Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans

Abstract Warfarin dose requirements have been associated with 2 main haplotypes in VKORC1, but the responsible polymorphisms remain unknown. To search for regulatory polymorphisms, we measured allelic mRNA expression of VKORC1 in human liver, heart, and B lymphocytes. The observed 2-fold allelic mRNA expression imbalance narrowed possible candidate SNPs to −1639G>A and 1173C<T. This genotype effect was observed selectively in the liver but not in heart or lymphocytes. In vitro expression of VKORC1 gene constructs, including coding and promoter regions, failed to reveal any genotype effect on transcription and mRNA processing. Chromatin immunoprecipitation with antibodies against acetyl-histone3 and K4-trimethyl-histone3 revealed preferential association of the promoter −1639 G allele with active chromatin, consistent with enhanced mRNA expression. The minor −1639 A allele generates a suppressor E-box binding site, apparently regulating gene expression by a mechanism undetectable with reporter gene assays. A clinical association study demonstrated that promoter SNP −1639G>A, and the tightly linked intron1 SNP 1173C>T, predict warfarin dose more accurately than intron 2 SNP 1542G>C in blacks. Increased warfarin dose requirement in blacks was accounted for by lower frequency of the −1639 A allele. Therefore, −1639G>A is a suitable biomarker for warfarin dosing across ethnic populations.

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VKORC1 Asp36Tyr geographic distribution and its impact on warfarin dose requirements in Egyptians

Thrombosis and Haemostasis ◽

10.1160/th12-10-0789 ◽

2013 ◽

Vol 109 (06) ◽

pp. 1045-1050 ◽

Cited By ~ 15

Author(s):

Mohamed Hossam A. Shahin ◽

Larisa H. Cavallari ◽

Minoli A. Perera ◽

Sherief I. Khalifa ◽

Anne Misher ◽

...

Keyword(s):

African Americans ◽

Middle Eastern ◽

Linear Regression Analysis ◽

Warfarin Dose ◽

The United States ◽

Eastern Africa ◽

Dose Requirement ◽

Population Prevalence ◽

Warfarin Dose Requirement ◽

Dose Variability

SummaryThe VKORC1 Asp36Tyr single nucleotide polymorphism (SNP) is one of the most promising predictors of high warfarin dose, but data on its population prevalence is incomplete. We determined the frequency of this SNP in participants from seven countries on four continents and investigated its effect on warfarin dose requirement. One thousand samples were analysed to define the population prevalence of this SNP. Those samples included individuals from Egypt, Ghana, Sudan, Kenya, Saudi Arabia, Peru and African Americans from the United States. A total of 206 Egyptian samples were then used to investigate the effect of this SNP on warfarin dose requirements. This SNP was most frequent among Kenyans and Sudanese, with a minor allele frequency (MAF) of 6% followed by Saudi Arabians and Egyptians with a MAF of 3% and 2.5%, respectively. It was not detected in West Africans, based on our data from Ghana, and a large cohort of African Americans. Egyptian carriers of the VKORC1 Tyr36 showed higher warfarin dose requirement (57.1 ± 29.4 mg/week) than those with the Asp36Asp genotype (35.8 ± 16.6 mg/week; p=0.03). In linear regression analysis, this SNP had the greatest effect size among the genetic factors (16.6 mg/week increase in dose per allele), and improved the warfarin dose variability explained in Egyptians (model R2 from 31% to 36.5%). The warfarin resistant VKORC1 Asp36Tyr appears to be confined to north-eastern Africa and nearby Middle-Eastern populations, but in those populations where it is present, it has a significant influence on warfarin dose requirement and the percent of warfarin dose variability that can be explained.

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Population-specific imputation of gene expression improves prediction of pharmacogenomic traits for African Americans

10.1101/115451 ◽

2017 ◽

Cited By ~ 2

Author(s):

Assaf Gottlieb ◽

Roxana Daneshjou ◽

Marianne DeGorter ◽

Stephen B. Montgomery ◽

Russ B. Altman

Keyword(s):

Gene Expression ◽

Genetic Variation ◽

Association Studies ◽

Warfarin Dose ◽

Prediction Algorithm ◽

Specific Gene ◽

Genome Wide Association Studies ◽

Dose Requirement ◽

Protein Coding ◽

Specific Mapping

ABSTRACTGenome-wide association studies (GWAS) are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power, and allows the effects of both protein coding variation as well as variation in expression to be combined into “gene level” effects.Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein coding regions. Here, we introduce a method that improves the predicted dose by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression—on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic (PK) and pharmacodynamic (PD) pathways of warfarin within training and validation sets comprising both European and African-descent individuals. We build gene-tissue signatures associated with warfarin dose, and identify a signature of eleven gene-tissue pairs that significantly augment the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations. Our results demonstrate that imputed expression can improve dose prediction, in a population-specific manner.

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Impact of gamma-glutamyl carboxylase gene polymorphisms on warfarin dose requirement: A systematic review and meta-analysis

Thrombosis Research ◽

10.1016/j.thromres.2015.01.029 ◽

2015 ◽

Vol 135 (4) ◽

pp. 739-747 ◽

Cited By ~ 16

Author(s):

Yifan Sun ◽

Zhitong Wu ◽

Shan Li ◽

Xue Qin ◽

Taijie Li ◽

...

Keyword(s):

Systematic Review ◽

Gene Polymorphisms ◽

Meta Analysis ◽

Warfarin Dose ◽

Dose Requirement ◽

Gamma Glutamyl ◽

Warfarin Dose Requirement

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The impact of VKORC1-1639G > A genetic polymorphism upon warfarin dose requirement in different ethnic populations

Current Medical Research and Opinion ◽

10.1185/03007995.2014.912982 ◽

2014 ◽

Vol 30 (8) ◽

pp. 1505-1511 ◽

Cited By ~ 3

Author(s):

Bo Jin ◽

Yong Hong ◽

Jun Zhu ◽

Yong Li ◽

Hai-Ming Shi

Keyword(s):

Genetic Polymorphism ◽

Warfarin Dose ◽

Dose Requirement ◽

Ethnic Populations ◽

Warfarin Dose Requirement ◽

The Impact

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Association between polymorphisms in microRNA seed region and warfarin stable dose

Postgraduate Medical Journal ◽

10.1136/postgradmedj-2019-137197 ◽

2020 ◽

pp. postgradmedj-2019-137197

Author(s):

Maryam Hosseindokht ◽

Hamed Zare ◽

Rasoul Salehi ◽

Leyla Pourgholi ◽

Shayan Ziaee ◽

...

Keyword(s):

Fragment Length Polymorphism ◽

Interindividual Variability ◽

Warfarin Dose ◽

Optimal Dose ◽

Seed Region ◽

Dose Requirement ◽

Vitamin K Cycle ◽

Warfarin Dose Requirement ◽

Potential Factor ◽

Warfarin Maintenance Dose

BackgroundThe optimal dose of anticoagulant warfarin varies among patients to achieve the target international normalised ratio. Although genetic variations related to warfarin pharmacokinetics and vitamin K cycle are important factors associated with warfarin dose requirements, these variations do not completely explain the large interindividual variability observed in the most populations, suggesting that additional factors may contribute to this variability. microRNAs have recently been introduced as regulators of drug function genes, and therefore, may be involved in drug responses. In this study, we aimed to evaluate the possible association between variants in the seed region of microRNAs, which target the genes involved in the action of warfarin and warfarin dose requirement.Methods526 samples were collected from Iranian patients. Four selected polymorphisms in the seed region of microRNAs (rs2910164, rs66683138, rs12416605 and rs35770269 in miR-146a, miR-3622a, miR-938 and miR-449c, respectively) were genotyped by PCR-restriction fragment length polymorphism method.Resultsrs2910164 C/G in the seed region of miR-146a was associated with warfarin dose requirement (p<0.001); the patients with GG genotype had the higher mean dose of warfarin (40.6 mg/week, compared with 33.9 and 31.8 mg/week for GC and CC genotypes, respectively). The association of other polymorphisms with warfarin dose requirement was not statistically significant.Conclusionrs2910164 C/G in the seed region of miR-146a is associated with warfarin maintenance dose, likely by disrupting interaction between miR-146a and ATP-binding cassette subfamily B member 1 gene, ABCB1. Therefore, this polymorphism may possibly be a potential factor for assessment of warfarin dose requirements.

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The effects of CYP2C9 and VKORC1 gene polymorphisms on warfarin maintenance dose in Turkish cardiac patients

Future Cardiology ◽

10.2217/fca-2020-0027 ◽

2020 ◽

Author(s):

Cansu Selcan Akdeniz ◽

Mehtap Cevik ◽

Ismail Polat Canbolat ◽

Selen Yurdakul ◽

Penbe Cagatay ◽

...

Keyword(s):

Warfarin Dose ◽

Individual Variability ◽

Considerable Proportion ◽

Wild Type ◽

Dose Requirement ◽

Study Results ◽

Warfarin Dose Requirement ◽

Turkish Patients ◽

Vkorc1 Gene ◽

Warfarin Maintenance Dose

Aim: Our aim was to examine the effect of CYP2C9 and VKORC1 polymorphisms on warfarin dose requirements in Turkish patients. Materials & methods: 24 warfarin prescribed patients were included and analyzed for eight VKORC1 and 6 CYP2C9 polymorphisms in the study. Results: Patients with CYP2C9 *1/*1 and VKORC1 -1639 GG and GA genotypes required higher warfarin doses in comparison to wild type VKORC1 genotype. Patients with CYP2C9 *1/*3 and VKORC1 -1639 GG genotypes simultaneously, required the lowest dose of warfarin (4.64 mg/day). Patients with CYP2C9 *1/*1 and VKORC1 9041 AA genotype were found to require higher warfarin doses. Conclusion: Our results provide additional evidence to support the hypothesis that CYP2C9 *2, *3, VKORC1 9041 G > A polymorphisms explain considerable proportion of inter-individual variability in warfarin dose requirement.

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Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement

Blood ◽

10.1182/blood-2011-07-365502 ◽

2012 ◽

Vol 119 (3) ◽

pp. 861-867 ◽

Cited By ~ 52

Author(s):

Caroline Moreau ◽

Fanny Bajolle ◽

Virginie Siguret ◽

Dominique Lasne ◽

Jean-Louis Golmard ◽

...

Keyword(s):

Vitamin K ◽

Dose Response ◽

Maintenance Dose ◽

Vitamin K Antagonists ◽

Warfarin Dose ◽

International Normalized Ratio ◽

Individual Variability ◽

Dose Requirement ◽

Warfarin Dose Requirement ◽

Main Determinants

Abstract Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated.

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