Association of Warfarin Therapy with APOE and VKORC1 Genes Polymorphism in Iranian Population.
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SUBMITTER: Rafiee S
PROVIDER: S-EPMC5610779 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
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Association of Warfarin Therapy with <i>APOE</i> and <i>VKORC1</i> Genes Polymorphism in Iranian Population.
Rafiee Sajad S Rajabibazl Masoumeh M Meshkani Reza R Daraei Azam A Zargari Mehryar M Sharafeddin Fahimeh F Fazeli Zahra Z Toffani Milani Attabak A Taherkhani Maryam M
Iranian journal of pharmaceutical research : IJPR 20170101 3
Warfarin is a vitamin K antagonist that genetic and non-genetic factors affected on its dose requirement in the patients with cardio vascular disease. The aim of this study was whether the <i>APOE</i> and <i>VKORC1</i> polymorphisms influence on warfarin dose requirements in the part of Iranian patients. Blood samples were collected from 86 warfarin-treated patients. After extraction of genomic DNA, the <i>VKORC1</i> (rs9923231) and the <i>APOE</i> (rs429358 and rs7412) polymorphisms were genoty ...[more]
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Project description:What is already known about this subjectRecent studies on pharmacogenetics of warfarin have implicated apolipoprotein E (APOE) polymorphisms to influence the vitamin K dependent coagulation cascade and hence the efficacy of warfarin. Studies among Caucasian and African Americans showed a significant but conflicting role of apolipoprotein E (APOE) isoforms in warfarin pharmacogenetics. The contribution of APOE isoforms in influencing variations in warfarin requirements in Asian subjects remains to be investigated.What this study addsThis is the first report of a population study in Asians exploring the role of isoforms encoded by three APOE alleles (epsilon 2, epsilon 3, epsilon 4) in influencing warfarin dose requirements. The present study showed that the APOE epsilon 3/epsilon 3 isoform is the predominant genotype in the Asian population. The study also showed that APOE isoforms may not be important in affecting warfarin pharmacodynamics in Asian patients. It also suggested that the impact of different APOE isoforms depended on the frequency of APOE genotypes in the population, in particular the epsilon 4 allele containing genotypes.AimsTo investigate the influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients.MethodsA total of 174 Asian patients (Chinese, n = 96; Malays, n = 50; Indians, n = 28) who had stable daily warfarin doses for at least 1 month were recruited. Following genomic DNA extraction from venous blood, pharmacogenetic analysis of APOE and VKORC1 genes was done by DNA sequencing.ResultsThe majority of the Asian patients (78%) harboured the APOE epsilon 3/epsilon 3 genotype. Different APOE genotypes were found not to have any significant influence on mean daily warfarin dose requirements. Warfarin dose requirements in the pooled Asian patients homozygous for the VKORC1 H1 haplotype were significantly lower compared with patients homozygous for the H7 haplotype (H1-H1 vs. H7-H7: 2.79 +/- 1.06 mg day(-1)vs. 5.45 +/- 2.3 mg day(-1), P < 0.001).ConclusionsThe present study suggests that APOE variants have minimal impact on warfarin dose requirements in Asian patients, probably due to the low frequency of epsilon 4 allele containing genotypes.
| S-EPMC2291220 | biostudies-literature
Project description: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.
| S-EPMC2865873 | biostudies-literature
Project description:BackgroundAlthough multiple reports have documented the influence of CYP2C9 and VKORC1 variants on warfarin dose, risk of over-anticoagulation and hemorrhage, their influence on anticoagulation maintenance and individual proportion of time spent in target INR range (PPTR) is limited. Moreover the potential benefit of genotype-guided dosing implemented after initiation of therapy in a racially diverse population has not been explored. Herein we present the influence of CYP2C9 and VKORC1 C1173T on warfarin response during the first 30 days of therapy.MethodsWarfarin dose was empirically determined in 250 African Americans 271 European Americans. The influence of CYP2C9 and VKORC1 on rate of INR increase, anticoagulation maintenance, risk of over-anticoagulation, and change in dose over 30 days was evaluated after adjustment for socio-demographic, lifestyle and clinical factors. Possession of variant VKORC1 (+/- variant CYP2C9) genotype was associated with a more rapid attainment of target INR and higher frequency of dose adjustments. Patients possessing variant genotypes spent less time in target range. However adjustment for rate of INR increase rendered the association non-significant. European Americans (but not African Americans) possessing variant VKORC1 (+/- variant CYP2C9) genotype had a higher risk of over-anticoagulation. Neither CYP2C9 nor VKORC1 influenced the risk of minor hemorrhage. CYP2C9 and VKORC1 explained 6.3% of the variance in dose change over the first 30 days of therapy demonstrating that the usefulness of genotype-guided dosing may extend beyond first day of therapy.ConclusionThe benefit of genotype-based dose prediction may extend beyond first few days of therapy. Whether genotype-guided dosing will decrease the risk of over-anticoagulation, improve anticoagulation control and most importantly improve outcomes for chronic warfarin users remains to be proven.
| S-EPMC2789741 | biostudies-literature
Project description:BackgroundMale infertility is a heterogeneous disease which can occur due to spermatogenesis defects. The idiopathic azoospermia and oligospermia are the common cause of male infertility with unknown underlying molecular mechanisms. The aim of this study was to investigate association of idiopathic azoospermia and oligospermia with single-nucleotide polymorphisms of CATSPER1, SPATA16 and TEX11 genes in Iranian-Azeri men.MethodsIn this case-control study, we recruited 100 infertile men (case group) and 100 fertile men (control group) from Azeri population in north western provinces, Iran, population. The genomic DNA was extracted using a proteinase K method from peripheral blood leukocytes. The genotypes analysis was conducted using tetra-primer amplification refractory mutation system-polymerase chain reaction method. The obtained data were analyzed by statistical software.ResultsWe found a significant difference in the frequencies of heterozygote AB and mutant homozygote BB genotypes in the CATSPER1 (rs2845570) gene polymorphism between patients and healthy controls (p < 0.05). Moreover, we observed a significant difference in the frequencies of heterozygote BA genotype in the SPATA16 (rs1515442) gene polymorphism between patients and healthy controls (p < 0.05). However, no significant difference was found in genotypes distribution of case and control groups in the TEX11 (rs143246552) gene polymorphism.ConclusionOur finding showed that the CATSPER1 (rs2845570) and SPATA16 (rs1515442) genes polymorphism may play an important role in idiopathic azoospermia and oligospermia in Iranian Azeri population. However, more extensive studies with larger sample sizes from different ethnic origins are essential for access more accurate results.
| S-EPMC8897944 | biostudies-literature
Project description:IntroductionIdentifying obesity risk factors as a health problem facing communities is crucial given its complexity. The vitamin D receptor gene has been reported as a possible cause of this disease.ObjectiveTo study the association of the VDR gene ApaI, BsmI, and TaqI polymorphisms with obesity in an Iranian population.Material and methodsWe analyzed the genotypes of 348 obese (BMI≥30 kg/m2) and 320 non-obese people (BMI: 18.5-24.9 kg/m2) using PCR-RFLP. We measured FBS, TG, total cholesterol, and HDL and LDL cholesterol levels in an automatic biochemical analyzer.ResultsWe found significantly higher BMI, FBS, and TG levels in the obese group compared to the control. In the obese individuals, the frequency of genotype AA was 47.1% and that of the combined Aa+aa genotype, 52.9% while in the control group they were 30% and 70%, respectively (p=0.024, 95% confidence interval (CI)=1.100-3.933, odds ratio (OR)=2.08). A and a alleles frequencies for the ApaI polymorphism were statistically significant in the two groups (allele A vs. a; p=0.017). No significant relationship was observed between TaqI genotypes and alleles in the control and obese subjects.ConclusionWe found that VDR ApaI (rs7975232 C/A) polymorphism appeared to be a risk factor for obesity. Especially, the A allele and the AA genotype in ApaI were associated with the obesity phenotypes.
| S-EPMC8740557 | biostudies-literature
Project description:Warfarin demonstrates a wide interindividual variability in response that is mediated partly by variants in cytochrome P450 2C9 (CYP2C9) and vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1). It is not known whether variants in calumenin (CALU) (vitamin K reductase regulator) have an influence on warfarin dose requirements. We resequenced CALU regions in a discovery cohort of dose outliers: patients with high (>90th percentile, n = 55) or low (<10th percentile, n = 53) warfarin dose requirements (after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high doses (P = 0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: (i) 496 patients of mixed ethnicity and (ii) 194 African-American patients. The G allele of rs339097 (the allele frequency was 0.14 in African Americans and 0.002 in Caucasians) was associated with the requirement for a 14.5% (SD +/- 7%) higher therapeutic dose (P = 0.03) in the first replication cohort and a higher-than-predicted dose in the second replication cohort (allele frequency 0.14, one-sided P = 0.03). CALU rs339097 A>G is associated with higher warfarin dose requirements, independent of known genetic and nongenetic predictors of warfarin dose in African Americans.
| S-EPMC2928561 | biostudies-literature
Project description:BackgroundApolipoprotein E (apoE) induces the uptake of vitamin K-rich lipoproteins by the liver, which likely affects inter-individual variation of warfarin dosing requirements. Associations between APOE polymorphisms and warfarin dosing were previously reported inconsistently among different ethnic groups, so the present study investigated this association in northern Han Chinese patients with mechanical heart valve prosthesis.MethodsA total of 186 patients who underwent mechanical heart valve replacement and attained a stable warfarin dose were included. APOE single nucleotide polymorphisms (SNPs) rs7412 and rs429358 were genotyped using Illumina SNP GoldenGate Assay. Genotyping results were confirmed by direct sequencing. PHASE v2.1 software was used to construct rs7412 and rs429358 haplotypes. The effects of different APOE genotypes on warfarin dose were analyzed statistically.ResultsThe mean warfarin maintenance dose was 3.10 ± 0.96 mg/day, and the mean international normalized ratio (INR) was 2.09 ± 0.24. APOE E2, E3, and E4 allele frequencies were 11.6 %, 82.5 %, and 5.9 %, respectively. No E2/E2 or E4/E4 genotypes were detected in this population. E2/E3, E3/E3, E2/E4, and E3/E4 genotype frequencies were 21.0 %, 67.2 %, 2.2 %, and 9.7 %, respectively. Significant differences in warfarin dose requirements were observed among patients with E2/E3, E3/E3, and E3/E4 genotypes (p < 0.05). In post hoc comparison, daily warfarin maintenance doses were significantly higher in E2/E3 heterozygotes compared with E3/E3 homozygotes (p < 0.05), but no differences in dose requirements were found between E3/E4 and E3/E3, or E2/E3 and E3/E4 (p > 0.05). Patients were divided into low-intensity anticoagulant treatment group (1.6 ≤ INR <2.0) and relatively high-intensity anticoagulant treatment group (2.0 ≤ INR ≤ 2.5), and significantly higher warfarin dose requirements were observed in E2/E3 heterozygotes compared with E3/E3 homozygotes in both subgroups (p < 0.05). Multivariable analysis adjusting for other confounders showed that E2/E3 genotype was associated with a significantly higher warfarin dose compared with E3/E3 genotype (p < 0.05).ConclusionsAPOE allele and genotype frequencies in the northern Han Chinese population appear to differ from other racial groups or populations living in other regions of China. The APOE E2 variant was associated with a significantly higher warfarin maintenance dose. Thus, APOE polymorphisms could be one of the predictors influencing warfarin doses in this population.
| S-EPMC4765220 | biostudies-literature
Project description:OBJECTIVE:Multiple sclerosis (MS) is one of the leading neurodegenerative causes of physical disability world-wide. Genetic aberrations of autoimmunity pathway components have been demonstrated to significantly influence MS development. Cluster of Differentiation 58 (CD58) is pertained to a group of genes which had been assayed in several recent association studies. Given the significance of CD58 in modulation of T regulatory cells that control autoimmune responses, the present study was conducted to investigate the frequency of rs12044852 polymorphism and its effect on the outcome of interferon beta (IFN-β) therapy in a subset of Iranian MS patients. MATERIALS AND METHODS:Two hundred MS patients and equal number of healthy controls were recruited to be genotyped in an experimental case-control based study through polymerase chain reaction using specific sequence primers (PCR-SSP). Relapsing remitting multiple sclerosis (RRMS) patients administered IFN-β therapy were followed up with clinical visits every three months up to two years. The mean of multiple sclerosis severity score (MSSS) and expanded disability status scale (EDSS) were measured to monitor the change in severity of MS in response to IFN-β therapy. Pearson's Chi-square and analysis of variance (ANOVA) tests were the main statistical methods used in this study. RESULTS:Strong association was found between the CC genotype and onset of MS (p=0.001, OR=2.22). However, there was no association between rs12044852 and various classifications and severity of MS. Pharmacogenetics-based analysis indicated that carriers of CC genotype had the highest MSSS score compared to others, implying a negative impact of rs12044852 on response to IFN-β therapy. CONCLUSION:Taken together, our findings revealed the critical effect of rs12044852 polymorphism of CD58 on the progression of MS disease. This indicates that genotyping of MS patients may expedite achieving personalized medical management of MS patients.
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Project description:Background:Multiple Sclerosis (MS) is the most common cause of neurologic disability in young adults. Recently, the AIRE gene was identified as a genetic risk factor for several autoimmune diseases in genome wide association studies. The aim of this study was to further investigate the possible role of the AIRE gene in susceptibility to MS in Iranian population. Methods:A total of 112 MS patients and 94 ethnically matched controls were included in the study. The Single-Nucleotide Polymorphism (SNP) (rs1800520, C>G) with a global MAF=0.2282/1143 was selected and genotyped using HRM real-time PCR method. Results:Results showed that AIRE SNP rs1800520 was significantly less common in the MS patients than in healthy controls (17.8 vs. 28.7%, pc=0.032, OR=0.54,95% CI 0.279, 1.042). Also, the frequency of allele G was significantly higher among the control group than in the case group (37.77 vs. 25%, pc=0.014). Interestingly, mRNA transcribed on the rs1800520 SNP showed decreased free energy than the wild type suggesting that its increased stability may be responsible for the different activities of the polymorphic AIRE molecule. Conclusions:This is the first study investigating the relationship between AIRE gene and the susceptibility to MS. These results indicated that the rs1800520 SNP is not a susceptibility gene variant for the development of MS in Iranian population.
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Project description:Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disease and Late-Onset type (LOAD) is the most common form of dementia affecting people over 65 years old. CALHM1 (P86L) encodes a transmembrane glycoprotein that controls cytosolic Ca(2+) concentrations and A? levels and P86L polymorphism in this gene is significantly associated with LOAD in independent case controls in a number of studies. This study was performed to determine whether this polymorphism contributes to the risk for LOAD in Iranian population. One hundred and forty one AD patients and 141 healthy controls were recruited in this study. After extraction of genomic DNA, the genotype and allele frequencies were determined in case and control subjects using PCR/RFLP method. The statistical analysis showed a significant difference in the heterozygote genotype frequency in case and control groups and polymorphic allele had a protective role between two groups. Also after stratifying the subjects by their APOE-?4 status, no significant association was observed. Our study suggests that P86L polymorphism could be a protective factor for late-onset Alzheimer's disease (LOAD) in Iranian population. However, to confirm these results, further study with a bigger sample size may be required.
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