CYP2C9 Rs1057910 Research Articles

Exploring the role of genetic variability and exposure to bisphenols and parabens on excess body weight in Spanish children

Gene-environment interaction studies are emerging as a promising tool to shed light on the reasons for the rapid increase in excess body weight (overweight and obesity). We aimed to investigate the influence of several polymorphisms on excess weight in Spanish children according to a short- and long-term exposure to bisphenols and parabens, combining individual approach with the joint effect of them. This case-control study included 144 controls and 98 cases children aged 3-12 years. Thirty SNPs in genes involved in obesity-related pathways, xenobiotic metabolism and hormone systems were genotyped using the GSA microchip technology and qPCRs with Taqman® probes. Levels of bisphenols and parabens in urine and hair were used to assess short- and long-term exposure, respectively, via UHPLC-MS/MS system. LEPR rs9436303 was identified as a relevant risk variant for excess weight (ORDom:AAvsAG+GG=2.65, p<0.001), and this effect persisted across exposure-stratified models. For long-term exposure, GPX1 rs1050450 was associated with increased excess weight at low single paraben exposure (ORGvsA=2.00, p=0.028, p-interaction=0.016), whereas LEPR rs1137101 exhibited a protective function at high co-exposure (ORDom:AAvsAG+GG=0.17, p=0.007, p-interaction=0.043). ESR2 rs3020450 (ORDom:GGvsAG+AA=5.17, p=0.020, p-interaction=0.028) and CYP2C19 rs4244285 (ORDom:GGvsAG+AA=3.54, p=0.039, p-interaction=0.285) were identified as predisposing variants at low and high co-exposure, respectively. In short-term exposure, higher odds were observed for INSIG2 rs7566605 at high bisphenol exposure (ORCvsG=2.97, p=0.035, p-interaction=0.017) and for GSTP1 rs1695 at low levels (ORDom:AAvsAG+GG=5.38, p=0.016, p-interaction=0.016). At low and medium co-exposure, SH2B1 rs7498665 (ORAvsG=0.17, p=0.015, p-interaction=0.085) and MC4R rs17782313 (ORAvsG=0.10, p=0.023, p-interaction=0.045) displayed a protective effect, whereas ESR2 rs3020450 maintained its contributing role (ORGvsA=3.12, p=0.030, p-interaction=0.010). Our findings demonstrate for the first time that understanding the genetic variation in excess weight and how the level of exposure to bisphenols and parabens might interact with it, is crucial for a more in-depth comprehension of the complex polygenic and multifactorial aetiology of overweight and obesity.

Notable drug-drug interaction between omeprazole and voriconazole in CYP2C19 *1 and *2 (rs4244285, 681G>A) alleles in vitro

The drug-drug interaction (DDI) and CYP2C19 genetic variation can lead to a high blood concentration of voriconazole. CYP2C19 is a highly genetically polymorphic enzyme, and CYP2C19*2 is more frequent among Asians associated with reduced metabolism of drugs. Clinical study found that co-administration with omeprazole significantly increased voriconazole concentrations and there was an additive effect in CYP2C19*2 allele. CYP2C19 rs4244285 (681G>A) is the key polymorphism of CYP2C19*2 allele. This study aims to describe the in vitro effects of omeprazole on CYP2C19*1 and *2 (681G>A), and determine how CYP2C19 polymorphisms influence the DDI between omeprazole and voriconazole. Using the lentiviral expression system, we successfully generated HepG2-derived cell lines stably expressing CYP2C19*1 and *2 (681G>A). The results showed that the CYP2C19 mRNA level, protein level, and enzymatic activity were lower in HepG2-CYP2C19*2 (681G>A) than HepG2-CYP2C19*1 cells. Our study also showed that the inhibition rates of omeprazole on voriconazole had no significantly differences between CYP2C19*1 and *2 (681G>A). But the IC50 of omeprazole on CYP2C19*1 slightly lower than CYP2C19*2 (681G>A). Moreover, omeprazole inhibited CYP2C19 protein level in cells carrying CYP2C19*1 and CYP2C19*2 (681G>A). Our study demonstrated that omeprazole could inhibit voriconazole metabolism in both CYP2C19*1 and CYP2C19*2 (681G>A).

The Impact of CYP 2C9 rs1799853 and rs1057910 Polymorphism on Plasma Losartan Metabolic Ratio in a Sample of Iraqi Hypertensive Patients

Background: The challenge associated with interindividual diversity in CYP2C9 enzyme activity is primarily related to genetic variations among individuals. Polymorphisms in the CYP2C9 gene can lead to different enzyme activity, affecting how individuals metabolize drugs. The understanding of interindividual diversity in CYP2C9 enzyme activity has implications for personalized medicine. Objective: To examine the impact of CYP2C9 gene polymorphisms (rs1799853 and rs1057910) on the losartan metabolism in Iraqi hypertensive patients. Methods: This prospective interventional study was conducted on a sample of hypertension patients from Babylon governorate, Iraq. All patients received 100 mg of losartan once daily. After 4 weeks, blood samples were obtained for genetic analysis and measuring losartan and its carboxylic acid (LCA) metabolite levels. The plasma losartan-to-LCA ratio is used as an indirect determinant of CYP2C9 activity within CYP2C9 SNP genotypes. Results: Two major allelic polymorphisms, CYP2C9 rs1799853 (T allele 15.5%) on exon 3 and rs1057910 (C allele 8.5%) on exon 7, have been identified among the patients. Plasma losartan/E3174 metabolic ratio was significantly higher in patients with a CT genotype of rs1799853 SNP (1.65) than in patients with a CC wild-type genotype (1.03). The losartan/E3174 metabolic ratio in heterozygous mutant AC genotypes of rs1057910 (1.18) was also higher than in those with wild-type AA genotypes (1.15); however, these differences are not statistically significant. Conclusions: The rs1799853 SNP variant, but not the rs1057910 SNP variant, significantly impacts CYP2C9 metabolic activity. The plasma losartan/E3174 metabolic ratio appears to be a practical and reliable measure for CYP2C9 activity.

Effect of genetic factors on the interindividual variability of warfarin dosage requirements in Japanese patients after adjusting for renal function.

Renal function significantly influences the appropriate warfarin dosage. However, studies investigating the impact of genetic factors on warfarin dosage, considering renal function, are limited. This study aimed to assess the role of genetic polymorphisms in VKORC1, CYP2C9, CYP2C19, CYP4F2, GGCX, and APOE in warfarin dosage adjustment considering renal function. A total of 108 outpatients receiving warfarin treatment with controlled prothrombin time-targeted international normalized ratio (1.5-3.0) were included. Patient data, warfarin dosage, and laboratory results were collected from electronic medical records. Each SNP [VKORC1 rs9923231, CYP2C9 rs1057910, CYP4F2 rs2108622, CYP2C19* 2 (rs4244285) and* 3 (rs4986893), GGCX rs699664 and rs12714145, and APOE rs7421] was analyzed. Multiple regression analysis revealed estimated glomerular filtration rate as the most significant factor influencing warfarin dose (p <0.001) (β = -0.445). VKORC1 rs9923231 AA, CYP4F2 rs2108622 CT/TT, GGCX rs12714145 CT/TT, and CYP2C9 rs1057910 AC carriers were associated with warfarin dose (p <0.001, 0.015, 0.020, 0.038 and β = -0.317, 0.191, -0.188, -0.162, respectively); however, other genes showed no significant association. In conclusion, after adjusting for renal function, genetic factors of VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs12714145, and CYP2C9 rs1057910 were found to contribute to warfarin dosage, having impact in that order. In contrast, the contribution of other genes to warfarin dosage was absent or negligible.

Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study.

Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19, CYP2D6, CYP3A4, and ABCB1, and its effect on these outcomes. The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects. Eleven cis-SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain (q=0.027) and serum concentrations of ESCadj (q<0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESCadj concentrations. CITs did not indicate that these effects were epigenetically mediated. These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored.

Impact of CYP2C19, CYP2C9, CYP3A4, and FMO3 Genetic Polymorphisms and Sex on the Pharmacokinetics of Voriconazole after Single and Multiple Doses in Healthy Chinese Subjects.

Voriconazole is the first-line treatment for invasive aspergillosis. Its pharmacokinetics exhibit considerable inter- and intra-individual variability. The purpose of this study was to investigate the effects of CYP2C19, CYP2C9, CYP3A4, and FMO3 genetic polymorphisms and sex on the pharmacokinetics of voriconazole in healthy Chinese adults receiving single-dose and multiple-dose voriconazole, to provide a reference for its clinical individualized treatment. A total of 123 healthy adults were enrolled in the study, with 108 individuals and 15 individuals in the single-dose and multiple-dose doses, respectively. Plasma voriconazole concentrations were measured using a validated LC-MS/MS method, and pharmacokinetics parameters were calculated using the non-compartmental method with WinNonlin 8.2. CYP2C19, CYP2C9, CYP3A4, and FMO3 single-nucleotide polymorphisms were sequenced using the Illumina Hiseq X-Ten platform. The results suggested that CYP2C19 genetic polymorphisms significantly affected the pharmacokinetics of voriconazole at single doses of 4, 6, and 8 mg/kg and multiple doses of voriconazole. CYP3A4 rs2242480 had a significant effect on AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity) and MRT (mean residence time) of voriconazole at a single dose of 4 mg/kg in CYP2C19 extensive metabolizer. Regardless of the CYP2C19 genotype, CYP2C9 rs1057910 and FMO3 rs2266780 were not associated with the pharmacokinetics of voriconazole at three single-dose levels or multiple doses. No significant differences in most voriconazole pharmacokinetics parameters were noted between male and female participants after single and multiple dosing. For patients receiving voriconazole treatment, CYP2C19 genetic polymorphisms should be genotyped for its precision administration. In contrast, based on our study of healthy Chinese adults, it seems unnecessary to consider the effects of CYP2C9, CYP3A4, and FMO3 genetic polymorphisms on voriconazole pharmacokinetics.

Association between CYP2C9 and VKORC1 genetic polymorphisms and efficacy and safety of warfarin in Chinese patients.

Genetic variation has been a major contributor to interindividual variability of warfarin dosage requirement. The specific genetic factors contributing to warfarin bleeding complications are largely unknown, particularly in Chinese patients. In this study, 896 Chinese patients were enrolled to explore the effect of CYP2C9 and VKORC1 genetic variations on both the efficacy and safety of warfarin therapy. Univariate analyses unveiled significant associations between two specific single nucleotide polymorphisms rs1057910 in CYP2C9 and rs9923231 in VKORC1 and stable warfarin dosage (P < 0.001). Further, employing multivariate logistic regression analysis adjusted for age, sex and height, the investigation revealed that patients harboring at least one variant allele in CYP2C9 exhibited a heightened risk of bleeding events compared to those with the wild-type genotype (odds ratio = 2.16, P = 0.04). Moreover, a meta-analysis conducted to consolidate findings confirmed the associations of both CYP2C9 (rs1057910) and VKORC1 (rs9923231) with stable warfarin dosage. Notably, CYP2C9 variant genotypes were significantly linked to an increased risk of hemorrhagic complications (P < 0.00001), VKORC1 did not demonstrate a similar association. The associations found between specific genetic variants and both stable warfarin dosage and bleeding risk might be the potential significance of gene detection in optimizing warfarin therapy for improving patient efficacy and safety.

Influence of pharmacogenetics on the diversity of response to statins associated with adverse drug reactions.

Statins are one of the most prescribed medications in developed countries as the treatment of choice for reducing cholesterol and preventing cardiovascular diseases. However, a large proportion of patients experience adverse drug reactions, especially myotoxicity. Among the factors that influence the diversity of response, pharmacogenetics emerges as a relevant factor of influence in inter-individual differences in response to statins and can be useful in the prevention of adverse drug effects. A systematic review was performed of current knowledge of the influence of pharmacogenetics on the occurrence and prevention of statin-associated adverse reactions and clinical benefits of preemptive pharmacogenetics testing. Genetic variants SLCO1B1 (rs4149056) for all statins; ABCG2 (rs2231142) for rosuvastatin; or CYP2C9 (rs1799853 and rs1057910) for fluvastatin are associated with an increase in muscle-related adverse effects and poor treatment adherence. Besides, various inhibitors of these transporters and biotransformation enzymes increase the systemic exposure of statins, thereby favoring the occurrence of adverse drug reactions. The clinical preemptive testing of this pharmacogenetic panel would largely prevent the incidence of adverse drug reactions. Standardized methods should be used for the identification of adverse effects and the performance and interpretation of genotyping test results. Standardization would allow to obtain more conclusive results about the association between SLCO1B1, ABCG and CYP2C9 variants and the occurrence of adverse drug reactions. As a result, more personalized recommendations could be established for each statin.

Targeted next-generation sequencing of genes involved in Warfarin Pharmacodynamics and pharmacokinetics pathways using the Saudi Warfarin Pharmacogenetic study (SWAP).

Warfarin is an oral anticoagulant commonly used for treatment and prophylaxis against thromboembolic events. Warfarins's narrow therapeutic index window is one of the main challenges in clinical practice; thus, it requires frequent monitoring and dose adjustment to maintain patients' therapeutic range. Warfarin dose variation and response are attributed to several inter-and intra-individuals factors, including genetic variants in enzymes involved in warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways. Thus, we aim to utilize the next-generation sequencing (NGS) approach to identify rare and common genetic variants that might be associated with warfarin responsiveness. A predesigned NGS panel that included 16 genes involved in Warfarin PK/PD pathways was used to sequence 786 patients from the Saudi Warfarin Pharmacogenetic Cohort (SWAP). Identified variants were annotated using several annotation tools to identify the pathogenicity and allele frequencies of these variants. We conducted variants-level association tests with warfarin dose. We identified 710 variants within the sequenced genes; 19% were novel variants, with the vast majority being scarce variants. The genetic association tests showed that VKORC1 (rs9923231, and rs61742245), CYP2C9 (rs98332238, rs9332172, rs1057910, rs9332230, rs1799853, rs1057911, and rs9332119), CYP2C19 (rs28399511, and rs3758581), and CYP2C8 (rs11572080 and rs10509681) were significantly associated with warfarin weekly dose. Our model included genetics, and non-genetic factors explained 40.1% of warfarin dose variation. The study identifies novel variants associated with warfarin dose in the Saudi population. These variants are more likely to be population-specific variants, suggesting that population-specific studies should be conducted before adopting a universal warfarin genotype-guided dosing algorithm.

EFFECT OFVARIATIONSIN ABCC2, CYP2C9, CYP2C19 &amp; SCN2A GENESON TREATMENT RESPONSETO ANTICONVULSANTS- A SYSTEMATIC REVIEWAND META-ANALYSIS OF GENETIC ASSOCIATION STUDIES

Objective: This study was aimed to determine the effect of genetic polymorphisms (non-synonymous, missense, and copy number variations) in ABCC2, CYP2C9, CYP2C19&amp;SCN2A genes on treatment response to anticonvulsants. Methods: The search was carried out in PubMed, Scopus, Cochrane Central Register of Controlled Trials, Embase, LILACS, Google Scholar, MEDLINE, ScienceDirect, Web of Science, and the DOAJ database. Hardy Weinberg Equilibrium (HWE), New-Castle Ottawa scale value, Cochrane Review Manager 5.0 (&amp;R 4.0.3,) and Rayyan QCRI are used for assessing data synthesis, risk of bias, heterogeneity assessment using I[2]statistics and calculating Inter-rater agreement respectively. Publication bias assessment was performed using Eggers test and the Funnel plot. For statistical analysis, random effects modeling was used to explain the association between genetic variations in ABCC2, CYP2C9, CYP2C19 &amp; SCN2A genes related to drug resistance or treatment failure. Results: This meta-analysis includes a total of 29 studies. We found a greater risk of AED resistance in ABCC2rs2273697 genetic variations (OR=1.51 [ 0.93-2.47], p value=0.03 at 95% CI), ABCC2 rs3740066 genetic variation has a greater possibility of AED resistance was seen in pooled population (OR= 0.85 [0.12-5.85], p-value&lt;0.01 at 95% CI), risk of drug resistance was increased by ABCC2 rs717620 polymorphism. (OR =2.13, [1.02-4.44], p-value&lt;0.01 at 95% CI), CYP2C9 rs1799853 polymorphism had a significant increase in AED resistance (OR =1.27, [0.49-3.32] p-value&lt;0.01 at 95% CI), CYP2C9 rs1057910 polymorphism. (OR= 0.74, [0.32-1.70] p-value 0.01 at 95% CI), CYP2C19 rs4244285 polymorphism. (OR= 0.68, [0.29-1.62], p value=0.02 at 95% CI), SCN2A rs2304016 polymorphism. (OR= 1.20, [0.48-3.05], p value&lt;0.01 at 95% CI), SCN2Ars17183814 polymorphism. (OR =1.51, [1.12-2.03], p value=0.30 at 95% CI). Conclusions:Gene polymorphisms play a key role in epilepsy development and therapeutic efficacy, and could have greater impact treatment outcomes.

Impact of Insulin Receptor Substrate-1 rs956115 and CYP2C19 rs4244285 Genotypes on Clinical Outcome of Patients Undergoing Percutaneous Coronary Intervention.

BackgroundInsulin receptor substrate‐1 (IRS‐1) rs956115 is associated with vascular risk in patients with coronary artery disease and concomitant diabetes. CYP2C19*2 (rs4244285) modulates clopidogrel response and predicts the outcome of coronary artery disease. This study was designed to explore the association between IRS‐1, CYP2C19*2 genotypes, platelet reactivity, and 1‐year outcome in patients with coronary artery disease undergoing percutaneous coronary intervention.Methods and ResultsGenotyping was performed using an improved multiplex ligation detection reaction technique. Platelet aggregation was assessed by light transmission aggregometry. Major adverse cardiovascular events were defined as a composite of cardiovascular death, myocardial infarction, and ischemic stroke. A total of 2213 consecutive patients were screened and 1614 were recruited. At 1 month, patients with IRS‐1 CG genotype had significantly lower levels of ADP‐induced platelet aggregation compared with patients with CC homozygotes. Patients with IRS‐1 CG or GG genotype had a 2.09‐fold higher risk of major adverse cardiovascular events compared with those with CC homozygotes (95% CI, 1.04–4.19; P=0.0376). By comparison, patients with CYP2C19*2 GA or AA genotype had higher ADP‐induced platelet aggregation compared with patients with GG homozygotes. Although there was no significant difference in risk of major adverse cardiovascular events between patients with GA/AA and GG genotypes, patients with GA genotype had a 2.19‐fold higher risk than those with GG homozygotes (95% CI, 1.13–4.24; P=0.0200). No interaction between IRS‐1 and CYP2C19*2 genotypes was observed.ConclusionsIn patients following percutaneous coronary intervention, IRS‐1 GG/CG and CYP2C19*2 GA genotypes were associated with 2.09‐ and 2.19‐fold increased cardiovascular risk, respectively, at 1‐year follow‐up. The association between IRS‐1 genotypes and major adverse cardiovascular events appeared to be independent of known clinical predictors.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01968499.

Impact of VKORC1, CYP2C9, CYP1A2, UGT1A1, and GGCX polymorphisms on warfarin maintenance dose: Exploring a new algorithm in South Chinese patients accept mechanical heart valve replacement.

Background:Warfarin is the most recommended oral anticoagulant after artificial mechanical valve replacement therapy. However, the narrow therapeutic window and varying safety and efficacy in individuals make dose determination difficult. It may cause adverse events such as hemorrhage or thromboembolism. Therefore, advanced algorithms are urgently required for the use of warfarin.Objective:To establish a warfarin dose model for patients after prosthetic mechanical valve replacement in southern China in combination with clinical and genetic variables, and to improve the accuracy and ideal prediction percentage of the model.Methods:Clinical data of 476 patients were tracked and recorded in detail. The gene polymorphisms of VKORC1 (rs9923231, rs9934438, rs7196161, and rs7294), CYP2C9 (rs1057910), CYP1A2 (rs2069514), GGCX (rs699664), and UGT1A1 (rs887829) were determined using Sanger sequencing. Multiple linear regressions were used to analyze the gene polymorphisms and the contribution of clinical data variables; the variables that caused multicollinearity were screened stepwise and excluded to establish an algorithm model for predicting the daily maintenance dose of warfarin. The ideal predicted percentage was used to test clinical effectiveness.Results:A total of 395 patients were included. Univariate linear regression analysis suggested that CYP1A2 (rs2069514) and UGT1A1 (rs887829) were not associated with the daily maintenance dose of warfarin. The new algorithm model established based on multiple linear regression was as follows: Y = 1.081 − 0.011 (age) + 1.532 (body surface area)-0.807 (rs9923231 AA) + 1.788 (rs9923231 GG) + 0.530 (rs1057910 AA)-1.061 (rs1057910 AG)-0.321 (rs699664 AA). The model accounted for 61.7% of individualized medication differences, with an ideal prediction percentage of 69%.Conclusion:GGCX (rs699664) may be a potential predictor of warfarin dose, and our newly established model is expected to guide the individualized use of warfarin in clinical practice in southern China.

Blood Direct PCR for Detection of CYP2C19 and CYP4F2 Variants

Blood Direct PCR for Detection of CYP2C19 and CYP4F2 Variants

Blood direct PCR: impact of CYP2C19 and CYP4F2 variants for bleeding prediction in ST-elevation myocardial infarction patients with ticagrelor.

Aims: The goals of this study were to develop a new technique that could pave the way for a quicker determination of CYP4F2 rs3093135 and CYP2C19 rs4244285 variants directly from a patient's blood and to attempt to apply this technique in clinical practice. Patients & methods: The study included 144 consecutive patients admitted with ST elevation myocardial infarction. A blood-direct PCR and real-time PCR were used to detect variants of interest. Results & conclusion: Patients with bleeding events had the CYP2C19 GG (*1*1) variant more frequently than patients without bleeding events. The CYP4F2 TT variant was more frequently detected in patients with bleeding events 3months after hospitalization.

Genetic diversity of 'Very Important Pharmacogenes' in two South-Asian populations.

ObjectivesReliable identification of population-specific variants is important for building the single nucleotide polymorphism (SNP) profile. In this study, genomic variation using allele frequency differences of pharmacologically important genes for Gujarati Indians in Houston (GIH) and Indian Telugu in the U.K. (ITU) from the 1000 Genomes Project vis-à-vis global population data was studied to understand its role in drug response.MethodsJoint genotyping approach was used to derive variants of GIH and ITU independently. SNPs of both these populations with significant allele frequency variation (minor allele frequency ≥ 0.05) with super-populations from the 1000 Genomes Project and gnomAD based on Chi-square distribution with p-value of ≤ 0.05 and Bonferroni’s multiple adjustment tests were identified. Population stratification and fixation index analysis was carried out to understand genetic differentiation. Functional annotation of variants was carried out using SnpEff, VEP and CADD score.ResultsPopulation stratification of VIP genes revealed four clusters viz., single cluster of GIH and ITU, one cluster each of East Asian, European, African populations and Admixed American was found to be admixed. A total of 13 SNPs belonging to ten pharmacogenes were identified to have significant allele frequency variation in both GIH and ITU populations as compared to one or more super-populations. These SNPs belong to VKORC1 (rs17708472, rs2359612, rs8050894) involved in Vitamin K cycle, cytochrome P450 isoforms CYP2C9 (rs1057910), CYP2B6 (rs3211371), CYP2A2 (rs4646425) and CYP2A4 (rs4646440); ATP-binding cassette (ABC) transporter ABCB1 (rs12720067), DPYD1 (rs12119882, rs56160474) involved in pyrimidine metabolism, methyltransferase COMT (rs9332377) and transcriptional factor NR1I2 (rs6785049). SNPs rs1544410 (VDR), rs2725264 (ABCG2), rs5215 and rs5219 (KCNJ11) share high fixation index (≥ 0.5) with either EAS/AFR populations. Missense variants rs1057910 (CYP2C9), rs1801028 (DRD2) and rs1138272 (GSTP1), rs116855232 (NUDT15); intronic variants rs1131341 (NQO1) and rs115349832 (DPYD) are identified to be ‘deleterious’.ConclusionsAnalysis of SNPs pertaining to pharmacogenes in GIH and ITU populations using population structure, fixation index and allele frequency variation provides a premise for understanding the role of genetic diversity in drug response in Asian Indians.

Genetic and Nongenetic Determinants of Variable Warfarin Dose Requirements: A Report from North India

Introduction: Warfarin is widely used and will continue to be prescribed especially in developing countries due to its low cost. Given the huge patient load requiring anticoagulation, there is a need to develop strategies to optimize warfarin therapy for ensuring safe and effective anticoagulation. In the present work, we aimed at elucidating the association of genetic and nongenetic variables with warfarin dose requirement in patients attending the cardiovascular clinic in a tertiary care center of North India. Methods: This was a prospective study conducted over 1 year. Patient demographic and clinical details were captured in customized case record forms. Genotyping was done using the polymerase chain reaction-restriction fragment length polymorphism method. Pharmacogenetic influence of CYP2C9 (rs1799853 and rs1057910) and VKORC1 (rs9923231) variant alleles was studied. The association of genetic and nongenetic factors with warfarin dose was quantified using a stepwise multivariate linear regression model. Results: Two hundred and forty patients were screened. Data from 82 eligible patients were used for quantifying the association of genetic and nongenetic factors with warfarin dose. A descriptive model based on CYP2C9*3 (rs1057910) and VKORC1 (rs9923231) variant alleles and BMI was developed. The model explains nearly half of the interindividual variation in warfarin dose requirement. Conclusion: The model explains nearly half of the interindividual variation in warfarin dose in patients with atrial fibrillation and or requiring valve replacement.

Genetic Polymorphisms of Pesticide-Metabolizing Enzymes and Transporters in Agricultural Workers and Thyroid Hormone Levels.

PurposeChronic exposure to pesticides has been associated with thyroid dysfunction owing to their endocrine disruption ability. Genetic variations in genes encoding phase I and II enzymes and phase III transporters are partly responsible for individual responses to chemical pesticides. This study investigated the association between variations in genes involved in pesticide metabolism and altered thyroid hormone concentrations.MethodsWe assessed thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) in organic agriculture workers (n = 216) and workers who used chemical pesticides (n = 229). A questionnaire was used to collect sociodemographic, pesticide exposure, and health status data. Blood samples were analyzed for TSH, FT3, and FT4. Genomic DNA was extracted and genotyped using the TaqMan real-time PCR genotyping assay and restriction fragment length polymorphism method for 15 metabolically related genes.ResultsSignificant differences in the TSH (1.58 vs 1.12 µIU/mL) and FT3 (0.34 vs 0.31 ng/dL) concentrations between the chemical and organic worker groups were observed. The frequencies of all single nucleotide polymorphisms were in Hardy–Weinberg equilibrium and were mostly consistent with Asian populations. The findings showed the association between SNPs of enzymes and transporters and TSH, FT3, and FT4. The odd ratio and adjusted odd ratio (with sex, age, smoking status, alcohol consumption and exposure parameters) for subclinical thyroid disease by the variant alleles CYP1A1 rs1048943, CYP2B6 rs2279343, CYP2C19 rs4244285, NAT2 rs1799931, and PON1 rs662 in the chemical workers compared with the organic workers were found (P values < 0.05).ConclusionThis is the first study to assess gene–environment interactions in Thai agricultural workers by investigating disruptions of the hypothalamic–pituitary–thyroid axis. The investigated SNP profiles revealed several gene–thyroid hormone associations in which even low levels of pesticide exposure could disturb thyroid homeostasis. These findings provide a foundation for planning future studies investigating associations between complex diseases and occupational pesticide exposure.

Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study.

Warfarin is the most commonly evaluated drug in pharmacogenetic-guided dosing studies. However, gaps remain regarding the influence of the genetic polymorphisms of CYP2C9, VKORC1, and CYP4F2 on specific pharmacodynamic parameters like the warfarin sensitivity index (WSI), prothrombin time international normalized ratio (PT-INR), and log-INR variability. A cross-sectional study was conducted in non-smoking adults receiving warfarin for at least 6months. Their demographics, diagnoses, warfarin dosing regimen, concomitant drugs, PT-INR, and bleeding episodes were obtained. CYP2C9 (rs1057910-*3 and rs1799853-*2 alleles), CYP4F2 (rs2108622), and VKORC1 (rs9923231) polymorphisms were assessed using real-time polymerase chain reaction. Three genotype groups (I-III) were defined based on the combined genetic polymorphisms of CYP2C9 and VKORC1 from the FDA's recommendations. Key outcome measures included anticoagulation control, time spent in therapeutic range, stable warfarin dose, WSI, log-INR variability, and Warfarin Composite Measure (WCM). The study recruited 236 patients; 75 (31.8%) carried a functional CYP2C9 variant allele, and, 143 (60.6%) had at least one T allele in CYP4F2 and 133 (56.4%) had at least one T allelein VKORC1. Groups' II and III CYP2C9 and VKORC1 genotypes were observed with reduced stable warfarin dose, increased WSI, higher log-INR variability, and increased bleeding risk. The presence of *2 or *3 allele in CYP2C9 was observed with reduced stable warfarin doses akin to the presence of T alleles in VKORC1; however, the doses increased with T alleles in CYP4F2. The evaluated genetic polymorphisms significantly influenced all the pharmacodynamic parameters of warfarin. Evaluating CYP2C9, VKORC1, and CYP4F2 genetic polymorphisms prior to warfarin initiation is likely to optimize therapeutic response.

Impact of CYP2C19, CYP3A4, ABCB1, and FMO3 genotypes on plasma voriconazole in Thai patients with invasive fungal infections.

Voriconazole is the first‐line antifungal choice in the treatment of invasive fungal infections (IFIs). Single nucleotide polymorphisms (SNPs) in drug‐metabolizing and transporter genes may affect voriconazole pharmacokinetics. This study aimed to determine the frequency of the CYP2C19 rs4244285, rs4986893, rs72552267, and rs12248560, CYP3A4 rs4646437, ABCB1 rs1045642, and FMO3 rs2266782 alleles and determine the association between these genetic variants and voriconazole concentrations in Thai patients with invasive fungal infections. The study comprised 177 Thai patients with IFIs in whom seven SNPs in CYP2C19, CYP3A4, ABCB1, and FMO3 were genotyped using TaqMan real‐time polymerase chain reaction (RT‐PCR) 5´ nuclease assays, and voriconazole plasma concentrations were measured by high‐performance liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Of the 177 patients included, 31 were <12 years and 146 were ≥12 years. The CYP2C19 allele frequencies were 0.29 for *2, 0.060 for *3, 0.003 for *6, and 0.008 for *17. The allele frequency of CYP3A4 (rs4646437) was 0.26, ABCB1 (rs1045642) was 0.36, and FMO3 (rs2266782) was 0.16. The median voriconazole dose/weight was significantly lower in patients aged ≥12 years when compared to the patients aged <12 years (P < .001). Patients aged <12 years with CYP2C19*1/*2 exhibited significantly higher median voriconazole plasma concentrations than those with the CYP2C19*1/*1 (P = .038). However, there were no significant differences in median voriconazole plasma concentrations among the CYP2C19 genotypes in the patients aged ≥12 years. There was a lack of association observed among the CYP3A4, ABCB1, and FMO3 genotypes on the plasma voriconazole concentrations in both groups of patients. Our findings indicate that voriconazole plasma concentrations are affected by the CYP2C19*2 allele in patients aged <12 years but not in patients aged ≥12 years.

Effects of EPHX1 rs2260863 polymorphisms on warfarin maintenance dose in very elderly, frail Han-Chinese population.

Aim: This study was conducted to investigate the effects of VKORC1, CYP2C9, CYP4F2 andEPHX1 and nongenetic factors on warfarin maintenance dose in a very elderly, frail Han-Chinese population. Materials & methods:16variants of VKORC1, CYP2C9, CYP4F2 and EPHX1 were genotyped. Univariate analysis and multivariable regression model were performed for the associations of gene variants and warfarin maintenance dose. Results & conclusion:EPHX1 rs2260863 nonvariant CC homozygotes required significantly lower daily warfarin dose than GC heterozygotes. In the multivariable model, VKORC1 rs9923231, CYP2C9 rs1057910, EPHX1 rs2260863, CYP4F2 rs2189784 and body surface area altogether explained 26.9% of dosing variability. This study revealed the main impact of genetic factors on warfarin response in this special population.