Genetic and Nongenetic Factors Affecting Clopidogrel Response in the Egyptian Population.
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SUBMITTER: Khalil BM
PROVIDER: S-EPMC4760893 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and objectiveWarfarin is a commonly used oral anticoagulant with a narrow therapeutic index and various genetic and clinical factors that influence interpatient variability in dose requirements. This study investigated the impact of genetic and nongenetic factors on warfarin dose requirements in Egyptians.MethodsDNA was extracted from 207 patients taking warfarin for more than 2 months and genotyped for VKORC1 (3673 G>A), CYP2C9 *2*3*4*5*8, CYP4F2 (V33M; rs2108622), APOE (rs429358, rs7412), and CALU(rs339097) gene polymorphisms. Linear regression modeling was conducted to identify the genetic and nongenetic factors that independently influence warfarin dose requirements.ResultsVKORC1 3673 AA or GA genotype (P<0.0001), one or two variant alleles of CYP2C9 gene (P=0.0004), APOE ε2 haplotype (P=0.01), and increasing age (P<0.0001) were all associated with lower warfarin dose, whereas smoking (P=0.025) and pulmonary embolism (P=0.0059) showed association with higher warfarin doses. These factors explained 31% of the warfarin dose variability. This is the first independent confirmation of the association of the CALU rs339097 variant with higher warfarin dose requirement, although inclusion of this single nucleotide polymorphism in the multiple regression model failed to achieve significance (P=0.066). CYP4F2 (V33M) polymorphism was not significant (P=0.314), despite its high frequency in the studied population (42%).ConclusionThe study shows that VKORC1, CYP2C9 polymorphisms, APOE ε2 variant, and several clinical/demographic variables are important determinants of warfarin dose requirements in Egyptian patients. The percentage of variability explained by these factors is lower than in those of European ancestry, but similar to the variability explained in Asians and African ancestry.
| S-EPMC3038469 | biostudies-literature
Project description:BACKGROUNDRBC transfusion effectiveness varies due to donor, component, and recipient factors. Prior studies identified characteristics associated with variation in hemoglobin increments following transfusion. We extended these observations, examining donor genetic and nongenetic factors affecting transfusion effectiveness.METHODSThis is a multicenter retrospective study of 46,705 patients and 102,043 evaluable RBC transfusions from 2013 to 2016 across 12 hospitals. Transfusion effectiveness was defined as hemoglobin, bilirubin, or creatinine increments following single RBC unit transfusion. Models incorporated a subset of donors with data on single nucleotide polymorphisms associated with osmotic and oxidative hemolysis in vitro. Mixed modeling accounting for repeated transfusion episodes identified predictors of transfusion effectiveness.RESULTSBlood donor (sex, Rh status, fingerstick hemoglobin, smoking), component (storage duration, γ irradiation, leukoreduction, apheresis collection, storage solution), and recipient (sex, BMI, race and ethnicity, age) characteristics were associated with hemoglobin and bilirubin, but not creatinine, increments following RBC transfusions. Increased storage duration was associated with increased bilirubin and decreased hemoglobin increments, suggestive of in vivo hemolysis following transfusion. Donor G6PD deficiency and polymorphisms in SEC14L4, HBA2, and MYO9B genes were associated with decreased hemoglobin increments. Donor G6PD deficiency and polymorphisms in SEC14L4 were associated with increased transfusion requirements in the subsequent 48 hours.CONCLUSIONDonor genetic and other factors, such as RBC storage duration, affect transfusion effectiveness as defined by decreased hemoglobin or increased bilirubin increments. Addressing these factors will provide a precision medicine approach to improve patient outcomes, particularly for chronically transfused RBC recipients, who would most benefit from more effective transfusion products.FUNDINGFunding was provided by HHSN 75N92019D00032, HHSN 75N92019D00034, 75N92019D00035, HHSN 75N92019D00036, and HHSN 75N92019D00037; R01HL126130; and the National Institute of Child Health and Human Development (NICHD).
| S-EPMC8765041 | biostudies-literature
Project description:BackgroundUsing a genetic predisposition score (GPS), additively integrating the associations of 11 polymorphisms with coronary heart disease (CHD), we examined the consequences of the joint presence of a high GPS and nongenetic CHD risk factors.MethodsWithin the European Prospective Investigation Into Cancer and Nutrition, 202 case patients with medically confirmed incident coronary infarct and 197 control subjects were identified in Greece. Each polymorphism contributed 1 unit (high-risk homozygous), one-half unit (heterozygous), or no units (low-risk homozygous) to the GPS. Odds ratios of coronary infarction for those at high risk because of genetic predisposition and simultaneous presence of an established CHD risk factor were estimated, compared with subjects at low risk, for both GPS and each CHD risk factor.ResultsThe joint presence of a high GPS (> or =3.5) and each studied CHD risk factor was in all instances associated with a significantly increased risk of coronary infarction. The odds ratio (95% confidence interval) was 2.62 (1.14-6.02) for ever smoking, 2.88 (1.33-6.24) for hypertension, 3.50 (1.67-7.33) for low high-density lipoprotein (HDL) level, 3.05 (1.53-6.08) for high non-HDL level, and 3.66 (1.75-7.65) for poor adherence to the Mediterranean diet. The odds ratios were always lower and nonsignificant when the GPS was low. There was suggestive evidence for interaction of a high GPS with hypertension (P = .05) and non-HDL cholesterol level (P = .13).ConclusionsGenetic predisposition may interact with hypertension and, perhaps, also with the level of non-HDL cholesterol, in the causation of CHD. Genetic predisposition and the other studied exposures seem to have converging effects. Thus, the GPS may identify individuals who could realize disproportional benefits by controlling their hypertension and, possibly, their non-HDL cholesterol level.
| S-EPMC4426987 | biostudies-literature
Project description:Efavirenz pharmacokinetics is characterized by large between-subject variability, which determines both therapeutic response and adverse effects. Some of the variability in efavirenz pharmacokinetics has been attributed to genetic variability in cytochrome P450 genes that alter efavirenz metabolism, such as CYP2B6 and CYP2A6 While the effects of additional patient factors have been studied, such as sex, weight, and body mass index, the extent to which they contribute to variability in efavirenz exposure is inconsistently reported. The aim of this analysis was to develop a pharmacometric model to quantify the contribution of genetic and nongenetic factors to efavirenz pharmacokinetics. A population-based pharmacokinetic model was developed using 1,132 plasma efavirenz concentrations obtained from 73 HIV-seronegative volunteers administered a single oral dose of 600 mg efavirenz. A two-compartment structural model with absorption occurring by zero- and first-order processes described the data. Allometric scaling adequately described the relationship between fat-free mass and apparent oral clearance, as well as fat mass and apparent peripheral volume of distribution. Inclusion of fat-free mass and fat mass in the model mechanistically accounted for correlation between these disposition parameters and sex, weight, and body mass index. Apparent oral clearance of efavirenz was reduced by 25% and 51% in subjects predicted to have intermediate and slow CYP2B6 metabolizer status, respectively. The final pharmacokinetic model accounting for fat-free mass, fat mass, and CYP2B6 metabolizer status was consistent with known mechanisms of efavirenz disposition, efavirenz physiochemical properties, and pharmacokinetic theory. (This study has been registered at ClinicalTrials.gov under identifier NCT00668395.).
| S-EPMC5192152 | biostudies-literature
Project description:Clopidogrel is the cornerstone antiplatelet used in the treatment and prevention of thrombotic events. Some studies examined the effect of CYP2C19 polymorphism and nongenetic factors on clopidogrel response in the Middle East and North Africa (MENA) region. However, the consistency among these studies is yet unknown. This study aims to estimate the prevalence of CYP2C19 genetic variants in MENA region and to evaluate the effect of these variants as well as the nongenetic factors on clopidogrel responsiveness. A systematic literature search was performed to identify relevant articles. Only observational studies were included. A total of 20 studies in 8 different populations were included. The CYP2C19*2 variant is the most prevalent loss-of-function (LOF) allele in the MENA region (1.7%-35%). The frequency of CYP2C19*17 ranged from 5.3% to 26.9%. Of the 9 studies, 6 found an association between carriers of at least 1 LOF allele and clopidogrel resistance. Older age, high body mass index, females, and the use of calcium channel blockers were associated with clopidogrel resistance as well. Association between the CYP2C19*2 allele and clopidogrel resistance is common among MENA populations. Future studies should focus on having larger sample sizes to detect other minor variant alleles and their effect on bleeding and cardiovascular outcomes.
| S-EPMC6829969 | biostudies-literature
Project description:Study designCohort study.ObjectiveWe aimed to evaluate the associations of genetic and nongenetic factors with degenerative cervical myelopathy (DCM).Summary of background dataThere is mounting evidence for an inherited predisposition for DCM, but uncertainty remains regarding specific genetic markers involved. Similarly, nongenetic factors are thought to play a role.Materials and methodsUsing diagnosis codes from hospital records linked to the UK Biobank cohort, patients with cervical spondylosis were identified followed by the identification of a subset with DCM. Nongenetic variables evaluated included age, sex, race, Townsend deprivation index, body mass index, occupational demands, osteoporosis, and smoking. Genome-wide association analyses were conducted using logistic regression adjusted for age, sex, population principal components, and follow-up.ResultsA total of 851 DCM cases out of 2787 cervical spondylosis patients were identified. Several nongenetic factors were independently associated with DCM including age [odds ratio (OR)=1.11, 95% CI=1.01-1.21, P =0.024], male sex (OR=1.63, 95% CI=1.37-1.93, P <0.001), and relative socioeconomic deprivation (OR=1.03, 95% CI=1.00-1.06, P =0.030). Asian race was associated with lower DCM risk (OR=0.44, 95% CI=0.22-0.85, P =0.014). We did not identify genome-wide significant (≤5×10 -8 ) single-nucleotide polymorphisms (SNPs) associated with DCM. The strongest genome-wide signals were at SNP rs67256809 in the intergenic region of the genes LINC02582 and FBXO15 on chromosome 18 ( P =1.12×10 -7 ) and rs577081672 in the GTPBP1 gene on chromosome 22 ( P =2.9×10 -7 ). No SNPs reported in prior DCM studies were significant after adjusting for replication attempts.ConclusionsIncreasing age, male sex, and relative socioeconomic deprivation were identified as independent risk factors for DCM, whereas Asian race was inversely associated. SNPs of potential interest were identified in GTPBP1 and an intergenic region on chromosome 18, but these associations did not reach genome-wide significance. Identification of genetic and nongenetic DCM susceptibility markers may guide understanding of DCM disease processes, inform risk, guide prevention and potentially inform surgical outcomes.Level of evidencePrognostic level III.
| S-EPMC10524420 | biostudies-literature
Project description:BackgroundNatriuretic peptides (NPs) represent a critical pathway in heart failure (HF). However, there is wide individual variability in NP system activity, which could be partly genetic in origin. We explored genetic and nongenetic contributions to B-type natriuretic peptide (BNP) inactivation.MethodsChronic HF patients (n = 95) received recombinant human BNP (nesiritide) at standard doses, and BNP levels were measured at baseline, after 2 hours of infusion, and 30 minutes after discontinuation. Genomic DNA was genotyped for 91 single-nucleotide polymorphisms (SNP) in 2 candidate genes. We tested the association of patient characteristics and genotype with 5 pharmacokinetics (PK) parameters: elimination rate constant, ΔBNP, BNP clearance, adjusted BNP clearance, and half-life. Linear regression with pleiotropic analysis was used to test genotype associations with PK.ResultsParticipants' mean age was 63 years, 44% were female, and 46% were African American. PK parameters varied widely, some >10-fold. HF type (preserved vs reduced) was associated with PK (P < .01), whereas renal function, demographics, and body mass index and were not. Two SNPs in MME (rs989692, rs6798179) and 2 in NPR3 (rs6880564, rs2062708) also had associations with PK (P < .05).ConclusionsThe pharmacokinetics of BNP varies greatly in HF patients, differs by HF type, and possibly by MME or NPR3 genotype. Additional study is warranted.
| S-EPMC4189182 | biostudies-literature
Project description:PurposeA high interindividual variability is observed in the pharmacokinetics of clopidogrel, a widely used antiplatelet drug. In the present study, a joint parent-metabolite population pharmacokinetic model was developed to adequately describe observed concentrations of clopidogrel and its active thiol metabolite (H4).MethodsThe study included 63 patients undergoing elective coronarography or percutaneous coronary intervention. The population pharmacokinetic model was developed in the NONMEM 7.3 software, and first-order conditional estimation method with interaction was applied. Also, the influence of covariates was evaluated (age, weight, body mass index (BMI), obesity defined as BMI ≥ 30 kg/m2, sex, diabetes mellitus, co-administration of PPI or statins, presence of CYP2C19*2, CYP2C19*17, CYP3A4*1G alleles, and ABCB1 3435 TT genotype).ResultsIt was found that the only significant covariate was the presence of CYP2C19*2 allele, which had an impact on lower conversion of clopidogrel to H4. As a result, predicted area under the time-concentration curve values was lower in carriers of this allele, with median 5.94 ng h/ml (interquartile range 3.92-12.51 [ng∙h/ml]) vs. 12.70 ng h/ml in non-carriers (interquartile range, 7.00-19.39 [ng∙h/ml]), respectively (p = 0.004).ConclusionsDeveloped model predicts that the only significant covariate influencing the observed concentrations and therefore the exposure to the active H4 metabolite is the presence of CYP2C19*2 allele.
| S-EPMC5684285 | biostudies-literature
Project description:This prospective cohort study evaluated the association between the renin angiotensin aldosterone system genotypes and response to spironolactone in 155 Egyptian patients with heart failure with reduced ejection fraction (HFrEF). Genotype frequencies for AGT rs699 were: CC = 16%, CT = 48%, and TT = 36%. Frequencies for CYP11B2 rs1799998 were: TT = 33%, TC = 50%, and CC = 17%. After 6 months of spironolactone treatment, change in the left ventricular ejection fraction (LVEF) differed by AGT rs699 (CC, 14.6%; TC, 7.9%; TT, 2.7%; P = 2.1E-26), and CYP11B2 rs1799998 (TT, 9.1%; TC, 8.7%; CC, 1.4%; P = 0.0006) genotypes. Multivariate linear regression showed that the AGT rs699 and CYP11B2 rs1799998 polymorphisms plus baseline serum potassium explained 71% of variability in LVEF improvement (P = 0.001), 63% of variability in serum potassium increase (P = 2.25E-08), and 39% of the variability in improvement in quality of life (P = 2.3E-04) with spironolactone therapy. These data suggest that AGT and CYP11B2 genotypes as well as baseline serum K are predictors of spironolactone response in HFrEF.
| S-EPMC6951455 | biostudies-literature
Project description:Clopidogrel (Plavix®), is a widely used antiplatelet agent, which shows high inter-individual variability in treatment response in patients following the standard dosing regimen. In this study, a physiology-directed population pharmacokinetic/pharmacodynamic (PK/PD) model was developed based on clopidogrel and clopidogrel active metabolite (clop-AM) data from the PAPI and the PGXB2B studies using a step-wise approach in NONMEM (version 7.2). The developed model characterized the in vivo disposition of clopidogrel, its bioactivation into clop-AM in the liver and subsequent platelet aggregation inhibition in the systemic circulation reasonably well. It further allowed the identification of covariates that significantly impact clopidogrel's dose-concentration-response relationship. In particular, CYP2C19 intermediate and poor metabolizers converted 26.2% and 39.5% less clopidogrel to clop-AM, respectively, compared to extensive metabolizers. In addition, CES1 G143E mutation carriers have a reduced CES1 activity (82.9%) compared to wild-type subjects, which results in a significant increase in clop-AM formation. An increase in BMI was found to significantly decrease clopidogrel's bioactivation, whereas increased age was associated with increased platelet reactivity. Our PK/PD model analysis suggests that, in order to optimize clopidogrel dosing on a patient-by-patient basis, all of these factors have to be considered simultaneously, e.g. by using quantitative clinical pharmacology tools.
| S-EPMC5798599 | biostudies-literature