scholarly journals Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups

Blood ◽  
2010 ◽  
Vol 115 (18) ◽  
pp. 3827-3834 ◽  
Author(s):  
Nita A. Limdi ◽  
Mia Wadelius ◽  
Larisa Cavallari ◽  
Niclas Eriksson ◽  
Dana C. Crawford ◽  
...  
Keyword(s):  
Linear Regression ◽  
Warfarin Dose ◽  
Population Level ◽  
Racial Groups ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Dose Prediction ◽  
Similar Dose ◽  
Warfarin Dosing ◽  
Dose Variability

Abstract Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 −1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 −1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 −1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the −1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.

A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2477-2480 ◽  
Author(s):  
Ronen Loebstein ◽  
Ilana Dvoskin ◽  
Hillel Halkin ◽  
Manuela Vecsler ◽  
Aharon Lubetsky ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Odds Ratio ◽  
Confidence Limit ◽  
Warfarin Dose ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Warfarin Resistance ◽  
Warfarin Dosing ◽  
High Doses

Abstract CYP2C9 and VKORC1 genetic variants are associated with low and intermediate warfarin dose requirements, but markers of high doses are less well characterized. We analyzed the VKORC1 coding sequence and known CYP2C9 and VKORC1 polymorphisms in 15 selected warfarin-resistant (dose, 80 to 185 mg/wk) and 8 warfarin-sensitive patients (7 to 13 mg/wk) and 99 unselected controls (8 to 105 mg/wk). We identified a coding VKORC1 Asp36Tyr polymorphism in 7 of 15 resistant compared with 0 of 8 sensitive patients (P = .026) Carriers of Asp36Tyr in the control group (8 of 99) required significantly higher warfarin doses of 80.9 ± 10.1 mg/wk compared with 42.7 ± 7.5 mg/wk in noncarriers (F = 9.79, P = .002). Asp36Tyr was significantly associated with doses of more than 70 mg/wk (odds ratio, 13.0; 95% confidence limit, 1.3 to 124.2), while doses of 20 to 70 mg/wk were associated with Asp36Tyr (partial r2 = .11; P = .004), CYP2C9*2 and *3 (r2 = .08; P = .01), and VKORC1*2 and *3 markers (r2 = .05; P = .05). All Asp36Tyr carriers also had VKORC1*1 tag–single nucleotide polymorphisms (tag-SNPs) indicating a new haplotype. Asp36Tyr was common in Jewish ethnic groups of Ethiopian (15%) and Ashkenazi (4%) origin. We suggest that Asp36Tyr is a new marker of the high end of the warfarin dosing range.

scholarly journals Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 578 ◽  
Author(s):  
Laith AL-Eitan ◽  
Ayah Almasri ◽  
Rame Khasawneh
Keyword(s):  
Warfarin Therapy ◽  
Catalytic Properties ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Haplotype Blocks ◽  
Cardiovascular Patients ◽  
Cyp2c9 Gene ◽  
Vkorc1 Gene

Warfarin is an oral anticoagulant frequently used in the treatment of different cardiovascular diseases. Genetic polymorphisms in the CYP2C9 and VKORC1 genes have produced variants with altered catalytic properties. A total of 212 cardiovascular patients were genotyped for 17 Single Nucleotide Polymorphisms (SNPs) within the CYP2C9 and VKORC1 genes. This study confirmed a genetic association of the CYP2C9*3 and VKORC1 rs10871454, rs8050894, rs9934438, and rs17708472 SNPs with warfarin sensitivity. This study also found an association between CYP2C9 and VKORC1 genetic haplotype blocks and warfarin sensitivity. The initial warfarin dose was significantly related to the CYP2C9*3 polymorphism and the four VKORC1 SNPs (p < 0.001). There were significant associations between rs4086116 SNP and TAT haplotype within CYP2C9 gene and rs17708472 SNP and CCGG haplotype within VKORC1 gene and warfarin responsiveness. However, possessing a VKORC1 variant allele was found to affect the international normalized ratio (INR) outcomes during initiation of warfarin therapy. In contrast, there was a loose association between the CYP2C9 variant and INR measurements. These findings can enhance the current understanding of the great variability in response to warfarin treatment in Arabs.

scholarly journals Emergence and Magnitude of ML336 Resistance in Venezuelan Equine Encephalitis Virus Depend on the Microenvironment

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Jasper Lee ◽  
Jyothi Parvathareddy ◽  
Dong Yang ◽  
Shruti Bansal ◽  
Kathryn O’Connell ◽  
...  
Keyword(s):  
Population Level ◽  
Venezuelan Equine Encephalitis Virus ◽  
Encephalitis Virus ◽  
Nucleotide Polymorphisms ◽  
Venezuelan Equine Encephalitis ◽  
Single Nucleotide ◽  
Equine Encephalitis Virus ◽  
Antiviral Compounds ◽  
Generation Sequencing ◽  
Over Time

ABSTRACT Venezuelan equine encephalitis virus (VEEV) is a New World Alphavirus that can cause neurological disease and death in humans and equines following transmission from infected mosquitoes. Despite the continued epidemic threat of VEEV, and its potential use as a bioterrorism agent, there are no FDA-approved antivirals or vaccines for treatment or prevention. Previously, we reported the discovery of a small molecule, ML336, with potent antiviral activity against VEEV. To further explore the population-level resistance profiles of ML336, we developed a whole-genome next-generation sequencing (NGS) approach to examine single nucleotide polymorphisms (SNPs) from virus passaged in dose escalation studies in a nonhuman primate kidney epithelial and a human astrocyte cell line, Vero 76 and SVGA, respectively. We passaged VEEV TC-83 in these two cell lines over seven concentrations of ML336, starting at 50 nM. NGS revealed several prominent mutations in the nonstructural protein (nsP) 3 and nsP4 genes that emerged consistently in these two distinct in vitro environments—notably, a mutation at Q210 in nsP4. Several of these mutations were stable following passaging in the absence of ML336 in Vero 76 cells. Network analyses showed that the trajectory of resistance differed between Vero and SVGA. Moreover, the penetration of SNPs was lower in SVGA. In conclusion, we show that the microenvironment influenced the SNP profile of VEEV TC-83. Understanding the dynamics of resistance in VEEV against newly developed antiviral compounds will guide the design of optimal drug candidates and dosing regimens for minimizing the emergence of resistant viruses. IMPORTANCE RNA viruses, including Venezuelan equine encephalitis virus (VEEV), have high mutation rates that allow for rapid adaptation to selective pressures in their environment. Antiviral compounds exert one such pressure on virus populations during infections. Next-generation sequencing allows for examination of viruses at the population level, which enables tracking of low levels of single-nucleotide polymorphisms in the population over time. Therefore, the timing and extent of the emergence of resistance to antivirals can be tracked and assessed. We show here that in VEEV, the trajectory and penetration of antiviral resistance reflected the microenvironment in which the virus population replicates. In summary, we show the diversity of VEEV within a single population under antiviral pressure and two distinct cell types, and we show that population dynamics in these viruses can be examined to better understand how they evolve over time.

5′-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3055-3057 ◽  
Author(s):  
Harumi Takahashi ◽  
Ichiro Ieiri ◽  
Grant R. Wilkinson ◽  
Gail Mayo ◽  
Toshitaka Kashima ◽  
...  
Keyword(s):  
Warfarin Dose ◽  
Japanese Patients ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Coding Region ◽  
Single Nucleotide ◽  
Therapeutic Anticoagulation ◽  
Flanking Region ◽  
Wild Type Promoter ◽  
Cyp2c9 Activity

Abstract White and Japanese patients require different warfarin dosages to achieve therapeutic anticoagulation, but this can be only partly explained by genetic variability in the coding region of CYP2C9—a critical enzyme in the drug's metabolism. Accordingly, analysis of the -2.1-kb 5′-flanking region of CYP2C9 was undertaken in 22 white and 38 Japanese patients whose unbound oral clearance of S-warfarin had been previously determined. Thirteen single nucleotide polymorphisms (SNPs) were identified, some of which were in linkage disequilibrium with functionally defective coding region variants. Those 5′-flanking patterns linked with at least one CYP2C9*3 allele or CYP2C9*2/*3 were associated with reduced CYP2C9 activity and warfarin dose. Japanese patients possessing the wild-type promoter and coding sequences had significantly (P &lt; .01) greater CYP2C9 activity than white patients with the corresponding genotype. In conclusion, either unidentified polymorphisms further upstream in the promoter region or environmental factor(s) account for the differences in the warfarin doses between whites and Japanese. (Blood. 2004;103: 3055-3057)

scholarly journals COVID-19: Variant screening, an important step towards precision epidemiology

2020 ◽  
Author(s):  
Amrita Chattopadhyay ◽  
Tzu-Pin Lu ◽  
Ching-Yu Shih ◽  
Liang-Chuan Lai ◽  
Mong-Hsun Tsai ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Population Level ◽  
Copy Number Variations ◽  
Nucleotide Polymorphisms ◽  
Structural Variations ◽  
Single Nucleotide ◽  
Genomic Technologies ◽  
Gender And Age ◽  
Informed Treatment ◽  
The Difference

AbstractPrecision epidemiology using genomic technologies allows for a more targeted approach to COVID-19 control and treatment at individual and population level, and is the urgent need of the day. It enables identification of patients who may be at higher risk than others to COVID-19-related mortality, due to their genetic architecture, or who might respond better to a COVID-19 treatment. The COVID-19 virus, similar to SARS-CoV, uses the ACE2 receptor for cell entry and employs the cellular serine protease TMPRSS2 for viral S protein priming. This study aspires to present a multi-omics view of how variations in the ACE2 and TMPRSS2 genes affect COVID-19 infection and disease progression in affected individuals. It reports, for both genes, several variant and gene expression analysis findings, through (i) comparison analysis over single nucleotide polymorphisms (SNPs), that may account for the difference of COVID-19 manifestations among global sub-populations; (ii) calculating prevalence of structural variations (copy number variations (CNVs) / insertions), amongst populations; and (iii) studying expression patterns stratified by gender and age, over all human tissues. This work is a good first step to be followed by additional studies and functional assays towards informed treatment decisions and improved control of the infection rate.

scholarly journals SNPs in microRNA target sites and their potential role in human disease

Open Biology ◽  
2017 ◽  
Vol 7 (4) ◽  
pp. 170019 ◽  
Author(s):  
Adrianna Moszyńska ◽  
Magdalena Gebert ◽  
James F. Collawn ◽  
Rafał Bartoszewski
Keyword(s):  
Association Studies ◽  
Population Level ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Microrna Target ◽  
Promoter Regions ◽  
Single Nucleotide ◽  
Coding Regions ◽  
Genome Wide ◽  
Splice Junctions

In the post-genomic era, the goal of personalized medicine is to determine the correlation between genotype and phenotype. Developing high-throughput genotyping technologies such as genome-wide association studies (GWAS) and the 1000 Genomes Project ( http://www.internationalgenome.org/about/#1000G_PROJECT ) has dramatically enhanced our ability to map where changes in the genome occur on a population level by identifying millions of single nucleotide polymorphisms (SNPs). Polymorphisms, particularly those within the coding regions of proteins and at splice junctions, have received the most attention, but it is also now clear that polymorphisms in the non-coding regions are important. In these non-coding regions, the enhancer and promoter regions have received the most attention, whereas the 3′-UTR regions have until recently been overlooked. In this review, we examine how SNPs affect microRNA-binding sites in these regions, and how mRNA stability changes can lead to disease pathogenesis.

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