CYP3A4 Variants Research Articles

Alcohol intake potentiates clozapine adverse effects associated to CYP1A2*1C in patients with refractory psychosis.

Clozapine (CLZ) is an atypical antipsychotic and the gold standard for refractory psychosis treatment. However, there is little information regarding pharmacogenetics of CLZ in patients with refractory psychosis and its clinical correlation with alcohol intake. Although neurological effects of CLZ in patients with concomitant alcohol intake are documented, its use is very common in patients with psychosis. We explored the impact of CYP1A2, CYP2D6, CYP2C19, and CYP3A4 genetic variants on CLZ pharmacokinetics and side effects, along with coffee/alcohol/tobacco consumption habits and clinical data of 48 adult patients with refractory psychosis on CLZ antipsychotic monotherapy. Relevant CYP variants in CLZ metabolism were evaluated by targeted genotyping and multiplex ligation-dependent probe amplification. CLZ and its main metabolite plasma concentrations were determined by high performance liquid chromatography. Biochemical and molecular data, along with other potential confounders, were included in the analysis by linear regression. Overall, CYP variants showed no effect on CLZ pharmacokinetics. The rs2069514 variant in homozygous genotype (also known as CYP1A2*1C/*1C) was associated with CLZ adverse reactions in Mexican patients with refractory psychosis (OR=3.55 CI95 = 1.041-12.269, p=.043) and demonstrated that this effect is doubled by concomitant alcohol consumption (OR=7.9 CI95 =1.473-42.369, p=.016). Clinicians should be aware of this information before starting CLZ use, when treating patients with refractory psychosis, who are alcohol drinkers and carriers of this genetic variant in order to prevent CLZ-related adverse reactions. Nevertheless, our findings should be replicated in larger samples.

Effects of Genetic Polymorphisms of Drug Transporter ABCB1 (MDR1) and Cytochrome P450 Enzymes CYP2A6, CYP2B6 on Nicotine Addiction and Smoking Cessation

ObjectivesTo determine the effects of genetic polymorphisms of ABCB1 (MDR1), CYP2A6, CYP2B6 on smoking status, and clinical outcomes of smoking cessation therapies in a Turkish population.Methods130 smokers and 130 non-smokers were recruited. Individuals who never smoked were described as non-smokers. 130 smokers were treated with nicotine replacement therapy (NRT) (n = 40), bupropion (n = 47), bupropion + NRT (n = 15), and varenicline (n = 28). Smokers were checked by phone after 12 weeks of treatment whether they were able to quit smoking or not. Genotyping and phenotyping were performed.ResultsCessation rates were as follows; 20.0% for NRT, 29.8% for bupropion, 40.0% for bupropion + NRT, 57.1% for varenicline (p = 0.013). The frequency of ABCB1 1236TT-2677TT-3435TT haplotype was significantly higher in non-smokers as compared to smokers (21.5% vs. 10.8, respectively; p = 0.018). Neither smoking status nor smoking cessation rates were associated with genetic variants of CYP2A6 (p = 0.652, p = 0.328, respectively), or variants of CYP2B6 (p = 0.514, p = 0.779, respectively).ConclusionGenetic variants of the drug transporter ABCB1 and the 1236TT-2677TT-3435TT haplotype was significantly associated with non-smoking status. Neither ABCB1 nor CYP2A6, CYP2B6 genetic variants were associated with smoking cessation rates at the 12th week of drug treatment.

Pharmacokinetics and Pharmacogenetics of Apixaban

Apixaban is oral anticoagulant, it is widely used in prevention of stroke in non-valvular atrial fibrillation and treatment of deep vein thrombosis and pulmonary embolism. Its main mechanism of action is through reversible inhibition of factor Xa. It specifically binds and inhibits both free and bound factor Xa which ultimately results in reduction in the levels of thrombin formation. Apixaban is mainly metabolized by CYP3A4 with minor contributions from CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP2J2 isoenzymes. Some of the major metabolic pathways of apixaban include o-demethylation, hydroxylation, and sulfation, with o-demethylapixabansulphate being the major metabolite. The aim of this review is analysis of associated researches of single nucleotide variants (SNV) of CYP3A5 and SULT1A1 genes and search for new candidate genes reflecting effectiveness and safety of apixaban. The search for full-text publications in Russian and English languages containing key words “apixaban”, “pharmacokinetics”, “effectiveness”, “safety” was carried out amongst literature of the past twenty years with the use of eLibrary, PubMed, Web of Science, OMIM data bases. Pharmacokinetics and pharmacogenetics of apixaban are considered in this review. The hypothesis about CYP и SULT1A enzymes influence on apixaban metabolism was examined. To date, numerous SNVs of the CYP3A5 and SULT1A1 genes have been identified, but their potential influence on pharmacokinetics apixaban in clinical practice needs to be further studies. The role of SNVs of other genes encoding beta-oxidation enzymes of apixaban (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2J2) and transporter proteins (ABCB1, ABCG2) in its efficacy and safety are not well understood, and ABCB1 and ABCG2 genes may be potential candidate genes for studies of the drug safety.

Functional Measurement of CYP2C9 and CYP3A4 Allelic Polymorphism on Sildenafil Metabolism.

AimWe aimed to systematically examine the effects of enzymatic activity of 38 human CYP2C9 alleles and 21 human CYP3A4 alleles, including wild-type CYP2C9.1 and CYP3A4.1, which contain the 24 CYP2C9 novel alleles (*36–*60) and 6 CYP3A4 novel alleles (*28–*34) newly found in the Chinese population, on sildenafil metabolism through in vitro experiment.MethodsThe recombinant cytochrome P450 alleles protein of CYP2C9 and CYP3A4 expressed in insect baculovirus expression system were reacted with 10–500 µM sildenafil for 30 minutes at 37°C, and the reaction was terminated by cooling to −80°C immediately. Next, we used ultra-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) detection system to detect sildenafil and its active metabolite N-desmethyl sildenafil.ResultsThe intrinsic clearance (Vmax/Km) values of most CYP2C9 variants were significantly altered when compared with the wild-type CYP2C9*1, with most of these variants exhibiting either reduced Vmax and/or increased Km values. Four alleles (CYP2C9*11, *14, *31, *49) exhibited no markedly decreased relative clearance (1-fold). The relative clearance of the remaining thirty-three variants exhibited decrease in different levels, ranging from 1.81% to 88.42%. For the CYP3A4 metabolic pathway, when compared with the wild-type CYP3A4*1, the relative clearance values of four variants (CYP3A4*3, *10, *14 and *I335T) showed significantly higher relative clearance (130.7–134.9%), while five variants (CYP3A4*2, *5, *24, *L22V and *F113I) exhibited sharply reduced relative clearance values (1.80–74.25%), and the remaining nine allelic variants showed no statistical difference. In addition, the kinetic parameters of two CYP3A4 variants (CYP3A4*17 and CYP3A4*30) could not be detected, due to the defect of the CYP3A4 gene.ConclusionThese findings were the first evaluation of all these infrequent CYP2C9 and CYP3A4 alleles for sildenafil metabolism; when treating people who carry these CYP2C9 and CYP3A4 variants, there should be more focus on the relation of dose intensity, side effects and therapeutic efficacy when administering sildenafil. The study will provide fundamental data on effect of CYP2C9 and CYP3A4 allelic variation on sildenafil metabolism for further clinical research.

P.513 Metabolic syndrome in schizophrenia and polymorphic variants of CYP1A2 and GSTP1 genes

Scientific workflows stand as practical solutions useful for maintaining data intensive applications representation and execution purposes, which entail not only powerful computing resources, but also massive storage. With the emergence of cloud environment, which enhanced the execution of such applications, the study of workflow placement strategies, as targeted to effectively reduce data movements across data centers, has grown into a highly challenging objective. Given the fact that the workflow execution process is implemented in conformity with a task-execution order, and that each task may deal with either a single or multi-dataset, within a unique data center, various data partitioning or clustering methods have been devised in a bid to retrieve the most optimally effective workflow datasets’ distribution among data centers with the aim of remarkably reducing the datasets’ movements. In this work, a fuzzy data-dependencies based partitioning layer is implemented. More specifically, a dynamic massive data placement strategy is advanced through application of an Interval Type-2 Fuzzy C-Means technique. The latter is opted for as a means whereby the cluster related data centers can be rendered more consistent, thereby, making datasets rather closely associated in terms of related dependency, which helps in remarkably influencing the amounts of transferred data. The proposed strategy is evaluated by means of a simulation technique, using both random and real-world scientific workflows. The performed experiments appear to reveal well that our suggested strategy proves to outperform noticeably the relevant state-of-the-art methods, in that it noticeably helps in reducing the number of data movements across data centers.

Role of CYP3A4*1B Gene Variant In Substance Use Disorder

Objective: This study aims to find out the possible association between the CYP3A4*1B gene variant (rs2740574) and substance use disorder susceptibility in the Turkish population. Materials and Methods: 158 patients with substance use disorder and 100 healthy individuals matched for gender, age, and ethnicity were enrolled in the study. Genotyping was analyzed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method using the MboII restriction endonuclease. The association between the CYP3A4*1B variant and substance use disorder was analyzed using SPSS 21 and de-Finetti program. Results: The CYP3A4 gene (MboII gene variant in 5’ promoter region) genotype distributions of substance use disorder patients were not significantly different from the healthy controls. When the substance use and control groups were compared in terms of allele frequency, increased G allele frequency was observed in CYP3A4 variants in the substance use group (p: 0,042). Conclusion: This is the first study that investigates the association between the MboII gene variant in CYP3A4 gene 5’promoter region and substance use disorder in the literature. It was demonstrated that an increased G allele existed in Turkish substance use disorder patients. Plans have been made to research the other variants of the CYP3A4 gene in the future. 

The influence of CYP1A1 and CYP1A2 polymorphisms on stroke risk in the Chinese population

BackgroundsStroke is a sudden disorder of cerebral blood circulation. Many studies have illustrated that dyslipidemia, hypertension, diabetes, smoking and excessive drinking are the traditional risk factors for stroke. This study aimed to observe the relationship between CYP1A1 and CYP1A2 variants and stroke risk in the Chinese population.MethodsAgena MassARRAY Assay was used to genotype four single nucleotide polymorphisms (SNPs) in 477 cases and 480 controls. The chi-square test and logistic-regression analysis were used to explore the relationship between CYP1A1 and CYP1A2 variants and stroke risk.ResultsIndividuals with CYP1A2 rs762551 C was associated with a lower risk of stroke than that of allele A. Age stratification analysis showed that rs762551 was only observed to be associated with a lower risk of stroke in ≤64ys age group. After gender stratification analysis, a significant association between rs762551 and stroke risk was found in males, but not in females. The four SNPs were found to be correlated with stroke risk in patients with hypertension, coronary heart disease, cerebral infarction and lacunar infarction.ConclusionIn this study, the results first showed that CYP1A1 and CYP1A2 variants were associated with stroke risk. Larger and well-designed studies are needed to confirm the results.

CYP3A5 genetic variants and their associations with carbamazepine and valproic acid response in Malaysian epileptic patients.

Epilepsy is a common chronic neurological condition characterized by recurrent seizures. Approximately 30 - 40% of epileptic patients do not respond to antiepileptic drugs. Previous studies suggest that CYP3A5 polymorphisms affect carbamazepine metabolism. To examine this hypothesis, in the present study, the associations between CYP3A5 variants (rs776746 and rs1419745) and response to carbamazepine and valproic acid monotherapy in Malaysian epileptic patients were evaluated. A total of 288 Malaysian epileptic patients were recruited and further reviewed, of whom 63 patients were on carbamazepine monotherapy, and 85 patients were on valproic acid monotherapy. There was no patient with drug hypersensitivity syndrome within the population. Subjects were genotyped by using Sequenom MassARRAY platform. This study found a significant association of CYP3A5 rs776746 with the carbamazepine treatment response in total patients (p=0.026) and Malay ethnic subgroup (p=0.006). In addition, a marginal significant association of CYP3A5 rs1419745 with carbamazepine treatment response was reported in the Malays. Similarly, CYP3A5 rs776746 was associated with valproic acid response in total patients (p=0.037) and Malays (marginal p=0.05). Our findings suggest that CYP3A5 polymorphisms affect carbamazepine and valproic acid response in Malaysian epileptic patients.

Sickle Cell Anemia: Variants in the CYP2D6, CAT, and SLC14A1 Genes Are Associated With Improved Hydroxyurea Response.

Differences in hydroxyurea response in sickle cell anemia may arise due to a series of factors with genetic factors appearing to be predominant. This study aims to investigate the effects of single nucleotide polymorphisms in genes encoding drug-metabolizing enzymes and solute carriers on hydroxyurea response, in patients with sickle cell anemia. For that purpose, a total number of 90 patients with sickle cell anemia were recruited, 45 were undergoing hydroxyurea treatment, while 45 were not under the treatment. Association analyses were performed between CYP3A4 (rs2740574), CYP2D6 (rs3892097), CAT (rs7943316 and rs1001179), and SLC14A1 (rs2298720) variants and laboratory parameters. According to our findings, patients with hydroxyurea treatment demonstrated higher HbF levels and a significant improvement in hemolytic, hepatic, inflammatory, and lipid parameters in comparison to those without the treatment. We also found significant associations between the CYP2D6 (rs3892097), CAT (rs7943316 and rs1001179), and SLC14A1 (rs2298720) variants and an improvement of the therapeutic effects, specifically the hemolytic, hepatic, inflammatory, lipid, and renal parameters. In conclusion, our results highlight the importance of the investigated variants, and their strong association with hydroxyurea efficacy in patients with sickle cell anemia, which may be considered in the future as genetic markers.

Dissecting the genetic overlap of smoking behaviors, lung cancer, and chronic obstructive pulmonary disease: A focus on nicotinic receptors and nicotine metabolizing enzyme.

Smoking is a major contributor to lung cancer and chronic obstructive pulmonary disease (COPD). Two of the strongest genetic associations of smoking-related phenotypes are the chromosomal regions 15q25.1, encompassing the nicotinic acetylcholine receptor subunit genes CHRNA5-CHRNA3-CHRNB4, and 19q13.2, encompassing the nicotine metabolizing gene CYP2A6. In this study, we examined genetic relations between cigarettes smoked per day, smoking cessation, lung cancer, and COPD. Data consisted of genome-wide association study summary results. Genetic correlations were estimated using linkage disequilibrium score regression software. For each pair of outcomes, z-score-z-score (ZZ) plots were generated. Overall, heavier smoking and decreased smoking cessation showed positive genetic associations with increased lung cancer and COPD risk. The chromosomal region 19q13.2, however, showed a different correlational pattern. For example, the effect allele-C of the sentinel SNP (rs56113850) within CYP2A6 was associated with an increased risk of heavier smoking (z-score = 19.2; p = 1.10 × 10-81 ), lung cancer (z-score = 8.91; p = 5.02 × 10-19 ), and COPD (z-score = 4.04; p = 5.40 × 10-5 ). Surprisingly, this allele-C (rs56113850) was associated with increased smoking cessation (z-score = -8.17; p = 2.52 × 10-26 ). This inverse relationship highlights the need for additional investigation to determine how CYP2A6 variation could increase smoking cessation while also increasing the risk of lung cancer and COPD likely through increased cigarettes smoked per day.

The effect of CYP3A4 genetic variants on the susceptibility to chronic obstructive pulmonary disease in the Hainan Han population

PurposeGenetic polymorphisms act a crucial role in chronic obstructive pulmonary disease (COPD) progression. This study aimed to investigate the correlation between CYP3A4 variants and COPD risk. MethodsWe carried out a case-control study of 821 individuals (313 patients and 508 healthy subjects) to identify the correlation of CYP3A4 SNPs with COPD risk in the Hainan Han population. The association was evaluated by Odds ratios (OR) and 95% confidence intervals (CI). ResultsOur study showed that rs4646437 polymorphism was related to a significantly increased susceptibility to COPD (OR 1.45, 95% CI = 1.10–1.90, p = 0.008). Stratified analyses indicated that rs4646437 polymorphism was significantly related to an increased risk of COPD in males (OR 1.95, 95% CI = 1.19–3.20, p = 0.008). However, rs4646440 played a protective role in females (OR 0.54, 95% CI = 0.31–0.93, p = 0.024). Rs4646437 was found to significantly improve the risk of COPD in smokers (OR 1.67, 95% CI = 1.12–2.48, p = 0.011). While rs4646440 had a significantly lower susceptibility to COPD in non-smokers (OR 0.64, 95% CI = 0.45–0.90, p = 0.010). Haplotype analysis revealed that Ars4646440Trs35564277 haplotype of CYP3A4 was found to increase the risk of COPD in non-smokers (OR 1.71, 95% CI = 1.04–2.82, p = 0.034). ConclusionOur result gives a new understanding of the association between CYP3A4 gene and COPD in the Hainan Han population.

Aromatase deficiency: A case series of 46, XX Chinese children and a systematic review of the literature.

Aromatase deficiency (AD) caused by cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1) variants is characterized by a deficiency in androgen-to-oestrogen conversion. To investigate the clinical characteristics and accurate management of aromatase-deficient children. We described three 46, XX aromatase-deficient children, searched PubMed with "(aromatase deficiency) AND (46, XX OR ovaries)" and manually searched citations in identified studies for the literature review. Two girls and one boy (3.4-9.2years) with the 46, XX karyotype presented ambiguous genitalia and maternal antenatal virilization, normal-low height, delayed bone age, normal glucose and lipid profiles, markedly elevated follicle-stimulating hormone (FSH) levels and poor oestradiol responses to human menopausal gonadotropin stimulation. Ultrasound revealed normal-sized uterus and ovaries with undetectable follicles. Histopathology revealed primordial follicles and few primary follicles in ovaries. One patient presented granulosa and follicular membrane cell proliferation and interstitial sclerosis. We identified four CYP19A1 variants; c.146_158del and c.344G >A were unreported. We reviewed available data from thirty 46, XX patients (0.2-32years). Some patients were not diagnosed until puberty/adulthood; three were initially misdiagnosed with congenital adrenocortical hyperplasia. The main characteristics were maternal antenatal virilization (21/29), ambiguous genitalia (mainly Prader IV or III, 19/23), delayed bone age (16/17), low bone mass (5/8), markedly elevated FSH levels and ovarian cysts (13/30). 46, XX AD is easily neglected or misdiagnosed. Ambiguous genitalia, maternal antenatal virilization and markedly elevated FSH levels are important diagnostic indicators. We described two novel variants, new histopathological features of ovaries and an early management strategy.

Abstract IA15: Role of environment in genetic predisposition: Lessons from tobacco studies

Abstract While it is well recognized that tobacco smoke is the leading cause of preventable cancer mortality and morbidity, efforts to control its impact on population health have been only partially successful. In this talk we describe population characteristics relating to nicotine dependence. Among those who initiate tobacco smoking, about 80% become dependent, but even among this set there is a variable degree of dependence, affecting the propensity to quit. Twin and family studies have shown a very strong impact of genetic factors on smoking behavior, which is a relatively easier behavior to measure. Therefore, massive studies involving about 500,000 individuals have now been completed and these give comprehensive descriptions of the genetic profiles that influence tobacco smoking initiation, smoking behavior, and cessation. Genetic analysis of lung cancer risk and nicotine dependence identified a region of chromosome 15q25.1 that is strongly implicated in influence risk for both diseases. Further research using retrospective data from population studies and tobacco cessation trials showed a profound influence of genotypes on propensity to quit smoking and an interaction between efficacy of pharmacologic intervention and successful tobacco cessation. These findings, along with observations about similar striking effects of CYP2A6 variation on smoking behavior, have led to the design and conduct of novel studies that integrate genetic information into the allocation of participants into tobacco cessation trials, which we will discuss. As it is the primary driver of lung cancer risk, tobacco smoking is a key driver in identifying individuals who will benefit from low-dose spiral CT, which is among the only screening protocols that has a proven impact in reducing overall mortality and which also results in a striking stage shift for lung cancer and a substantial reduction in lung cancer-specific mortality. Despite the individual benefits of screening, the cost of lung cancer screening remains high and current guidelines, which restrict access to the highest risk participants, exclude from consideration most cases of lung cancer. Towards building improved risk prediction models for lung cancer, we discuss results from lung cancer genetic studies that have identified multiple genetic factors predisposing to lung cancer risk and that can identify biomarkers and host-specific factors that associate with lung cancer risk and identify more susceptible individuals. We similarly describe findings from large head and neck cancer studies that have identified sets of susceptibility loci according to the histology or location of the cancers. Finally, we discuss future goals in integrating genetic and biomarker information for further streamlining risk assessment for lung cancer and identifying gaps and needs for risk assessment in smoking-related diseases. Citation Format: Christopher I. Amos, Laura Bierut, Margaret R. Spitz, James McKay. Role of environment in genetic predisposition: Lessons from tobacco studies [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA15.

Five genetic polymorphisms of cytochrome P450 enzymes in the Czech non-Roma and Czech Roma population samples.

Objectives Cytochromes P450 play a role in human drugs metabolic pathways and their genes are among the most variable in humans. The aim of this study was to analyze genotype frequencies of five common polymorphisms of cytochromes P450 in Roma/Gypsy and Czech (non-Roma) population samples with Czech origin. Methods Roma/Gypsy (n=302) and Czech subjects (n=298) were genotyped for CYP1A2 (rs762551), CYP2A6 (rs4105144), CYP2B6 (rs3745274) and CYP2D6 (rs3892097; rs1065852) polymorphisms using PCR-RFLP or Taqman assay. Results We found significant allelic/genotype differences between ethnics in three genes. For rs3745274 polymorphism, there was increased frequency of T allele carriers in Roma in comparison with Czech population (53.1vs. 43.7%; p=0.02). For rs4105144 (CYP2A6) there was higher frequency of T allele carriers in Roma in comparison with Czech population (68.7 vs. 49.8%; p<0.0001). For rs3892097 (CYP2D6) there was more carriers of the A allele between Roma in comparison with Czech population (39.2 vs. 38.2%; p=0.048). Genotype/allelic frequencies of CYP2D6 (rs1065852) and CYP1A2 (rs762551) variants did not significantly differ between the ethnics. Conclusions There were significant differences in allelic/genotype frequencies of some, but not all cytochromes P450 polymorphisms between the Czech Roma/Gypsies and Czech non-Roma subjects.

Five genetic polymorphisms of cytochrome P450 enzymes in the Czech non-Roma and Czech Roma population samples.

Objectives Cytochromes P450 play a role in human drugs metabolic pathways and their genes are among the most variable in humans. The aim of this study was to analyze genotype frequencies of five common polymorphisms of cytochromes P450 in Roma/Gypsy and Czech (non-Roma) population samples with Czech origin. Methods Roma/Gypsy (n=302) and Czech subjects (n=298) were genotyped for CYP1A2 (rs762551), CYP2A6 (rs4105144), CYP2B6 (rs3745274) and CYP2D6 (rs3892097; rs1065852) polymorphisms using PCR-RFLP or Taqman assay. Results We found significant allelic/genotype differences between ethnics in three genes. For rs3745274 polymorphism, there was increased frequency of T allele carriers in Roma in comparison with Czech population (53.1vs. 43.7%; p=0.02). For rs4105144 (CYP2A6) there was higher frequency of T allele carriers in Roma in comparison with Czech population (68.7 vs. 49.8%; p<0.0001). For rs3892097 (CYP2D6) there was more carriers of the A allele between Roma in comparison with Czech population (39.2 vs. 38.2%; p=0.048). Genotype/allelic frequencies of CYP2D6 (rs1065852) and CYP1A2 (rs762551) variants did not significantly differ between the ethnics. Conclusions There were significant differences in allelic/genotype frequencies of some, but not all cytochromes P450 polymorphisms between the Czech Roma/Gypsies and Czech non-Roma subjects.

The correlation of combined OGG1, CYP1A1 and GSTP1 gene variants and risk of lung cancer of male Iraqi waterpipe tobacco smokers.

Genetic polymorphisms of genes whose products are responsible for activities, such as xenobiotic metabolism, mutagen detoxification and DNA-repair, have been predicted to be associated with the risk of developing lung cancer (LC). The association of LC with tobacco smoking has been extensively investigated, but no studies have focused on the Arab ethnicity. Previously, we examined the association between genetic polymorphisms among Phase I and Phase II metabolism genes and the risk of LC. Here, we extend the data by examining the correlation of OGG1 Ser326Cys combined with CYP1A1 (Ile462Val and MspI) and GSTP1 (Ile105Val and Ala103Val) polymorphisms with the risk of LC. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and gene sequencing were carried out for genotyping the OGG1 polymorphisms of 123 LC patients and 129 controls. No significant differences in the frequencies of the OGG1 mutant allele between patients and controls were found. The distributions of heterozygous Ser/Cys or Cys/Cys genotypes of OGG1 were not associated with the risk of LC either according to the histological types of LC or based on waterpipe tobacco (WP) smoking status. In contrast, the combined effect of OGG1 variants with CYP1A1 and GSTP1 variants revealed a significant correlation with the OGG1 Ser326Cys-CYP1A1 MspI variants pairing. This association was significant (p = 0.001) in individuals who carried homozygous or heterozygous variant type genotypes of both genes in a reference with carriers of both wild-type genotypes (wt/wt - wt/wt). The odds ratios were 2.99 (95% CI 1.67-5.36), 2.68 (95% CI 1.08-6.62), and 2.80 (95% CI 1.18-6.69) for those who carried (wt/wt - wt/vt + vt/vt), (wt/vt + vt/vt - wt/wt), and (wt/vt + vt/vt - wt/vt + vt/vt), respectively. The study suggests a limited correlation is present between carrying OGG1 Ser326Cys polymorphism and the risk of developing LC in Arab populations.

Drug metabolising enzyme polymorphisms and chemotherapy-related ovarian failure in young breast cancer survivors

Cyclophosphamide is associated with chemotherapy-related ovarian failure (CROF) in breast cancer survivors, however little is known about predicting individual risks. We sought to identify genetic alleles as biomarkers for risk of CROF after cyclophosphamide treatment. One hundred fifteen premenopausal women with newly diagnosed breast cancer were genotyped for single nucleotide polymorphisms (SNPs) in genes involved in cyclophosphamide activation (CYP3A4 and CYP2C19) and detoxification (GSTP1 and GSTA1). Patients prospectively completed menstrual diaries. With median follow up of 808 days, 28% experienced CROF. Survivors homozygous for the GSTA1 minor allele had lower hazards for developing CROF (HR 0.22 [95% CI 0.05–0.94], p=.04), while survivors homozygous for the CYP2C19 minor allele had higher hazards for developing CROF (HR 4.5 [95% CI 1.5–13.4], p=.007) compared to patients with at least one major allele. In separate multivariable models adjusting for age and tamoxifen use, the associations were no longer statistically significant (GSTA1 HR 0.24 [95% CI 0.06–1.0], p=.05; CYP2C19 HR 2.5 [0.8–7.6], p=.11). CYP3A4 and GSTP1 SNPs were not significantly related to CROF. In younger breast cancer survivors undergoing cyclophosphamide-based chemotherapy, genetic variation in CYP2C19 and GSTA1 merits further study to determine its relationship with CROF. IMPACT STATEMENT What is already known on this subject? Young breast cancer survivors face important potential implications of chemotherapy-related ovarian failure (CROF). Little is known about individual risk for CROF. Cyclophosphamide, a particularly gonadotoxic drug commonly used in breast cancer treatment, is metabolised by various cytochrome p450 enzymes. Studies have shown genetic variation in p450 enzymes is associated with differential clinical outcomes after cyclophosphamide treatment: breast cancer patients homozygous for GSTA1 minor allele had improved overall survival; lupus patients homozygous for CYP2C19 minor allele had increased risk for CROF; and CYP3A4*1B I was associated with decreased risk for CROF. What do the results of this study add? We show a surprising opposite trend for the risk of CROF in breast cancer patients with GSTA1 and CYP2C19 variants, while we did not show a significant risk for genetic variation in CYP3A4 (which had previously been shown to have a protective effect) or GSTP1. What are the implications of these findings for clinical practice and/or further research? This study shows the complexity of genetic variation in predicting outcomes to treatment. We advocate for future replicative studies to potentially validate GSTA1 and CYP2C19 and definitively negate CYP3A4 and GSTP1 as biomarkers for risk of CROF after cyclophosphamide treatment. Understanding genetic variation in chemotherapy metabolism has the potential to individualise treatment regimens to maximise efficacy and minimise toxicity.

Using pharmacogenetics to structure individual pain management protocols in total knee arthroplasty

The purpose of this study was to use pharmacogenetics to determine the frequency of genetic variants in our total knee arthroplasty (TKA) patients that could affect postoperative pain medications. Pharmacogenetic testing evaluates patient DNA to determine if a drug is expected to have a normal clinical effect, heightened effect, or no effect at all on the patient. It also predicts whether patients are likely to experience side effects from medicine. We further sought to determine if changing the multimodal programme based on these results would improve pain control or reduce side effects. In this pilot study, buccal samples were collected from 31 primary TKA patients. Pharmacogenetics testing examined genetic variants in genes OPRM1, CYP1A2, CYP2B6, CYP2C19, CYP3A4, CYP2C9, and CYP2D6. These genes affect the pharmacodynamics and pharmacokinetics of non-steroidal anti-inflammatory drugs and opioids. We examined the frequency of genetic variants to any of the medications we prescribed including celecoxib, hydrocodone, and tramadol. Patients were randomized to one of two groups: the control group received the standard postoperative pain regimen, and the study group received a customized regimen based on the pharmacogenetic results. For the first ten postoperative days, patients recorded pain scores, medication, and side effects. Genetic variants involving one or more medications in the multimodal pain protocol occurred in 13 of the 31 patients (42%). In total, eight patients (26%) had variants affecting more than one of the medications. For the 25 patients who recorded pain and medication logs, the mean pain levels and morphine equivalents (MEQs) consumed in the first ten days were higher in the control group than in the custom-guided group (p = 0.019 for pain and p = 0.655 for MEQ). Overall, 42% of patients had a variant involving one of the pain medications prescribed in our perioperative pain program for TKA. Ongoing research will help determine if using these data to modify a patient's medication will improve outcomes. Cite this article: Bone Joint J 2020;102-B(6 Supple A):73-78.

Expediency of the study of the ESR1 [rs 2234693], CYP19A1 [rs2414096], and IL10 [rs1800896] single nucleotide polymorphisms as feasible markers of risk that malocclusion develops in persons born macrosomic

The article deals with analyzing the influence of polymorphic variants of CYP19A1 [rs2414096, rs936306], ESR1 [rs2234693, rs9340799], RANKL [rs9594738, rs9594759], IL1 [rs1143627], IL6 [rs1800796] and IL10 [rs1800896] genes on malocclusion development in individuals born macrosomic.The purpose of this study is to investigate the influence of the polymorphic variants of the CYP19A1 [rs2414096, rs936306], ESR1 [rs2234693, rs9340799], RANKL [rs9594738, rs9594759], IL1 [rs1143627], IL6 [rs1800796] and IL10 [rs1800896] genes on malocclusion development in individuals of the Kharkiv Region and adjacent area population born macrosomic.Material and methods. In total, one hundred and sixty-one individuals participated in this multi-stage study (144 macosomic-at-birth individuals and 17 normosomic-at-birth persons). The study participants were divided into groups according to the value of their Dental Aesthetic Index (DAI), which characterizes the severity of dental disorders and defines the need for orthodontic treatment.Results. Moderate malocclusion (DAI values in the 26–30 point range) in the surveyed persons were associated with the ESR1 gene variants ([rs 2234693], an over-dominant model of inheritance), CYP19A1 ([rs2414096], an additive, dominant, and multiplicative model of inheritance), and IL 10 ([rs1800896], dominant model of inheritance). The polymorphism of the IL10 [rs1800896] gene was significantly associated with the development of both the moderate and significant malocclusion (a dominant model of inheritance). Protection against significant malocclusion (DAI values of 31-35 points) was associated with the IL10 variant gene ([rs1800896], the dominant model of inheritance). In the presence of the heterozygous GA genotype, the risk of developing disorders decreased by 6.7 times. Analysis of ESR1 gene variants [rs 2234693], CYP19A1 [rs2414096], and IL10 [rs1800896], performed back in childhood, may be the basis for identifying at-risk individuals to developing dental disorders and for developing personalized preventive measures.Conclusions. In individuals born macrosomic, the dependence of the dentoalveolar system state on the variants of CYP19A1 genes: A&gt; G [rs2414096], ESR1: -397 T&gt; C [PvuII], and IL10: -1082 G&gt; A [rs1800896] has been revealed.

Influence of CYP2C9 and CYP2A6 on plasma concentrations of valproic acid: a meta-analysis.

Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However, the correlation between plasma VPA concentrations and CYP2C9 and CYP2A6 gene variations is uncertain. This meta-analysis aimed to investigate the relationship between CYP2C9 and CYP2A6 variants and plasma concentrations of VPA. The PubMed, Web of Science, and EMBASE databases were searched for qualifying studies published until July 2019. Cohort studies that included standardized plasma VPA concentrations and CYP2C9 and CYP2A6 genotypes were reviewed. The mean difference and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. Data analysis was performed using Review Manager (version 5.3) and RStudio (version 3.6). In total, we analyzed data from six studies involving 807 patients. We found that CYP2C9*3 was associated with standardized plasma VPA concentration; *3 allele carriers had a 0.70-μg/mL higher concentration per mg/kg than non-carriers (95% CI 0.25, 1.15; P = 0.002). We also found a significant association between the CYP2A6*4 and standardized trough VPA concentration; patients with the *4 allele had a 0.48-μg/mL higher concentration per mg/kg than patients without the *4 allele (95% CI 0.10, 0.86; P = 0.01). This meta-analysis demonstrated that CYP2C9*3 and CYP2A6*4 genetic variants affect plasma VPA concentrations. For epilepsy patients with these genotypes, dose adjustment may be necessary to ensure VPA's therapeutic effect.