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Pharmacogenomics of warfarin in populations of African descent.

ABSTRACT: Warfarin is the most commonly prescribed oral anticoagulant worldwide despite its narrow therapeutic index and the notorious inter- and intra-individual variability in dose required for the target clinical effect. Pharmacogenetic polymorphisms are major determinants of warfarin pharmacokinetic and dynamics and included in several warfarin dosing algorithms. This review focuses on warfarin pharmacogenomics in sub-Saharan peoples, African Americans and admixed Brazilians. These 'Black' populations differ in several aspects, notably their extent of recent admixture with Europeans, a factor which impacts on the frequency distribution of pharmacogenomic polymorphisms relevant to warfarin dose requirement for the target clinical effect. Whereas a small number of polymorphisms in VKORC1 (3673G > A, rs9923231), CYP2C9 (alleles *2 and *3, rs1799853 and rs1057910, respectively) and arguably CYP4F2 (rs2108622), may capture most of the pharmacogenomic influence on warfarin dose variance in White populations, additional polymorphisms in these, and in other, genes (e.g. CALU rs339097) increase the predictive power of pharmacogenetic warfarin dosing algorithms in the Black populations examined. A personalized strategy for initiation of warfarin therapy, allowing for improved safety and cost-effectiveness for populations of African descent must take into account their pharmacogenomic diversity, as well as socio-economical, cultural and medical factors. Accounting for this heterogeneity in algorithms that are 'friendly' enough to be adopted by warfarin prescribers worldwide requires gathering information from trials at different population levels, but demands also a critical appraisal of racial/ethnic labels that are commonly used in the clinical pharmacology literature but do not accurately reflect genetic ancestry and population diversity.

SUBMITTER: Suarez-Kurtz G

PROVIDER: S-EPMC3579249 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Pharmacogenomics of warfarin in populations of African descent.

Suarez-Kurtz Guilherme G Botton Mariana R MR

British journal of clinical pharmacology 20130201 2

Warfarin is the most commonly prescribed oral anticoagulant worldwide despite its narrow therapeutic index and the notorious inter- and intra-individual variability in dose required for the target clinical effect. Pharmacogenetic polymorphisms are major determinants of warfarin pharmacokinetic and dynamics and included in several warfarin dosing algorithms. This review focuses on warfarin pharmacogenomics in sub-Saharan peoples, African Americans and admixed Brazilians. These 'Black' populations ...[more]

PMID: 22676711

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Project description:ImportanceMajor warfarin-related bleeding occurs more frequently in African Americans than in other populations. Identification of potential genetic factors related to this adverse event may help identify at-risk patients.ObjectiveTo identify genetic factors associated with warfarin-related bleeding in patients of African descent at an international normalized ratio (INR) of less than 4.Design, setting, and participantsA case-control genome-wide association study involving patients of African descent taking warfarin was conducted in a discovery cohort (University of Chicago [2009-2011] and the University of Illinois at Chicago [2002-2011]), and associations were confirmed in a replication cohort (University of Chicago [2015-2016]). Potential population stratification was examined in the discovery cohort by principal component analysis. Odds ratios (ORs) and 95% CIs were computed for bleeding risk by logistic regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis. The potential influence of single-nucleotide polymorphisms (SNPs) on gene expression was studied by luciferase expression assays.ExposuresSingle-nucleotide polymorphisms associated with warfarin-related bleeding.Main outcomes and measuresMajor bleeding-defined as bleeding requiring hospitalization, causing a decrease in hemoglobin level of more than 2 g/dL, requiring blood transfusion, or any combination of the 3-while taking warfarin at an INR of less than 4.ResultsThe discovery cohort consisted of 31 cases (mean age, 60.1 years [SD, 14.9 years], 26 women [83.9%]) and 184 warfarin-treated controls (mean age, 57.1 years [SD, 15.7 years]) with no documented bleeding. The replication cohort consisted of 40 cases (mean age, 55.6 years [SD, 17.3 years], 27 women [67.5%]), and 148 warfarin-treated controls (mean age, 55.4 years [SD, 17.1 years]; 98 women [66.2%]) with no documented bleeding. In the discovery cohort, 4 SNPs in linkage disequilibrium on chromosome 6 (rs115112393, rs16871327, rs78132896, and rs114504854) were associated with warfarin-related bleeding but did not reach genome-wide significance. The SNP rs78132896 occurred in 11 cases (35.5%) and 9 controls (4.9%) in the discovery cohort (OR, 8.31; 95% CI, 3.2-21.5; P < 6.21 × 10-8), and the association was confirmed in the replication cohort (the SNP was present in 14 cases [35.0%] and 7 controls [4.8%]; OR, 8.24; 95% CI, 3.1-25.3, P = 5.64 × 10-5). Genome-wide significance of this SNP was achieved when the cohorts were combined via meta-analysis (OR, 8.27; 95% CI, 4.18-16.38; P = 2.05 × 10-11). These SNPs are found only in people of African descent. In vitro luciferase expression assays demonstrated that rs16871327 (enhancer SNP) and rs78132896 (promoter SNP) risk alleles together increased EPHA7 gene (Entrez Gene 2045) transcription by a mean of 14.95 (SD, 1.7) compared with wild-type alleles (mean, 9.56 [SD, 0.84]; difference, 5.39; 95% CI, 4.1-6.6; P < .001).Conclusions and relevanceIn this preliminary study involving patients of African descent taking warfarin, 4 single-nucleotide polymorphisms in linkage disequilibrium on chromosome 6 were associated with an increased risk of major bleeding at INR of less than 4. Validation of these findings in an independent prospective cohort is required.

Project description:Background: Predicting undiagnosed diabetes is a critical step toward addressing the diabetes epidemic in populations of African descent worldwide. Objective: To review characteristics of equations developed, tested, or modified to predict diabetes in African descent populations. Methods: Using PubMed, Scopus, and Embase databases, a scoping review yielded 585 research articles. After removal of duplicates (n = 205), 380 articles were reviewed. After title and abstract review 328 articles did not meet inclusion criteria and were excluded. Fifty-two articles were retained. However, full text review revealed that 44 of the 52 articles did not report findings by AROC or C-statistic in African descent populations. Therefore, eight articles remained. Results: The 8 articles reported on a total of 15 prediction equation studies. The prediction equations were of two types. Prevalence prediction equations (n = 9) detected undiagnosed diabetes and were based on non-invasive variables only. Non-invasive variables included demographics, blood pressure and measures of body size. Incidence prediction equations (n = 6) predicted risk of developing diabetes and used either non-invasive variables or both non-invasive and invasive. Invasive variables required blood tests and included fasting glucose, high density lipoprotein-cholesterol (HDL), triglycerides (TG), and A1C. Prevalence prediction studies were conducted in the United States, Africa and Europe. Incidence prediction studies were conducted only in the United States. In all these studies, the performance of diabetes prediction equations was assessed by area under the receiver operator characteristics curve (AROC) or the C-statistic. Therefore, we evaluated the efficacy of these equations based on standard criteria, specifically discrimination by either AROC or C-statistic were defined as: Poor (0.50 - 0.69); Acceptable (0.70 - 0.79); Excellent (0.80 - 0.89); or Outstanding (0.90 - 1.00). Prediction equations based only on non-invasive variables reported to have poor to acceptable detection of diabetes with AROC or C-statistic 0.64 - 0.79. In contrast, prediction equations which were based on both non-invasive and invasive variables had excellent diabetes detection with AROC or C-statistic 0.80 - 0.82. Conclusion: Equations which use a combination of non-invasive and invasive variables appear to be superior in the prediction of diabetes in African descent populations than equations that rely on non-invasive variables alone.

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Pharmacogenomics of warfarin in populations of African descent.

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Pharmacogenomics of warfarin in populations of African descent.

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