A potentially deleterious new CYP2C9 polymorphism identified in an African American patient with major hemorrhage on warfarin therapy.
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ABSTRACT:
SUBMITTER: Goldstein JA
PROVIDER: S-EPMC2662477 | biostudies-literature | 2009 Mar-Apr
REPOSITORIES: biostudies-literature
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A potentially deleterious new CYP2C9 polymorphism identified in an African American patient with major hemorrhage on warfarin therapy.
Goldstein J A JA Blaisdell J A JA Limdi N A NA
Blood cells, molecules & diseases 20081211 2
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Project description:BACKGROUND: Cytochrome P4502C9 (CYP2C9) plays a vital role in drug metabolism. There has been an increased effort to identify polymorphisms within the gene and determine their clinical consequences. However, most of these efforts have focused on populations of European descent. Herein we report the influence of CYP2C9 genotype on warfarin dose among European American and African American patients. We also identify two new mutations; one in the coding region and one in the non-coding region of the CYP2C9 gene. METHODS: Patients (?20 years of age) are enrolled after obtaining medical, lifestyle and concomitant medication history. Changes in International Normalized Ratio (INR), warfarin dose, co-medications, diet, physical activity and the occurrence of complications are documented. CYP2C9 genotype was determined using PCR-RFLP and pyrosequencing. Differences in genotype frequencies and HWE assumptions were assessed using ?(2) statistics and exact tests. The genotype dose association was evaluated using multivariable linear regression. RESULTS: This report includes 490 patients (mean age 60.6 ± 15.6, 51.3% men). African American patients comprise 48.9% of the cohort with mean follow-up of 13.5 (±10.6) months. Both the CYP2C9 *2 and *3 allele were more frequent in European Americans (11.24%, 5.1%) compared to African Americans (1.1% and 1.8%). CYP2C9 *5 (0.9%), *6 (0.4%), and *11 (1.1%) variants were only observed in African Americans. The variant genotype is more frequent among European Americans compared to African Americans (29.8% vs. 9.73%, p<0.0001). Warfarin dose was significantly related to CYP2C9 genotype (p<0.0001) both in univariate and multivariate analyses. Multivariable race-specific analyses highlight the contribution of CYP2C9 genotype among European American but not among African American patients. CONCLUSION: The variant CYP2C9 genotype is more frequent among European Americans compared to African Americans. Among African Americans the variant genotype frequency is higher than previously reported. CYP2C9 genotype predicts warfarin dose in European Americans, but not in African Americans.
| S-EPMC2756088 | biostudies-literature
Project description:Warfarin is a widely used anticoagulant whose active S-enantiomer is primarily metabolized by the CYP2C9 enzyme. The CYP2C9*2 and CYP2C9*3 alleles are associated with lower warfarin dose requirement and decreased enzyme activity. In contrast, we previously identified a novel single-nucleotide polymorphism (SNP) (rs7089580A > T) in CYP2C9 that is associated with higher warfarin dose requirement in African Americans (AAs). In this study, we examine the effect of rs7089580 on warfarin pharmacokinetics and CYP2C9 expression in 63 AA patients and 32 AA liver tissues, respectively. We found oral clearance of S-warfarin to be higher among carriers of the minor rs7089580 allele (T) compared with wild-type homozygotes (3.73 ± 1.46 vs 2.95 ± 1.39 mL/min; P = 0.04). CYP2C9 messenger RNA expression in liver tissue was also higher among A/T and T/T genotypes compared with A/A (P < 0.02). Our findings indicate that rs7089580 is associated with higher S-warfarin clearance and CYP2C9 expression and may help explain the higher dose requirement of warfarin in AAs. Furthermore, rs7089580 is in complete linkage disequilibrium with the promoter SNP rs12251841 in AAs, which may provide a biologically plausible explanation for the observed effect on CYP2C9 expression levels. Given the many clinically relevant substrates of CYP2C9, identifying polymorphisms that affect expression levels and metabolism across ethnicities is essential for individualization of doses with a narrow therapeutic index.
| S-EPMC4433569 | biostudies-literature
Project description:ObjectiveWe evaluated whether percent time in target range (PTTR), risk of over-anticoagulation [international normalized ratio (INR)>4], and risk of hemorrhage differ by race. As PTTR is a strong predictor of hemorrhage risk, we also determined the influence of PTTR on the risk of hemorrhage by race.Participants and methodsAmong 1326 warfarin users, PTTR was calculated as the percentage of interpolated INR values within the target range of 2.0-3.0. PTTR was also categorized as poor (PTTR<60%), good (60≤PTTR<70%), or excellent (PTTR≥70%) anticoagulation control. Over-anticoagulation was defined as INR more than 4 and major hemorrhages included serious, life-threatening, and fatal bleeding episodes. Logistic regression and survival analyses were carried out to evaluate the association of race with PTTR (≥60 vs. <60) and major hemorrhages, respectively.ResultsCompared with African Americans, European Americans had higher PTTR (57.6 vs. 49.1%; P<0.0001) and were more likely to attain 60≤PTTR<70% (22.9 vs. 13.1%; P<0.001) or PTTR of at least 70% (26.9 vs. 18.2%; P=0.001). Older (>65 years) patients without venous thromboembolism indication and chronic kidney disease were more likely to attain PTTR of at least 60%. After accounting for clinical and genetic factors, and PTTR, African Americans had a higher risk of hemorrhage [hazard ratio (HR)=1.58; 95% confidence interval (CI): 1.04-2.41; P=0.034]. Patients with 60≤PTTR<70% (HR=0.62; 95% CI: 0.38-1.02; P=0.058) and PTTR of at least 70% (HR=0.27; 95% CI: 0.15-0.49; P<0.001) had a lower risk of hemorrhage compared with those with PTTR less than 60%.ConclusionDespite the provision of warfarin management through anticoagulation clinics, African Americans achieve a lower overall PTTR and have a significantly higher risk of hemorrhage. Personalized medicine interventions tailored to African American warfarin users need to be developed.
| S-EPMC5657532 | biostudies-literature
Project description:The cytochrome P450 (CYP) 2C9 R150H (*8) allele occurs commonly in African Americans and is associated with lower warfarin dose requirements. We conducted a pharmacokinetic study to examine whether the CYP2C9*8 allele impacts warfarin clearance in African-American patients. We also conducted an in vitro kinetic study of S-warfarin 7-hydroxylation using complementary DNA (cDNA)-expressed CYP2C9 enzymes. We observed a 30% reduction in the unbound oral clearance of S-warfarin and a 25% lower R- to S-warfarin plasma concentration ratio in patients with the CYP2C9*8 allele (n = 12) as compared to CYP2C9*1 homozygotes (n = 26). Consistent with these findings, the in vitro intrinsic clearance of S-warfarin was 30% lower with the cDNA-expressed R150H protein as compared to the wild-type protein. These data show that the R150H variant protein expressed by the CYP2C9*8 allele is associated with lower S-warfarin clearance. This finding provides clinical and experimental evidence to explain the lower warfarin dose requirements in patients with the CYP2C9*8 allele.
| S-EPMC3879795 | biostudies-other
Project description:Alaska Native and American Indian (AN/AI) people have unique pharmacogene variation that may affect warfarin disposition and therapeutic response. We performed targeted genotyping for cytochrome P450 (CYP)2C9, vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1), CYP4F2, CYP4F11, and gamma-glutamyl carboxylase (GGCX) variants in AN/AI people receiving warfarin. The primary outcome was stable warfarin dose, defined as one dose, and associated international normalized ratio within the target range, at least 6 months after starting therapy, with two matching doses at least 2 weeks apart. Genotype-phenotype relationships were assessed by multivariate regression analysis, adjusted for self-reported heritage, age, gender, and concurrent statin use. VKORC1 genotype explained 34% of dose variability, with VKORC1 -1639G>A and 1173C>T associated with a 1.7 mg/day (P = 1.4e-05) dose reduction. Additionally, CYP2C9 N218I was suggestively significant (P = 0.077), with heterozygotes requiring 1.1 mg/day less than reference individuals. Self-reported heritage was significantly associated with dose, largely driven by differences in the diagnostic VKORC1 allele frequencies among AN/AI people.
| S-EPMC6510382 | biostudies-literature
Project description:Warfarin continues to be the mainstay therapy for preventing thrombus formation. Although pharmacogenetic algorithms have shown higher predictability of the optimal warfarin dose and lower occurrence of bleeding episodes, they often do not include ethno-specific genetic variants relevant to non-Europeans. This case report describes a rare missense variant at exon 9 of CYP2C9 (rs202201137; c.1370A>G transition; p.Asn457Ser) found in a Puerto Rican patient with low warfarin dose requirements (3 mg/day). The haplotype characterized by two amino acid changes, Asn457Ser and Arg144Cys (rs1799853; c.430C>T), has been designated CYP2C9*61 by the Pharmacogene Variation Consortium. According to prediction scores assessed with the Combined Annotation Dependent Depletion tool, CYP2C9*61 (p.Asn457Ser) was classified as nondeleterious, therefore its impact on CYP2C9 enzymatic activity cannot be postulated.
| S-EPMC6479273 | biostudies-literature
Project description:Precise dosing of warfarin is important to achieve therapeutic benefit without adverse effects. Pharmacogenomics explains some interindividual variability in warfarin response, but less attention has been paid to drug-drug interactions in the context of genetic factors. We investigated retrospectively the combined effects of cytochrome P450 (CYP)2C9 and vitamin K epoxide reductase complex (VKORC)1 genotypes and concurrent exposure to CYP2C9-interacting drugs on long-term measures of warfarin anticoagulation. Study participants predicted to be sensitive responders to warfarin based on CYP2C9 and VKORC1 genotypes, had significantly greater international normalized ratio (INR) variability over time. Participants who were concurrently taking CYP2C9-interacting drugs were found to have greater INR variability and lesser time in therapeutic range. The associations of INR variability with genotype were driven by the subgroup not exposed to interacting drugs, whereas the effect of interacting drug exposure was driven by the subgroup categorized as normal responders. Our findings emphasize the importance of considering drug interactions in pharmacogenomic studies.
| S-EPMC7485961 | biostudies-literature
Project description:AimsThe influence of CYP2C9 and VKORC1 on warfarin dose, time to target International Normalized Ratio (INR), time to stabilization, and risk of over-anticoagulation (INR: > 4) was assessed after adjustment for clinical factors, intraindividual variation in environmental factors and unobserved heterogeneity.Materials & methodsCommon CYP2C9 and VKORC1 polymorphisms were assessed in 302 European-Americans and 273 African-Americans receiving warfarin. Race-stratified multivariable analyses evaluated the influence of CYP2C9 and VKORC1 on warfarin response.Results & conclusionCYP2C9 and VKORC1 accounted for up to 30% of the variability in warfarin dose among European-Americans and 10% among African-Americans. Neither CYP2C9 nor VKORC1 influenced the time to target INR or stabilization among patients of either race, and neither influenced the risk of over-anticoagulation among African-Americans. The risk of over-anticoagulation was higher among European-Americans with variant VKORC1 1173C/T (p < 0.01) and marginally significant among those with variant CYP2C9 (p = 0.08) genotype. Although CYP2C9 and VKORC1 genotyping can facilitate individualized initiation of warfarin dose in African and European-Americans, the ability to predict the risk of over-anticoagulation is inconsistent across race. Identification of other factors that can predict such risk consistently in a racially diverse group will facilitate individualized maintenance of warfarin therapy.
| S-EPMC2757655 | biostudies-literature
Project description:Differences in the tumor immune microenvironment may result in differences in prognosis and response to treatment in cancer patients. We hypothesized that differences in the tumor immune microenvironment may exist between African American (AA) and NonAA patients, due to ancestry-related or socioeconomic factors, that may partially explain differences in clinical outcomes. We analyzed clinically matched triple-negative breast cancer (TNBC) tissues from self-identified AA and NonAA patients and found that stromal TILs, PD-L1 IHC-positivity, mRNA expression of immune-related pathways, and immunotherapy response predictive signatures were significantly higher in AA samples (p < 0.05; Fisher's Exact Test, Mann-Whitney Test, Permutation Test). Cancer biology and metabolism pathways, TAM-M2, and Immune Exclusion were significantly higher in NonAA samples (p < 0.05; Permutation Test, Mann-Whitney Test). There were no differences in somatic tumor mutation burden. Overall, there is greater immune infiltration and inflammation in AA TNBC and these differences may impact response to immune checkpoint inhibitors and other therapeutic agents that modulate the immune microenvironment.
| S-EPMC9307813 | biostudies-literature
Project description:ObjectivesPharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide interindividual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K-dependent blood clotting factors.MethodsWe resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation in Anchorage, Alaska and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific single nucleotide polymorphisms in larger cohorts of each study population (380 and 350, respectively).ResultsWe identified high frequencies of the lower-warfarin dose VKORC1 haplotype (-1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2, and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity.ConclusionOverall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the USA, a finding consistent with clinical experience in Alaska.
| S-EPMC4461509 | biostudies-literature