, CYP4F2 and EPHX1 were genotyped. Univariate analysis and multivariable regression model were performed for the associations of gene variants and warfarin maintenance dose. Results & conclusion: EPHX1 rs2260863 nonvariant CC homozygotes required significantly lower daily warfarin dose than GC heterozygotes. In the multivariable model, VKORC1 rs9923231, CYP2C9 rs1057910, EPHX1 rs2260863, CYP4F2 rs2189784 and body surface area altogether explained 26.9% of dosing variability. This study revealed the main impact of genetic factors on warfarin response in this special population.

Aim: To analyze the impact of nongenetic factors and gene polymorphisms on warfarin dose requirements in elderly Shanghai Han Chinese patients. Materials & methods: Genotypes of CYP2C9 (rs1799853 and rs1057910), FPGS (rs7856096), ApoE (rs7412 and rs429358), GGCX (rs699664 and rs12714145), EPHX1 (rs4653436, rs1877724, rs1051740 and rs1131873), NQO1 (rs1800566 and rs10517), ABCB1 (rs1045642), VKORC1 (rs9923231) and CYP4F2 (rs2108622) in 214 patients with stable warfarin dose were determined and their demographic characteristics were recorded. Results: Multiple linear regression analysis revealed that VKORC1 rs9923231, CYP2C9*3 rs1057910, ApoE rs7412, age, BMI and concomitant amiodarone could explain 37.0% of the individual variations of daily stable warfarin dose. Conclusion: VKORC1 rs9923231, CYP2C9*3 rs1057910, ApoE rs7412, age, BMI and concomitant amiodarone play an important role in stable dose variation of warfarin in elderly Shanghai Han Chinese patients, whereas ABCB1 rs1045642 is not a significant genetic factor.

Aim: The aim of this study was to determine the impact of genetic and nongenetic factors on treatment outcomes in patients receiving dual antiplatelet therapy after percutaneous coronary intervention and stent implantation. Materials & methods: Patients (n = 628) used clopidogrel or ticagrelor for at least 1 week before platelet aggregation test. Results: Multivariate binary regression analysis demonstrated that aspirin use and CYP4F2 T allele significantly increased odds for bleeding in clopidogrel users (OR: 2.488, 95% CI: 1.452–4.265; p = 0.001 and OR: 1.573, 95% CI: 1.066–2.320; respectively; p = 0.022). CYP4F2 T allele significantly increased odds for bleeding in ticagrelor users (OR: 8.270, 95% CI: 3.917–17.462; p

Aim: We conducted a genome-wide association study using the Illumina Exome Array to identify coding SNPs that may explain additional warfarin dose variability. Patients & methods: Analysis was performed after adjustment for clinical variables and genetic factors known to influence warfarin dose among 1680 warfarin users (838 European–Americans and 842 African–Americans). Replication was performed in an independent sample. Results: We confirmed the influence of known genetic variants on warfarin dose variability. Our study is the first to show the association between rs12772169 and warfarin dose in African–Americans. In addition, genes COX15 and FGF5 showed significant association in European–Americans. Conclusion: We identified some novel genes/SNPs that underpin warfarin dose response. Further replication is needed to confirm our findings.

Assessing the distinct prevalence or absence of genetic variants associated with differential response to the anticoagulant medication of warfarin in different population groups is actively pursued by pharmacogenomics community. Populations from Arabian Peninsula are underrepresented in such studies. By way of examining exome- and genome-wide genotype data from 1395 Arab individuals in Kuwait, we report distinct occurrence of warfarin response-related variants rs12460590_A/CYP2A7, rs2108622_T/CYP4F2, rs2884737_C/VKORC1 and distinct absence of rs11150606_C/PRSS53 in Kuwaiti population. The presented results in conjunction with similar literature reports on Qatari population enhance the worldwide understanding on population-specific distributions of genetic variants associated with warfarin drug dosage.

Aim: To determine the main clinical and genetic factors having impact on early coronary stent thrombosis. Materials & methods: Genotyping of CYP2C19*2, *17 and CYP4F2*3 in patients with (n = 31) and without stent thrombosis (n = 456) was performed. Clinical and genetic data were analyzed by binary logistic regression. Results: Smoking (OR: 0.317; 95% CI: 0.131–0.767), high-density lipoprotein level in mmol/l (OR: 0.142; 95% CI: 0.040–0.506), CYP2C19*2*2 versus *1*1 and *1*2 genotype (OR: 11.625; 95% CI: 3.498–38.633), CYP4F2 AA versus GA and GG genotype (OR: 3.532; 95% CI: 1.153–10.822) were associated with early stent thrombosis. Conclusion: For the first time we have identified a clinically important polymorphism (CYP4F2 G1347A) that was independently associated with early stent thrombosis. Original submitted 18 August 2014; Revision submitted 10 November 2014

Aim: To analyze VKORC1, CYP2C9 and CYP4F2 polymorphisms in relation to the main outcomes in the first stages of acenocoumarol therapy. Patients & methods: Nine hundred and forty one patients who had started therapy and in whom time to stable dosage, time to over-anticoagulation and adverse events occurred during 3 first months were retrospectively analyzed. Results: VKORC1 AA patients needed fewer days to reach stable dosage (p = 0.017). International normalized ratio [INR] at 72 h, and VKORC1 and CYP2C9 genotypes conditioned INR values >2.5 (p 2.5 during the first weeks of acenocoumarol therapy. Original submitted 22 July 2013; Revision submitted 14 November 2013

Aim: The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. Patients & methods: The following were assessed in a cohort of 260 African–Americans and 53 Hispanic–Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Results: Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs 0.18; p < 0.05) allele frequencies were higher in Hispanic–Americans compared with African–Americans. Multiple regression analysis in the Hispanic–American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African–Americans after adjusting for known genetic and clinical predictors. Conclusion: In our cohort of inner-city Hispanic–Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic–Americans. Original submitted 13 July 2012; Revision submitted 21 September 2012

Aims: CYP4F2*3 (p.V433M) has been associated with higher warfarin dose requirements; however, its frequency, like other CYP2C9 and VKORC1 variants, has not been systematically assessed in major racial/ethnic populations. Thus, we determined the individual and combined frequencies of important CYP2C9, VKORC1 and CYP4F2 variants in several racial/ethnic groups. Materials & methods: Healthy African–American, Asian, Caucasian, Hispanic and Ashkenazi Jewish (AJ) blood donors were genotyped for CYP2C9 (*2, *3, *4, *5, *6, *8, *11 and *13), VKORC1 (g.-1639G>A) and CYP4F2 (*3 [p.V433M] and rs2189784). Results: The combined frequencies of variant CYP2C9 alleles were 0.133, 0.078, 0.212, 0.178 and 0.212 among African–American, Asian, Caucasian, Hispanic and AJ individuals, respectively. CYP4F2*3 frequencies were prevalent (0.233–0.342) among Asian, Caucasian, Hispanic and AJ individuals, while significantly less frequent among African–Americans (0.117; p < 0.0001). In addition, CYP4F2*3 was in linkage disequilibrium with rs2189784, an allele recently associated with time-to-therapeutic international normalized ratio, among all studied populations. Importantly, 87–95% of Asian, Caucasian, Hispanic and AJ individuals had a variant CYP2C9, VKORC1 and/or CYP4F2*3 allele, compared with only 53% of African–Americans (p < 0.0001). Conclusions: Compared with other racial/ethnic populations studied, only approximately one in 80 African–Americans were CYP4F2*3 homozygous, indicating that this population would benefit less from dosing algorithms that include this variant. In addition, the unique allele frequency profiles identified among the different populations partly explain why genotype-guided warfarin dosing algorithms perform less well for African–Americans and suggest that other unidentified genetic and/or nongenetic factors that influence warfarin dosage may exist in this population.

Introduction: It is known that warfarin treatment is problematic, due to its narrow therapeutic range and to the great interindividual variability. Numerous papers have shown the important contribution of CYP2C9 and VKORC1 genetic variants to this variability. Recently, a new SNP within the CYP4F2 gene was found associated with warfarin dose in the USA. Aims: The aim of our work was to replicate this study in the Italian population and to assess the new CYP4F2 variant relative contribution in explaining warfarin dose variability with respect to CYP2C9 and VKORC1 genetic variants together with age and weight. Materials & methods: CYP4F2 rs2108622 genotyping was performed by allelic discrimination assay by TaqMan®technology. Analysis of variance and multiple linear regression analyses were carried out to examine the contribution of genetic and nongenetic factors. Results: Our TT patients require 5.49 mg/day versus 2.93 mg/day of our CC patients. Analysis of variance indicates that about 7% of mean weekly warfarin dose variance is explained by CYP4F2 genotype. Our linear regression model including CYP4F2, CYP2C9 and VKORC1 genetic variants, age and weight, explains 60.5% of the interindividual variability. Conclusion: Our data confirm and strengthen the role of this variant.