CYP2D6 Gene Polymorphisms Research Articles

ASSOCIATION OF CYP2D6 GENE POLYMORPHISMWITH FLUOXETINE INDUCED ADVERSE REACTIONSIN PATIENTS WITH MAJOR DEPRESSION

This study rigorously explores the intricate relationship between geneticpolymorphisms within the CYP2D6 gene, and the manifestation of adverse drug reactions induced by fluoxetine in individuals diagnosed with MDD. MDD represents a debilitating and challenging condition with a multifaceted etiology, encompassing genetic predisposition as a contributing factor. Nevertheless, a frequently recommended antidepressant that is the response to fluoxetine differs notably amongpeople. This variability results in the attribution to genetic variations in the gene encoding an enzyme CYP2D6 that is essential for the metabolism of fluoxetine. In this study, we intend to delve into the connection among CYP2D6 gene polymorphisms and adverse drug reactions to fluoxetine as well as evaluate the effect on productiveness of fluoxetine in MDD, and to inquire into their impact on the antidepressant effect of fluoxetine. The study also shows that there is polymorphic CYP2D6 alleles that is connected to an elevated probability of adverse drug reactionsto the fluoxetine, lessening the treatment productiveness, and low enhancement in the depressive symptoms. So, to address this issue the study delves into a sample of MDD patients, encompassing the clinical scales, and genetic testing to evaluate the role of CYP2D6 gene variations in fluoxetine response. The outcomes of this research arewide-ranging. This study also contributes to the evolving field of pharmacogenomics in psychiatry that facilitates the personalized treatment methods for MDD patients. Adverse reactions can be reduced, productivity can be increased, and patient safety can be improved by changing medication choices and doses based on geneticinformation. So, this research thus inquiries into enhance the standard of life and welfare of individuals who are struggling with this MDD.

Pharmacogenetic features of tramadol metabolism affecting the quality of postoperative analgesia in vascular surgery

BACKGROUND: The issue of the efficacy and safety of medications employed for postoperative analgesia has not been resolved to date. Insufficient analgesia constitutes one of the primary risk factors for developing cardiovascular complications postoperatively. Tramadol is a medication that is frequently used for postoperative pain relief following minor and moderately traumatic operations. The biotransformation of this drug is considerably slowed by the presence of CYP2D6 gene polymorphisms G1846A and C100T, which play a significant role in its metabolism. In such patients, a decrease in the quality of postoperative analgesia can be anticipated, which will consequently lead to an increase in cardiac complications. AIM: To assess the efficacy of a postoperative analgesia regimen based on tramadol and the incidence of cardiac complications during vascular operations depending on the presence/absence of polymorphisms of the CYP2D6 gene polymorphisms, an isoenzyme of cytochrome P-450. MATERIALS AND METHODS: An examination of 109 patients undergoing planned vascular surgery was conducted. The frequency of occurrence of polymorphisms G1846A and C100T of the CYP2D6 gene was determined. All patients were assessed for the severity of postoperative pain syndrome during activity and at rest using a visual analog scale on the first day following surgery. Cardiovascular complications that arose while the patients were in the hospital were documented. To assess the autonomic nervous system, patients underwent cardiointervalography. RESULTS: Polymorphism G1846A was detected in 28 (25.7%), while C100T was detected in four (3.7%) patients. Patients without polymorphisms were included in group 1 (n=77). Patients with polymorphisms were assigned to group 2 (n=32). Pain syndrome at rest and during activity was higher in group 2 patients (p 0.05). The tension index before surgery did not differ between the groups; however, it was greater in group 2 patients after surgery (p 0.001). Cardiac complications were identified in 9.1% of group 1 and 18.8% of group 2 patients (p=0.20). CONCLUSION: The frequency of polymorphisms G1846A and C100T of the CYP2D6 gene in patients who underwent vascular surgery was 29.4%. Such patients experienced pain syndrome of greater severity. The patient groups did not exhibit any significant differences in the frequency of cardiac complications.

CYP2D6, CYP2E1 Gene Polymorphisms and Gastrointestinal Cancer Risk in Rural Maharashtra: A Hospital Based Case-Control Study.

Cytochrome P450 (CYP) is a family phase I metabolizing enzymes important in xenobiotics metabolism. Genetic polymorphisms of CYPs have been comprehensively studied for their association with a range of diseases including cancer risk. In this study we assessed single nucleotide polymorphism (SNP) CYP2D6 and CYP2E1 genes and their role in gastrointestinal (GI) cancer susceptibility in the rural population of Maharashtra. Genotyping of CYP2D6*4, CYP2E1*5B, CYP2E1*6, CYP2E1*7B genes among 200 GI cancer cases and equal number of controls was studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The Odds ratio (OR) with 95% confidence interval and p-value were evaluated to get the level of association of polymorphisms with risk of GI cancer, where p ≤0.005 was considered as statistically significant. After the analysis of CYP2D6 and CYP2E1 gene polymorphisms, we noticed that CYP2D6*4 (rs3892097) with heterozygous genotype (G/C) showed negative association with GI cancer risk (OR=0.43, 95% CI: 0.25-0.74; p=0.002) and CYP2E1*6 (rs6413432) variant genotype showed positive association (OR=2.85, 95% CI: 1.40-5.81; p=0.003) showed positive association with GI cancer risk in studied population. The findings obtained from this study concluded that the polymorphic CYP2D6 was negatively associated; however CYP2E1*6 polymorphism was significantly associated with GI cancer risk in studied population.

Exploring CYP2D6 polymorphisms and angiotensin receptor blocker response in the Bai hypertensive population.

The CYP2D6 enzyme is crucial for the metabolism and disposition of a variety of drugs. This study was conducted to examine the relationship between CYP2D6 gene polymorphisms and the response to angiotensin receptor blocker (ARB)-based treatment in patients of Chinese Bai ethnicity with hypertension. Seventy-two hypertensive adults from the Chinese Bai ethnic group, exhibiting systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg, were recruited. Targeted regional sequencing was utilized to genotype single nucleotide polymorphisms in the CYP2D6 gene, aiming to assess their frequency and to evaluate their influence on the therapeutic efficacy of ARB medications. Our research identified nine significant CYP2D6 polymorphisms associated with the efficacy of ARB treatment in the Bai hypertensive cohort. Specifically, patients possessing certain mutant genotype at rs111564371 exhibited substantially greater reductions in SBP and DBP, with P -values of 0.021 and 0.016, respectively, compared to those carrying the wild genotype. Additionally, these mutant genotype at rs111564371 and rs112568578 were linked to approximately 20% higher overall efficacy rates and a 10% increased achievement rate relative to the wild genotype. Our research with the Bai hypertensive group shows that certain CYP2D6 polymorphisms significantly influence ARB treatment outcomes. Mutations at rs111564371 led to better blood pressure control ( P -values: 0.021 for SBP, 0.016 for DBP), improving ARB efficacy by appromixately 20% and increasing treatment goal achievement by 10% over the wild-type genotype. Our investigation into CYP2D6 polymorphisms within the Bai hypertensive cohort marks a substantial advancement towards personalized healthcare, underscoring the pivotal influence of genetic constitution on the effectiveness of ARB therapy.

Distribution of CYP2D6 and CYP2C19 gene polymorphisms in Han and Uygur populations with breast cancer in Xinjiang, China.

The aim of this study was to investigate the frequency distribution of the cytochrome P450 (CYP450) enzymes, CYP2D6 and CYP2C19, and the form of tamoxifen metabolisation in premenopausal patients with breast cancer in the Han and Uygur ethnic groups of Xinjiang to guide rational clinical drug use. A total of 125 Han patients and 121 Uygur patients with premenopausal hormone-receptor-positive breast cancer treated at the Xinjiang Uygur Autonomous Region Cancer Hospital between 1 June 2011 and 1 December 2013 were selected. The common mutation sites in CYP450 were analysed using TaqMan® minor groove binder technology. Genetic testing was performed to determine other metabolic types of tamoxifen, and the genotypes and metabolic types were compared using a Chi-squared test. Between the Han and Uygur groups, there were significant differences in the frequencies of the CYP2D6 (*10/*10) and CYP2C19 (*1/*1) genotypes, with P-values of 0.002 and 0.015, respectively. Genotypes of CYP2D6 (*1/*1), CYP2D6 (*1/*5), CYP2D6 (*5/*5), CYP2D6 (*5/*10) and CYP2C19 (*3/*3) were expressed in the two patient groups, and the difference was not statistically significant (P > 0.05). In the Han patients, the proportions of extensive, intermediate and poor metabolisers of tamoxifen were 72, 24 and 4%, respectively, whereas those in the Uygur patients were 76.9, 17.4 and 5.7%, respectively, with no significant difference (P > 0.05). In conclusion, There were partial differences in the CYP2D6 and CYP2C19 gene polymorphisms of CYP450 between the Han and Uygur patients with premenopausal breast cancer, but there was no significant difference between the CYP2D6 and CYP2C19 phenotypes. Further research is needed to determine the relationship between the enzyme genetic differences of CYP450 and the pharmacokinetics and efficacy of tamoxifen. Although there were some differences in genotypes, these did not result in differences in the predicted tamoxifen metabolisation phenotype between the Han and Uygur patients with breast cancer. Therefore, the doses should be adjusted according to the individual genotype data.

CYP2D6 gene polymorphisms and the quality of postoperative analgesia with tramadol after vascular surgery

Relevance. The quality of postoperative anesthesia may depend on the individual genetic characteristics of the patient. Thus, the C100T and G1846A polymorphisms in the CYP2D6 gene can change the biotransformation of tramadol and, consequently, its clinical effect.Objective. To evaluate the quality of postoperative pain relief based on tramadol after vascular operations depending on the presence/absence of polymorphisms in CYP2D6, an isoenzyme of cytochrome P450.Materials and methods. We examined 78 patients aged 52 [49–61] years who underwent routine operations on the vertebral arteries. Every 3 h after surgery, pain was assessed using a visual analog scale. Before and after the operation, variability in heart rate was analyzed according to the method described by Baevsky. The presence of polymorphisms C100T and G1846A in CYP2D6 was determined from whole blood samples. The obtained data were analyzed using nonparametric statistics.Results. When assessing the CYP2D6 gene, polymorphisms were identified in 22 (28.2 %) patients: G1846A in 18 (23.1 %) patients and C100T in 4 (5.1 %). Patients were retrospectively divided into 2 groups: group 1 (n=56) included patients without studied polymorphisms of the CYP2D6 gene and group 2 (n=22) — with identified polymorphisms. Pain syndrome according to VAS at rest was more intense in group 2 at 18:00, 21:00, and 09:00 on the first postoperative day, when patients were activated — at 18:00 and 09:00 (p<0.05). The stress index after surgery was also higher in group 2 (p<0.05).Conclusions. The frequency of occurrence of polymorphisms G1846A and C100T of the CYP2D6 gene in vascular patients was 28.2 %. These patients had a more pronounced postoperative pain syndrome and greater activity of the sympathetic nervous system. The determination of these polymorphisms can be used to create an effective personalized plan for postoperative pain relief.

Effects of CYP2D6 gene polymorphism on plasma concentration and therapeutic effect of olanzapine

This study aimed to evaluate the relationship between gene polymorphisms of metabolic enzymes, particularly the CYP2D6 gene, and the plasma concentration of olanzapine, as well as treatment response in patients with chronic schizophrenia. We recruited olanzapine-treated patients and examined their plasma olanzapine levels. Additionally, a common mutation site within each of the nine exons of the full-length CYP2D6 sequence was assayed. The Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, and Overall Clinical Impression were used to assess schizophrenic symptoms, whereas the Barnes Akathisia Scale and Extrapyramidal Symptom Rating Scale were used to evaluate adverse effects. The results showed no significant differences in plasma olanzapine concentrations, treatment response, or the occurrence of adverse effects among different CYP2D6 genotypes. However, an association between olanzapine concentrations and improvement in clinical symptoms and adverse reactions was observed. In conclusion, the CYP2D6 genotype did not significantly impact plasma olanzapine concentrations, treatment response, or the occurrence of adverse effects.

Personalized approach to outpatient management of patients taking tamoxifen by gynecologists

BACKGROUND: 30% of women with luminal breast cancer receiving adjuvant tamoxifen experience disease recurrence within 15 years. This demonstrates the wide variability in clinical response to tamoxifen. Both nongenetic (age, gender, body mass index, duration of drug use) and genetic factors have been described to influence the high variability of response to tamoxifen. Differences in the genes encoding the enzymes CYP2D6, CYP2C, and CYP3A (CYP2D6*4, CYP3A5*3, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3) and the ABCB1 gene (C3435T) may also be the main factors of susceptibility to the occurrence of undesirable effects when taking tamoxifen, which in turn may lead to decreased patient adherence to therapy.
 AIM: The aim of this study was to create a concept and an algorithm for a personalized approach to outpatient management of patients taking tamoxifen by a gynecologist in connection with the carriage of polymorphisms of cytochrome P450 and drug transporter genes.
 MATERIALS AND METHODS: In 2017–2018, the outpatient records of 230 patients with breast cancer were analyzed retrospectively. A single-stage pharmacogenetic study of 120 women with stage I–III luminal breast cancer taking tamoxifen was conducted prospectively for the presence of cytochrome P450 gene polymorphisms using the polymerase chain reaction method and assessing associations with adverse drug reactions, and 54 patients were interviewed after five-year follow-up to assess adherence and satisfaction with medical supervision.
 RESULTS: The likelihood of developing endometrial hyperplasia has been shown to increase while taking tamoxifen with increasing average age, body mass index, duration of tamoxifen use, and postmenopause. Significant associations have been identified between the carriage of the CYP2D6, CYP2C9, CYP2C19, CYP3A5, and ABCB1 gene polymorphisms and the development of adverse drug reactions. Predictive models have been developed to determine the risk of adverse drug reactions. All studied adverse drug reactions associated with various genetic polymorphisms predominated in the group of patients who stopped taking tamoxifen due to poor intolerance. Gynecologists regularly observed 57.4% of patients. Moreover, the higher the adherence to therapy was, the higher was the regularity of observation by a gynecologist.
 CONCLUSIONS: A plan for outpatient management of patients receiving adjuvant endocrine therapy with tamoxifen by a gynecologist has been developed.

Personalized Medicine of flecainide (The Impact of the CYP2D6 and CYP1A2 Polymorphism on Responses to Flecainide)

Flecainide is an antiarrhythmic drug (AAD) class IC that has a narrow therapeutic index. The enzymes CYP2D6 and CYP1A2 are thought to catalyse the metabolism of this medication. This gene's polymorphism permits metabolic adjustments and modifies the pharmacokinetic profile. The objective of this review is to elucidate the impact of CYP2D6 and CYP1A2 gene polymorphisms on the pharmacological response to flecainide within the human body. Using the search terms "flecainide and CYP2D6; "flecainide and CYP1A2," papers on PubMed and Science Direct were found for the review. When the terms "flecainide and CYP2D6" were searched for in PubMed for all publications published between 2000 and 2023, 23 results were identified; when the same terms were searched on SD (Research article & English version), 97 results were found, just 13 of which were open access. With the keyword "flecainide and CYP1A2" in PubMed, a search of all articles published from 1995 to 2023 there were 7 articles and 52 articles in SD (Research article & English version), meanwhile open access were 8 articles. We add several articles other than PubMed and SD. The kinetic profile of flecainide is influenced by CYP2D6 gene polymorphism, however the effect of CYP1A2 gene polymorphism on flecainide is unknown due to a lack of studies.

Physiologically Based Pharmacokinetic Modeling to Unravel the Drug-gene Interactions of Venlafaxine: Based on Activity Score-dependent Metabolism by CYP2D6 and CYP2C19 Polymorphisms.

Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable variations in plasma concentrations across different phenotypes. This divergence in phenotypic responses leads to notable differences in both the efficacy and tolerance of the drug. A physiologically based pharmacokinetic (PBPK) model for VEN and its metabolite O-desmethylvenlafaxine (ODV) to predict the impact of CYP2D6 and CYP2C19 gene polymorphisms on VEN pharmacokinetics (PK). The parent-metabolite PBPK models for VEN and ODV were developed using PK-Sim® and MoBi®. Leveraging prior research, derived and implemented CYP2D6 and CYP2C19 activity score (AS)-dependent metabolism to simulate exposure in the drug-gene interactions (DGIs) scenarios. The model's performance was evaluated by comparing predicted and observed values of plasma concentration-time (PCT) curves and PK parameters values. In the base models, 91.1%, 94.8%, and 94.6% of the predicted plasma concentrations for VEN, ODV, and VEN + ODV, respectively, fell within a twofold error range of the corresponding observed concentrations. For DGI scenarios, these values were 81.4% and 85% for VEN and ODV, respectively. Comparing CYP2D6 AS = 2 (normal metabolizers, NM) populations to AS = 0 (poor metabolizers, PM), 0.25, 0.5, 0.75, 1.0 (intermediate metabolizers, IM), 1.25, 1.5 (NM), and 3.0 (ultrarapid metabolizers, UM) populations in CYP2C19 AS = 2.0 group, the predicted DGI AUC0-96h ratios for VEN were 3.65, 3.09, 2.60, 2.18, 1.84, 1.56, 1.34, 0.61, and for ODV, they were 0.17, 0.35, 0.51, 0.64, 0.75, 0.83, 0.90, 1.11, and the results were similar in other CYP2C19 groups. It should be noted that PK differences in CYP2C19 phenotypes were not similar across different CYP2D6 groups. In clinical practice, the impact of genotyping on the in vivo disposition process of VEN should be considered to ensure the safety and efficacy of treatment.

Risperidone plasma level, and its correlation with CYP2D6 gene polymorphism, clinical response and side effects in chronic schizophrenia patients

BackgroundTo explore the influence of CYP2D6 genetic polymorphism on risperidone metabolism, thereby affecting risperidone’s effects and safeties in patients with chronic schizophrenia.MethodsSixty-nine subjects with chronic schizophrenia treated with risperidone were recruited. CYP2D6 genotypes was determined using targeted sequencing and translated into phenotype using activity system. Risperidone plasma concentrations were measured using HPLC. Positive and Negative Symptom Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) were used to evaluate the existence and severity of psychiatric symptoms, Barnes Akathisia Scale (BAS) and Extrapyramidal Symptom Rating Scale (ESRS) for neurological side effects. Metabolic and endocrine status assess were also included.ResultsThe plasma drug concentrations varied hugely among individuals. Intermediate metabolizer (IM) group had higher plasma levels of RIP and dose corrected RIP concentration, RIP/9-OH-RIP ratio and C/D ratio than normal metabolizer (NM) group (p < 0.01). There was no statistic difference between responders and non-responders in dose-adjusted plasma concentrations and ratios of RIP/9-OH-RIP and C/D. The occurrence of EPS was related to active moiety levels in 4th week (p < 0.05). The prolactin (PRL) levels in two follow-ups were both significantly higher than baseline (p < 0.01). PRL change from baseline to week 4 and week 8 were both positively associated with active moiety concentration detected in week 4 (p < 0.05).ConclusionsThe risperidone plasma levels have great inter- and intraindividual variations, and are associated with the CYP2D6 phenotypes, as well as the changes in serum prolactin in patients diagnosed with chronic schizophrenia.

Allele and Phenotype Frequencies of CYP2D6 In The Turkish Population

Aim: Cytochrome P450 is a hepatic enzyme system responsible for drug metabolism comprising different iso-enzymes. CYP2D6 enzyme, which composes 2-4% of all cytochrome enzymes, is responsible for 25% of the metabolisms of the drugs used in clinics. The genetic polymorphisms of this enzyme can change the efficiency and toxicity of the drugs used. In this study, the retrospective evaluation of CYP2D6 gene polymorphisms that influence enzyme activity in the Turkish population is targeted. Materials and Methods: From the 192 patients sent from psychiatry, medical genetics and neurology polyclinics to our laboratory, by the methods of Multiplex Polymerase Chain Reaction (PCR) and Multiplex Allele Specific Primer Extension (ASPE), CYP2D6 enzyme gene polymorphisms were determined. Results: Of all the cases, 82,29% were determined as extensive, 12,5% as intermediate, 2,08% as poor and 3,13% as ultra-rapid metabolizers. In our population, the most frequent alleles were *1 (37,63%), *2 (24,75%), *41 (15,15%), *4 (9,85%) and *10 (4,29%), respectively. Conclusion: In the current examined population, compared to the previous studies conducted on Turkish society, it was determined that the percentage of extensive metabolizers was higher while the percentages of poor metabolizers and ultra-rapid metabolizers were lower. In addition, *41 allele that follows the decrease in enzyme function was detected as the most frequent allele in this study. The fact that the percentage of the cases in which changes were observed was 17,1% will help determine the CYP2D6 gene mutations in the pre-treatment cases.

Evaluation of linkage disequilibrium between CYP2D6 gene polymorphisms associated with breast cancer in women

Introduction: the CYP2D6 gene is highly polymorphic and is involved in the metabolism of a wide variety of drugs and xenobiotics. Three allelic variants of the gene (rs3892097, rs1065852 and rs28371725) have been studied in relation to breast cancer, but the degree of genetic linkage between them is unknown.Objetive: to test whether the three breast cancer-associated SNPs are inherited en bloc.Methods: genotypes of 280 SNPs of the CYP2D6 gene were obtained from the 1000Genomes database and linkage disequilibrium between the three breast cancer-associated SNPs and the other 277 SNPs in the gene was analysed. A threshold of r2= 0,7 was used to identify loci in linkage disequilibrium.Results: a strong correlation was found between rs3892097 and rs1065852 in Europe and Latin America. In addition, eleven polymorphisms with a high level of linkage were identified, four of which have a non-synonymous mutation effect.Conclusions: both polymorphisms could have a causal effect on breast cancer or that one of them is associated by linkage. Continuing to study both polymorphisms and considering the eleven new polymorphisms for analysis would be of relevance to deepen knowledge in relation to breast cancer in women

Associations between Selected ADRB1 and CYP2D6 Gene Polymorphisms in Children with Ventricular and Supraventricular Arrhythmias.

Background and Objectives: Tachycardia is a common cardiovascular disease. Drugs blocking β1-adrenergic receptors (ADRB1) are used in the therapy of arrhythmogenic heart diseases. Disease-related polymorphisms can be observed within the ADRB1 gene. The two most important are Ser49Gly and Arg389Gly, and they influence the treatment efficacy. The family of the cytochrome P450 system consists of the isoenzyme CYP2D6 (Debrisoquine 4-hydroxylase), which is involved in phase I metabolism of almost 25% of clinically important drugs, including antiarrhythmic drugs. A study was conducted to detect the ADRB1 and CYP2D6 gene polymorphisms. Materials and Methods: The material for the test was whole blood from 30 patients with ventricular and supraventricular tachycardia and 20 controls. The samples were obtained from the Department of Pediatric Cardiology. The first to be made was the extraction of DNA using a GeneMATRIX Quick Blood DNA Purification Kit from EURx. The selected ADRB1 and CYP2D6 gene polymorphisms were detected by high-resolution melting polymerase chain reaction (HRM-PCR) analysis. Results: Based on the analysis of melt profile data for each PCR product, the identification of polymorphisms was carried out. Heterozygotes and homozygotes were found in the examined alleles. Conclusions: The frequency of the Arg389Gly polymorphism differs statistically significantly between the control group and patients with supraventricular and ventricular arrhythmias, as well as between these two groups of patients. Moreover, the Arg389Gly polymorphism was statistically more prevalent in the group of girls with SVT arrhythmia compared to girls with VT. A few carriers of homozygous and heterozygous systems of the S49G polymorphism were detected among patients with arrhythmias, as well as control group. The percentage of individuals carrying the CYP2D6 4 allele as either homozygous or heterozygous was observed in the study and control groups. The high prevalence of the CYP2D6*4 allele carriers in both groups prompts the optimization of beta-1 blocker therapy.

Genetic polymorphisms in ADRB1, ADRB2 and CYP2D6 genes and response to beta-blockers in patients with acute coronary syndrome

Betablockers (BBs) are prescribed for ischaemia in patients with acute coronary syndrome (ACS). In Spain, bisoprolol and carvedilol are the most prescribed BBs, but patients often had to discontinue them due to adverse effects. Single nucleotide polymorphisms (SNPs) in ADRB1, ADRB2 and CYP2D6 genes have strong evidence of pharmacogenetic association with BBs in heart failure or hypertension, but the evidence in ACS is limited. Therefore, our study focuses on investigating how these genes influence the response to BBs in ACS patients. We analysed the association between SNPs in ADRB1 Gly389Arg (rs1801253) and Ser49Gly (rs1801252), ADRB2 Gly16Arg (rs1042713) and Glu27Gln (rs1042714), and CYP2D* 6 (*2– rs1080985, *4- rs3892097, *10 – rs1065852) and the occurrence of bradycardia/hypotension events during one year of follow-up. We performed an observational study and included 285 ACS-PCI-stent patients. A first analysis including patients treated with bisoprolol and a second analysis including patients treated with other BBs were performed. We found that the presence of the G allele (Glu) of the ADRB2 gene (rs1042714; Glu27Gln) conferred a protective effect against hypotension-induced by BBs; OR (CI 95%) = 0,14 (0,03−0,60), p < 0.01. The ADRB2 (rs1042713; Gly16Arg) GG genotype could also prevent hypotensive events; OR (CI 95%) = 0.49 (0.28–0.88), p = 0015. SNPs in ADRB1 and CYP2D6 * 2, CYP2D6 * 4 weren´t associated with primary events. The effect of CYP2D6 * 10 does not seem to be relevant for the response to BBs. According to our findings, SNPs in ADRB2 (rs1042713, rs1042714) could potentially affect the response and tolerance to BBs in ACS-patients. Further studies are necessary to clarify the impact of ADRB2 polymorphisms.

CYP2D6 genotyping and the clinical impact on outcomes in breast cancer tamoxifen-treated patients.

Aims: To report the distribution of allele frequencies of CYP2D6 gene and to evaluate their influence on the clinical outcomes of a group of breast cancer patients receiving adjuvant tamoxifen treatment from Uruguay. Patients & methods: 199samples were genotyped through real-time polymerase chain reaction assays. Metabolization profiles were inferred from the genotypes. Correlations were evaluated using Pearson's χ2 test. Results: Phenotype frequencies were0.65 normal (NM), 0.30 intermediate (IM)and 0.05 poor metabolizers (PM). Similar clinical outcomes between NM and (PM+IM) patient groups (odds ratio=1.011, 95% CI=0.2703-3.7826;p=0.987) were found. Conclusion: CYP2D6 allele frequencies were analyzed for the first time in a cohort from Uruguay. Results did not support any impact of CYP2D6 gene polymorphisms on clinical outcomes.

The Impact of the CYP2D6 and CYP1A2 Gene Polymorphisms on Response to Duloxetine in Patients with Major Depression.

Depression is a global mental health concern, and personalized treatment approaches are needed to optimize its management. This study aimed to investigate the influence of the CYP2D6 and CYP1A2 gene polymorphisms on the efficacy of duloxetine in reducing depressive and anxiety symptoms. A sample of 100 outpatients with major depression, who initiated monotherapy with duloxetine, were followed up. Polymorphisms in the CYP2D6 and CYP1A2 genes were assessed. The severity of depressive and anxiety symptoms was recorded using standardized scales. Adverse drug reactions (ADRs) were analyzed. Statistical analyses, including linear regression, were conducted to examine the relationships between genetic polymorphisms, clinical variables, and treatment outcomes. Patients with higher values of the duloxetine metabolic index (DMI) for CYP2D6, indicating a faster metabolism, achieved a greater reduction in anxiety symptoms. The occurrence of ADRs was associated with a lower reduction in anxiety symptoms. However, no significant associations were found between studied gene polymorphisms and reduction in depressive symptoms. No significant effects of the DMI for CYP1A2 were found. Patients with a slower metabolism may experience less benefit from duloxetine therapy in terms of anxiety symptom reduction. Personalizing treatment based on the CYP2D6 and CYP1A2 gene polymorphisms can enhance the effectiveness of antidepressant therapy and improve patient outcomes.

Tamoxifen pharmacokinetics and pharmacodynamics in older patients with non-metastatic breast cancer

BackgroundWe aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer.MethodsData for this analysis were derived from the CYPTAM study (NTR1509) database. Patients were stratified by age (age groups < 65 and 65 and older). Steady-state trough concentrations were measured of tamoxifen, N-desmethyltamoxifen, 4-hydroxy-tamoxifen, and endoxifen. CYP2D6 and CYP3A4 phenotypes were assessed for all patients by genotyping. Multiple linear regression models were used to analyze tamoxifen and endoxifen variability. Outcome data included recurrence-free survival at time of tamoxifen discontinuation (RFSt) and overall survival (OS).Results668 patients were included, 141 (21%) were 65 and older. Demographics and treatment duration were similar across age groups. Older patients had significantly higher concentrations of tamoxifen 129.4 ng/ml (SD 53.7) versus 112.2 ng/ml (SD 42.0) and endoxifen 12.1 ng/ml (SD 6.6) versus 10.7 ng/ml (SD 5.7, p all < 0.05), independently of CYP2D6 and CYP3A4 gene polymorphisms. Age independently explained 5% of the variability of tamoxifen (b = 0.95, p < 0.001, R2 = 0.051) and 0.1% of the variability in endoxifen concentrations (b = 0.45, p = 0.12, R2 = 0.007). Older patients had worse RFSt (5.8 versus 7.3 years, p = 0.01) and worse OS (7.8 years versus 8.7 years, p = 0.01). This was not related to differences in endoxifen concentration (HR 1.0, 95% CI 0.96–1.04, p = 0.84) or CYP polymorphisms.ConclusionSerum concentrations of tamoxifen and its demethylated metabolites are higher in older patients, independent of CYP2D6 or CYP3A4 gene polymorphisms. A higher bioavailability of tamoxifen in older patients may explain the observed differences. However, clinical relevance of these findings is limited and should not lead to a different tamoxifen dose in older patients.

The frequencies of CYP2D6 alleles and their impact on clinical outcomes of adjuvant tamoxifen therapy in Syrian breast cancer patients

BackgroundTamoxifen is one of the fundamental pillars of adjuvant endocrine therapy for hormone receptor-positive breast cancer; however, 30–50% of patients receiving tamoxifen experience tumor relapse. CYP2D6, encoded by an extremely polymorphic CYP2D6 gene, is the rate-limiting enzyme of tamoxifen bioactivation. This study aimed at determining the frequencies of the most clinically relevant CYP2D6 alleles and evaluating their impact on the responsiveness to tamoxifen in a cohort of Syrian breast cancer patients.MethodsThis case–control study encompassed positive estrogen and/or progesterone receptor, stage 1–3 breast cancer female patients receiving tamoxifen at Al-Bairouni University Hospital, the major National Oncology Center in Syria. Successfully genotyped eligible patients (n = 97) were classified according to their response into; no recurrence group (n = 39) who had completed a five-year recurrence-free adjuvant tamoxifen therapy, and recurrence group (n = 58) who had experienced recurrence. Several star alleles including CYP2D6*4, CYP2D6*10, CYP2D6*41, and CYP2D6*69 were identified via targeted sequencing of specific polymerase chain reaction (PCR) products and phenotypes were assigned according to activity score (AS). The correlation between genotypes and disease-free survival (DFS) was assessed using Kaplan–Meier method and log-rank test. Hazard ratios were estimated using Cox proportional hazards regression models.ResultsThe allelic frequencies of CYP2D6*41, CYP2D6*10, CYP2D6*4, and CYP2D6*69 were found to be 9.28%, 7.22%, 7.22%, and 2.58%, respectively. No statistically significant differences were observed in the frequencies of CYP2D6 phenotypes between the two arms (P = 0.24), nor the incidence of tamoxifen-induced hot flashes (P = 0.109). Poor metabolizers (PMs) tended to display shorter DFS than intermediate metabolizers (IMs) and normal metabolizers (NMs) combined (adjusted HR = 2.34, 95% CI = 0.84–6.55, P = 0.104). Notably, patients homozygous for the null CYP2D6*4 allele (1847A/A) had an elevated risk of disease recurrence compared to patients with 1847G/G genotype (adjusted HR = 5.23, 95% CI = 1.22–22.49, P = 0.026).ConclusionsOur findings show no association between CYP2D6 phenotype and treatment outcomes of tamoxifen in Syrian breast cancer patients. Nevertheless, a worse DFS was revealed in patients with 1847A/A genotype (*4/*4).

Role of CYP1A1, CYP2D6, and NOS3 gene polymorphisms in idiopathic recurrent pregnancy loss in the Iranian Azeri population: A case-control study.

Background It is estimated that 1-5% of couples suffer from recurrent pregnancy loss (RPL). Recent studies have shown the effects of gene polymorphisms in RPL.ObjectiveThe aim of this study was to evaluate 3 gene polymorphisms including rs1048943 of CYP1A1, rs28371725 of CYP2D6, and rs7830 of NOS3 in idiopathic RPL to identify their association with RPL.Materials and MethodsBlood samples were collected from 136 women with at least 2 consecutive idiopathic miscarriages (case group) and 136 women with no history of miscarriage and at least one successful pregnancy (control group) from the Iranian Azeri population. This study was carried out between April 2018-April 2020. Amplification-refractory mutation system polymerase chain reaction was used for the rs7830, rs1048943 and rs28371725 polymorphisms in order to genotype each extracted genomic DNA sample. After that, Chi-square, Fisher's exact test and logistic regression were used to investigate whether each of these polymorphisms is associated with RPL.ResultsAmong these polymorphisms, only rs1048943 of CYP1A1 showed a statistically significant association with RPL in the Iranian Azeri women studied.ConclusionOur results suggest that CYP1A1 gene polymorphisms might be associated with a reduced risk of RPL. Further studies in other populations and in the same population with a larger sample size, as well as functional genomics analyses such as gene expression analyses or epigenetic studies are required to validate our results.