Poor Metabolizer Genotype Research Articles

Interaction of age and CYP2C19 genotypes on voriconazole steady-state trough concentration in Chinese patients.

Both age and CYP2C19 genotypes affect voriconazole plasma concentration; the interaction of age and CYP2C19 genotypes on voriconazole plasma concentration remains unknown. This study aims to investigate the combined effects of age and CYP2C19 genotypes on voriconazole plasma concentration in Chinese patients. A total of 480 patients who received voriconazole treatment were recruited. CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) polymorphisms were genotyped. Patients were divided into the young and the elderly groups by age of 60 years old. Influence of CYP2C19 genotype on steady-state trough concentration (C ss-min ) in overall patients and in age subgroups was analyzed. Voriconazole C ss-min correlated positively with age, and mean voriconazole C ss-min was significantly higher in the elderly group ( P < 0.001). CYP2C19 poor metabolizers showed significantly increased mean voriconazole C ss-min in the young but not the elderly group. The percentage of patients with subtherapeutic voriconazole C ss-min (<1.0 mg/l) was higher in the young group and that of supratherapeutic voriconazole C ss-min (>5.5 mg/l) was higher in the elderly patients. When the average C ss-min in the CYP2C19 normal metabolizer genotype was regarded as a reference, CYP2C19 genotypes showed greater impact on voriconazole C ss-min in the young group, while the influence of age on voriconazole C ss-min exceeded CYP2C19 genotypes in the elderly. CYP2C19 genotypes affects voriconazole exposure is age dependent. Influence of CYP2C19 poor metabolizer genotype on increased voriconazoleexposure is prominent in the young, while age is a more important determinant factor for increased voriconazole exposure in the elderly patients.

Pharmacogenetics of weight gain following switch from efavirenz- to integrase inhibitor-containing regimens.

Excessive weight gain affects some persons with HIV after switching to integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART). We studied associations between CYP2B6 genotype and weight gain after ART switch among ACTG A5001 and A5322 participants. Eligible participants switched from efavirenz- to INSTI-containing ART, had genotype data, and had weight data at least once from 4 weeks to 2 years post-switch. Multivariable linear mixed effects models adjusted for race/ethnicity, CD4, age, BMI and INSTI type assessed relationships between CYP2B6 genotype and estimated differences in weight change. A total of 159 eligible participants switched ART from 2007 to 2019, of whom 138 had plasma HIV-1 RNA < 200 copies/mL (65 CYP2B6 normal, 56 intermediate, 17 poor metabolizers). Among participants with switch HIV-1 RNA < 200 copies/mL, weight increased in all 3 CYP2B6 groups. The rate of weight gain was greater in CYP2B6 poor than in CYP2B6 normal metabolizers overall, and within 9 subgroups (male, female, White, Black, Hispanic, dolutegravir, elvitegravir, raltegravir, and TDF in the pre-switch regimen); only in Hispanic and elvitegravir subgroups were these associations statistically significant ( P < 0.05). Compared to normal metabolizers, CYP2B6 intermediate status was not consistently associated with weight gain. CYP2B6 poor metabolizer genotype was associated with greater weight gain after switch from efavirenz- to INSTI-containing ART, but results were inconsistent. Weight gain in this setting is likely complex and multifactorial.

Determining the CYP2C19*2 and CYP2C19*3 polymorphisms among patients with gastroduodenal diseases by PCR-RFLP technique

Background: Pharmacogenetics is at the heart of precision medicine. The CYP2C19 gene encodes the cytochrome P450 2C19 enzyme which is involved in the metabolism of proton pumps inhibitors in liver. The most common alelles encoding non-functional proteins are CYP2C19*2 and CYP2C19*3. Objectives: (1) Establish a process to identify CYP2C19*2 and *3 polymorphisms by PCR-RFLP technique; (2) Determine the prevalence of CYP2C19 genotypes by *2 and *3 polymorphisms among H. pylori-positive patients with gastroduodenal diseases. Materials and methods: DNA samples were extracted from 112 gastric biopsy specimens. The CYP2C19*2 and *3 polymorphisms were identified by PCR-RFLP technique. Confirming the results in 10% of the samples randomly by Sanger sequencing. Results: The PCR-RFLP results of validated samples were in 100% concordance with sequencing results. The frequencies of the *1, *2 and *3 alleles of the CYP2C19 gene were 67.9%, 29% and 3.1%, respectively. The proportion of groups with normal metabolizer, intermediate metabolizer and poor metabolizer genotypes were 45.5%, 44.7% and 9.8%, respectively. Conclusion: The intermediate/poor metabolizer genotype accounted for a high rate. PCR-RFLP is an accurate and cost-effective method to determine CYP2C19*2 and CYP2C19*3 polymorphisms. This technique can be applied to identify polymorphisms in patients with gastroduodenal disorders as a guidance for personalized therapy. Key words: CYP2C19*2, CYP2C19*3, PCR-RFLP, gastroduodenal diseases, pharmacogenetics.

The relationship between genetic polymorphism of CYP2C19 and the efficacy of Helicobacter pylori eradication therapy in children

Objective: To investigate the relationship between genetic polymorphisms of cytochrome P450 2C19 (CYP2C19) and the efficacy of Helicobacter pylori (Hp) eradication therapy in children. Methods: The retrospective cohort study was conducted on 125 children with gastroscopy and positive rapid urease test (RUT) from September 2016 to December 2018 who presented to the Children's Hospital of Zhejiang University School of Medicine due to gastrointestinal symptoms including nausea, vomiting, abdominal pain, bloating, acid reflux, heartburn, chest pain, vomiting blood and melena. Hp culture and drug susceptibility test were carried out with gastric antrum mucosa before treatment. All the patients completed 2 weeks of standardized Hp eradication therapy and had 13C urea breath test 1 month after that, which was used to evaluate the curative effect. The DNA of gastric mucosa after RUT was analyzed and CYP2C19 gene polymorphism was detected. Children were grouped according to metabolic type. Combined with the results of Hp culture and drug susceptibility, the relationship between CYP2C19 gene polymorphism and the efficacy of Hp eradicative treatment was analyzed in children. Chi square test was used for row and column variables, and Fisher exact test was used for comparison between groups. Results: One hundred and twenty five children were enrolled in the study, of whom 76 were males and 49 females. The genetic polymorphism of CYP2C19 in these children found poor metabolizer (PM) of 30.4% (38/125), intermediate metabolizer (IM) of 20.8% (26/125), normal metabolizer (NM) of 47.2% (59/125), rapid metabolizer (RM) of 1.6% (2/125), and ultrarapid metabolizer (UM) of 0. There were statistically significant in positive rate of Hp culture among these groups (χ2=124.00, P<0.001). In addition, the successful rates of Hp eradication in PM, IM, NM and RM genotypes were 84.2% (32/38), 53.8% (14/26), 67.8% (40/59), and 0, respectively, with significant differences (χ2=11.35, P=0.010); those in IM genotype was significantly lower than that in PM genotype (P=0.011). With the same standard triple Hp eradicative regimen, the successful rate of Hp eradication for IM type was 8/19, which was lower than that of PM (80.0%, 24/30) and NM type (77.3%, 34/44) (P=0.007 and 0.007, respectively). There was a significant difference in the efficacy of Hp eradication treatment among different genotypes (χ2=9.72, P=0.008). According to the clarithromycin susceptibility result, the successful rate of Hp eradication treatment for IM genotype was 4/15 in the sensitive group and 4/4 in the drug-resistant group (χ2=6.97, P=0.018). Conclusions: The genetic polymorphism of CYP2C19 in children is closely related to the efficacy of Hp eradication treatment. PM has a higher successful rate of eradication treatment than the other genotypes.

Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis.

In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC 0-8h ). We characterized the pharmacogenetics of these interactions. Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters. Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC 0-8h values similar to controls, while CYP2B6 poor metabolizers had AUC 0-8h values of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC 0-8h values similar to controls, while NAT2 slow acetylators had AUC 0-8h values 36% higher than controls. CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.

Utility of pharmacogenomic testing in predicting intolerance to BTK inhibitors.

7541 Background: Oral inhibitors of Bruton’s tyrosine kinase (BTKi) are used for a number of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL). Real-world data has demonstrated that BTKi discontinuation is commonly due to intolerance, but contributing factors are not fully understood. Prior work suggests that cytochrome P450 (CYP) polymorphisms may increase the risk of targeted therapy discontinuation in CLL. We utilized pharmacogenomic (PGx) testing in Veterans treated with BTKi to evaluate the potential contribution of CYP polymorphisms to intolerance and responses to BTKi. Methods: We identified Veterans receiving care through the Veterans Administration (VA) who were prescribed a BTKi and underwent testing through the Pharmacogenomic Testing for Veterans (PHASER) program, currently offered at 22 VA facilities. We analyzed factors including time on BTKi therapy, reasons for discontinuation, and use of concomitant medications known to strongly inhibit CYP. Event-free survival (EFS) was defined as time from BTKi initiation to discontinuation. Results: Eighty-nine Veterans treated with BTKi who had PGx testing were identified, of which 97% (86) were male and 85% (76) were diagnosed with CLL. Other diagnoses included LPL (4), MCL (3), and MZL (3). Seventy-seven patients (pts) were treated with ibrutinib, nine with acalabrutinib and three with zanubrutinib. Three pts had poor metabolizer genotype (PMG) for CYP2C19 and 25 pts received strong CYP2C19 inhibitors (inh). Thirty-two pts had PMG for CYP2D6, and 12 pts received strong CYP2D6 inh. With a median follow up time of 38.9 months, 25 pts (28%) permanently discontinued due to intolerance and 10 pts (11%) progressed on BTKi therapy. Another 25 pts temporarily discontinued therapy. Median duration of BTKi therapy was 11.0 months for pts discontinuing for intolerance, 23.2 months for pts discontinuing for progression, and 38.5 months for pts not discontinuing therapy. Reasons for intolerance included arrhythmia, bleeding, and infections. EFS due to intolerance or progression was not statistically different between pts who were either CYP2C19 PMG or who received strong CYP2C19 inh, compared to all other pts. Interestingly, EFS due to intolerance alone was statistically different comparing these groups (p = 0.014, median 49.4m vs NR), but EFS due to progression was not (p = 0.76, median 79.6m vs NR). EFS was not significantly different comparing pts who were either receiving strong CYP2D6 inh or were PM to those who were not. Conclusions: We found that Veterans who were treated with BTKi and who either took concomitant strong CYP2C19 inh or had a CYP2C19 PMG were more likely to have intolerable side effects of BTKi therapy leading to discontinuation. Our results suggest that evaluating polypharmacy and PGx factors should be considered when prescribing BTKi.

CYP2C19 loss-of-function is associated with increased risk of hypertension in a Hakka population: a case-control study

BackgroundGenetic factors have a certain proportion in the risk factors of hypertension. The purpose was to investigate the relationship of cytochrome P450 2C19 (CYP2C19) polymorphisms with hypertension in Hakka population.MethodsThe study included 1,872 hypertensive patients and 1,110 controls. The genotypes of CYP2C19 rs4244285 and rs4986893 of all individuals were detected and analyzed.ResultsThe genotype and allele distributions of CYP2C19 rs4244285 were significantly different between hypertension group and control group. The CYP2C19 *1/*1 genotype was the most predominant among the subjects (40.8%), followed by the CYP2C19 *1/*2 genotype (40.5%). The percentage of CYP2C19*1, *2, and *3 allele was 64.2%, 30.8%, and 5.0%, respectively. The proportion of intermediate metabolizers (IM) (49.3% vs. 42.9%), poor metabolizers (PM) (14.3% vs. 8.9%) (P < 0.001), and CYP2C19*2 allele (33.8% vs. 25.7%, P < 0.001) in hypertension group was significantly higher than that in control group. Multivariate logistic regression (adjusted for gender, age, smoking, and drinking) indicated that CYP2C19 *1/*2, *1/*3, and *2/*2 genotypes may increase susceptibility to hypertension. And the CYP2C19 IM genotype (IM vs. EM: OR 1.514, 95% CI: 1.291–1.775, P < 0.001), PM genotype (PM vs. EM: OR 2.120, 95% CI: 1.638–2.743, P < 0.001), IM + PM genotypes (IM + PM vs. EM: OR 1.617, 95% CI: 1.390–1.882, P < 0.001) may increase risk of hypertension.ConclusionsCYP2C19 loss-of-function (IM, PM genotypes) is independent risk factor for hypertension susceptibility. Specifically, the risk genotypes include CYP2C19 *1/*2, *1/*3, and *2/*2.

P2Y12 Reaction Units and Clinical Outcomes in Acute Large Artery Atherosclerotic Stroke: A Multicenter Prospective Study.

We aimed to determine the association between acute platelet reactivity and clinical outcome in acute ischemic stroke (AIS) or transient ischemic attack (TIA) with large-artery atherosclerosis (LAA). In this prospective, 16-multicenter study, we enrolled AIS/TIA patients with LAA receiving clopidogrel. We assessed the association of P2Y12 reaction units (PRU) 24 hours after initiation of antiplatelets with the CYP2C19 genotype and recurrent ischemic stroke within 90 days, and the difference between acute (≤ 7 days) and subacute (8-90 days) phases. Among the 230 AIS/TIA patients enrolled, 225 with complete outcome data and 194 with genetic results were analyzed. A higher PRU was significantly associated with recurrent ischemic stroke within 90 days (frequency, 16%), and within 7 days (10%). Twenty-nine patients (15%) belonged to a CYP2C19 poor metabolizer group (CYP2C19 ＊2/＊2, ＊2/＊3, or ＊3/＊3). Multivariable receiver-operating characteristic analysis showed a greater area-under-the-curve (AUC) in predicting recurrence within 7 days, compared to 8-90 days (AUC, 0.79 versus 0.64; p=0.07), with a cut-off PRU of 254. Multivariable analysis showed high PRU (≥ 254), which had a comparable predictive performance for recurrent ischemic stroke within 7 days (odds ratio, 6.82; 95% CI, 2.23-20.9; p＜0.001) to the CYP2C19 poor metabolizer genotype. The net reclassification improvement, calculated by adding high PRU (≥ 254) to a model including the CYP2C19 poor metabolizer genotype in the prediction of recurrence within 7 days, was 0.83 (p＜0.001). Acute PRU evaluation possesses predictive value for recurrent ischemic stroke, especially within 7 days in AIS/TIA with LAA.

Antiplatelet response to clopidogrel is associated with a haplotype in CYP2C19 gene in Pakistani patients

Clopidogrel, an antiplatelet drug, is frequently prescribed to patients diagnosed with ischemic diseases such as those suffering from acute coronary syndromes or ischemic stroke. Despite the drug being effective in majority of the patients, some still experience ischemic events early in the treatment which might be due to poor platelet inhibition. This study aims to investigate the association of cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms, haplotypes as well as a wide range of clinical and demographic variables with platelet aggregation phenotypes to clopidogrel in a Pakistani cohort. The study comprised of a total of 120 patients diagnosed with cardiovascular diseases and were treated with clopidogrel. Antiplatelet response to clopidogrel was monitored by Helena AggRAM (HL-2-1785P) and patients with maximal platelet aggregation more than 50% were categorized as low responders and those with less than 50% as high responders. Our results show that 56.6% of patients were homozygous for the CYP2C19 wild-type allele, 38.3% of patients possessed one copy of the CYP2C19*2 allele and 5% of patients possessed both CYP2C19*2 alleles. No CYP2C19*3 allele was found in our patient cohort. There was no statistically significant difference between the high and low responder groups to clopidogrel in terms of extensive, intermediate and poor metabolizer genotypes. However, haplotype (H1), leukocyte count, random blood glucose, and history of diabetes mellitus was associated with the antiplatelet response to clopidogrel. The prevalence of clopidogrel resistance in our population was in line with that reported for other regional and global populations.

CYP2C19 & UGT1A6 genetic polymorphisms and the impact on Valproic acid-induced weight gain in people with epilepsy: Prospective genetic association study

ObjectivesTo study the association between CYP2C19*2 (681 G > A) and UGT1A6*2 (552A > C) polymorphisms on Valproic acid (VPA)-induced weight gain in People with epilepsy (PWE). MethodsWe recruited PWE on VPA monotherapy and genotyped for CYP2C19 and UGT1A6 polymorphisms. Association between CYP2C19 polymorphism and weight gain was the primary outcome parameter. We followed them up monthly for six months and recorded Body mass index (BMI), drug compliance, side effects, food frequency, physical activity. ResultsOf 108 participants recruited, we assessed the association between the polymorphism and weight gain in 101 PWE for CYP2C19*2 and 103 PWE for UGT1A6*2 polymorphism. The proportion of participants with weight gain was higher in those with poor and intermediate metabolizer genotypes of CYP2C19 (*1/*2 and *2/*2) compared to extensive metabolizers (*1/*1) [53.3 % vs 31.7 %, RR 1.68, 95 % CI (1.01–2.79), P = 0.03]. However, CYP2C19*2 allele did not show an increased risk of weight gain over the CYP2C19*1 allele. No association could be demonstrated with UGT1A6 genotypes and weight gain. In logistic regression analysis, CYP2C19*2 carrier genotype was the independent predictor of weight gain. OR 2.89 [95% CI (1.07–7.84)]. There were no significant association with serum TSH, fT4, testosterone, and valproate levels with CYP2C19 or UGT1A6 polymorphisms. SignificancePeople with epilepsy carrying CYP2C19 polymorphisms (*1/*2) and (*2/*2) had 3 times higher risk of VPA-induced weight gain compared to wild type (*1/*1).

The effect of CYP2C19 gene polymorphism on the eradication rate of Helicobacter pylori by proton pump inhibitors-containing regimens in Asian populations: a meta-analysis.

Premise: The effects of proton pump inhibitors (PPI) depend on metabolic enzyme CYP2C19 that has different activity due to gene polymorphism. The purpose of this meta-analysis is to determine the potential effects of CYP2C19 polymorphism on the efficiency of PPI-based treatment. Materials & methods: The PubMed, EMBASE, Cochrane Library, etc. were searched for relevant articles published in English or Chinese from inception to 31May 2020. Finally, 26 randomized controlled trials and 15 cohort studies met the inclusion criteria and used for the meta-analysis via STATA version 15. Results: Poor metabolizer (PM)genotype Helicobacter pylori eradication rates were highest for Asian individuals receiving triple or quadruple first-line therapy based on PPIs (p<0.05). CYP2C19 polymorphism could influence H. pylori eradication rate only in Mainland China and Japan (p<0.05). Conclusion: PM genotype facilitates the elimination of H. pylori in Asian populations. Rabeprazole-, esomeprazole-and pantoprazole-based eradication program was less affected by the CYP2C19 polymorphism.

The role of the poor metabolizer genotype CYP2D6 and CYP1A2 phenotype in the pharmacokinetics of duloxetine and venlafaxine—A case report

The role of the poor metabolizer genotype CYP2D6 and CYP1A2 phenotype in the pharmacokinetics of duloxetine and venlafaxine—A case report

Associations of CYP2C9 and CYP2C19 Pharmacogenetic Variation with Phenytoin-Induced Cutaneous Adverse Drug Reactions.

The role of cytochrome P450 (CYP)2C9 and CYP2C19 genetic variation in risk for phenytoin‐induced cutaneous adverse drug events is not well understood independently of the human leukocyte antigen B (HLA‐B)*15:02 risk allele. In the multi‐ethnic resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we identified 382 participants who filled a phenytoin prescription between 2005 and 2017. These participants included 21 people (5%) who self‐identified as Asian, 18 (5%) as black, 29 (8%) as white Hispanic, and 308 (81%) as white non‐Hispanic. We identified 264 (69%) CYP2C9*1/*1, 77 (20%) CYP2C9*1/*2, and 29 (8%) CYP2C9*1/*3. We also determined CYP2C19 genotypes, including 112 with the increased activity CYP2C19*17 allele. Using electronic clinical notes, we identified 32 participants (8%) with phenytoin‐induced cutaneous adverse events recorded within 100 days of first phenytoin dispensing. Adjusting for age, sex, daily dose, and race/ethnicity, participants with CYP2C9*1/*3 or CYP2C9*2/*2 genotypes were more likely to develop cutaneous adverse events compared with CYP2C9*1/*1 participants (odds ratio 4.47; 95% confidence interval 1.64–11.69; P < 0.01). Among participants with low‐intermediate and poor CYP2C9 metabolizer genotypes, eight (22%) who also had extensive and rapid CYP2C19 metabolizer genotypes experienced cutaneous adverse events, compared with none of those who also had intermediate CYP2C19 metabolizer genotypes (P = 0.17). Genetic variation reducing CYP2C9 metabolic activity may increase risk for phenytoin‐induced cutaneous adverse events in the absence of the HLA‐B*15:02 risk allele.

CYP2C19 polymorphism has no correlation with the efficacy and safety of thalidomide in the treatment of immune-related bowel disease.

To explore the relationship between hepatic cytochrome P450 2C19 (CYP2C19) gene polymorphisms and the effectiveness and safety of thalidomide in the treatment of patients with immune-related bowel disease (IRBD). CYP2C19 variants in 79 patients treated with thalidomide were analyzed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The clinical response and adverse events of the thalidomide treatment were recorded. The potential influences of the CYP2C19 genotype polymorphisms on the clinical efficacy and adverse events of thalidomide were then investigated. Altogether 79 patients with IRBD (70 with Crohn's disease, three with ulcerative colitis and six with Behcet's disease) receiving thalidomide therapy were recruited from January 2013 to February 2015 in a tertiary IBD center in China. Overall, 21.5% (17/79) of these patients had CYP2C19 poor metabolizers genotype (PM). The overall response rate and the incidence of adverse events of CYP2C19 extensive metabolizers genotype were not significantly different from that of the PM when IRBD patients were treated with thalidomide (P = 0.517 and 0.816, respectively). CYP2C19 polymorphisms do not seem to be associated with efficacy of thalidomide and the incidence of adverse events in treating IRBD.

Prevalence of Cytochrome P450 2B6 Single Nucleotide Polymorphism in an HIV-Positive Cohort in Jos, Nigeria: Implication for HIV Therapy.

Background:Africans exhibit great diversity in cytochrome P450 2B6 isoenzyme (CYP2B6), the major enzyme in efavirenz metabolism.Aim:We examined the frequency of two functional single nucleotide polymorphisms (SNPs) of the CYP2B6 pharmacogene in HIV-infected Nigerians on efavirenz-based antiretroviral therapy. The potential implications of the SNPs for HIV therapy were discussed.Materials and Methods:A cross-sectional study conducted from July 2018 to December 2018 in a tertiary health facility in Nigeria. A random sample of a clinic cohort of HIV-infected adult Nigerians of different ethnicities was characterized for two key SNPs; CYP2B6:516G>, and CYP2B6:983T > C, defining the alleles CYP2B6*6 and CYP2B6*18, respectively. Hardy–Weinberg equilibrium was calculated to evaluate the genotype frequency distribution.Results:Genotyping was successful for 262 (83%) of the 316 study participants. Of those with genotype results, mean age was 41 ± 8 years and 182 (69.5%) were female. The CYP2B6:516 G/G (extensive metabolizers), CYP2B6:516 G/T (intermediate metabolizers), and CYP2B6:516 T/T (poor metabolizers) genotype frequency was 35.9%, 46.6%, and 17.6%, respectively. Also, 88.9% and 11.1% of participants were carriers of the CYP2B6:983 T/T and CYP2B6:983 T/C (poor metabolizers) genotypes, respectively. There were no gender or age-related differences in the genotype distribution. The CYP2B6:516G >T allele frequencies showed no significant deviations from the Hardy-Weinberg equilibrium (P = 0.66).Conclusions:The intermediate metabolizer genotype was more common than the extensive and poor metabolizer genotypes in our study sample. We recommended further studies to investigate the risk of efavirenz underexposure and overexposure in carries of the extensive and poor metabolizer genotypes respectively in our patient population.

Tacrolimus Therapeutic Drug Monitoring in Stable Kidney Transplantation and Individuation of CYP3A5 Genotype

The posology of tacrolimus (TAC) is usually guided by its therapeutic drug monitoring. Some patients reach target concentrations (CTs) quickly, others more slowly. In a retrospective study, 20 kidney transplant recipients were included (mean age, 50.7 ± 14.1 years; weight 64.0 ± 14.2 kg; patients clinically stable for over a year). We studied cytochrome CYP3A5 genotype, in particular CYP3A5 6986A>G, the most important polymorphism related to the metabolism of TAC (wild genotype CYP3A5 *1 genotype, and CYP3A5 *3 variants). One year after transplantation, the CTs were 5.0 to 8.0 ng/mL. The patients were divided into group A (TAC doses < 6.0 mg/d) and group B (TAC doses > 6.0 mg/d). All were tested for the CYP3A5 gene sequence to characterize their polymorphism. Patients with CYP3A5 *1/*1 and *1/*3 were extensive metabolizers, and those with CYP3A5 *3/*3 were poor metabolizers. In group A and group B, the average TAC doses at the time of therapeutic drug monitoring were 3.0 ± 1.4 ng/mL (0.05 ± 0.03 mg/kg) and 12.8 ± 3.7 ng/mL (0.2 ± 0.1 mg/kg), respectively (P < .001). Group A was the poor metabolizers genotype, while in group B, the extensive metabolizers genotype was present. Patients with the CYP3A5 *1/*1 or *1/*3 genotype required 1.5 to 2 times higher doses than patients *3/*3 to reach CT. This genetic test allows clinicians to know, before the kidney transplant, the patient's TAC metabolism pattern and then to optimize the drug exposure.

CYP2C19 Genotype, CagA Genotype and Antibiotic Resistant Strain of Helicobacter pylori Infection

Background: H. pylori is a class I carcinogen and major cause of gastric cancer. Few previous studies reported relationship between H. pylori infection, CYP2C19 genotype and functional dyspepsia (FD) subtype. The aim of this study was to determine relationship between CYP2C19 genotype and FD subtype patients(host factor) with antibiotic resistant strains of H. pylori infection and CagA genotype(bacterial factor). Methods:FD patients who were investigated with gastroscopy at Thammasat University Hospital, Thailand during March 2017-November 2017 were enrolled. Two antral gastric biopsies were obtained for rapid urease test, E-test and cultures. CagA genotypes (CagA1a and CagA2a) were determined by PCR and CYP2C19 genotype was determined by PCR-RFLP. FD patients were categorized as epigastric pain syndrome(EPS) and postprandial distress syndrome (PDS). Results:93 FD patients with H. pylori infection were enrolled (37 male, 56 female, mean age 54.5 years). There were 33 patients with EPS and 60 patients with PDS. CYP2C19 genotype revealed 55.9% rapid metabolizer (RM), 40.9% intermediate metabolizer (IM) and 3.2% poor metabolizer (PM) genotypes. Antibiotics susceptibility tests demonstrated 62.8% resistant to metronidazole, 12.9% resistant to clarithromycin and 27.1% resistant to fluoroquinolone. CagA 1a and CagA 2a were demonstrated in 6 patients(11.5%) and 46 patients(88.5%). CagA2a genotype was more prevalent in PDS than EPS patients (94.3%vs.76.5%; P =0.08) without significance. In intermediate metabolizer (IM), CagA2a genotype was significant higher in PDS than EPS(100% vs.25%; P=0.004). Conclusions:PDS, CYP2C19 RM genotype and CagA 2a gene of H. pylori infection were the predominant type of FD in Thailand. Metronidazole remain the most common antibiotic resistant strain of H. pylori infection in FD patients. PDS (host factor) was significantly related to CagA2a genotype (bacterial factors) only in patients with intermediate metabolizer. Appropriate dose of proton pump inhibitor (PPI) and correct regimens for H. pylori eradication in FD patients should be consider to improve clinical outcomes.

CYP2D6 genetic polymorphism and genetic ancestry on extrapyramidal side-effects of long-term treatment with classical antipsychotics in cuban patients with schizophrenia

Background: Different factors alter a patient’s susceptibility to adverse neuroleptic reactions. The CYP2D6 gene codes for a human cytochrome P450 2D6 enzyme, which is responsible for the metabolism of many psychiatric drugs. Ethnicity may also influence the susceptibility to adverse effects of long-term treatment with classical Antipsychotics (AP) because allele frequencies differ in correspondence with interethnic differences. Objective: To evaluate whether the CYP2D6 allelic variants/predicted metabolic capacity status and the genetic ancestry are associated with classical antipsychotic-induced extrapyramidal side-effects (EPS) in Cuban patients with schizophrenia. Methods and findings: A cross-sectional study was carried out. 209 patients were included: 61 of them with EPS at present and 148 patients without EPS. DNA samples were genotyped to estimate of admixture proportions and CYP2D6 genotype. Homozygous patients with non-functional alleles have a higher risk of developing EPS (RR=3.418). These patients have a higher proportion of European genes (0.82). Conclusion: The Poor Metabolizer (PM) genotype may be a predisposing factor for EPS. The study did not find evidence that ethnic differences played a large part in the risk of EPS.

CYP2D6*3 (A2549del), *4 (G1846A), *10 (C100T) and *17 (C1023T) genetic polymorphisms in Iranian breast cancer patients treated with adjuvant tamoxifen.

There is controversy regarding the efficacy of tamoxifen in breast cancer patients who are carriers of cytochrome P450 2D6 (CYP2D6) gene polymorphisms. Poor metabolizer genotypes may not fully convert tamoxifen to its active metabolite endoxifen and thus have less exposure to anti-estrogen therapy. The present study was conducted to identify the prevalence of CYP2D6 genotypes among Iranian breast cancer patients. A total of 84 estrogen receptor-positive breast cancer patients treated at a referral center in the north of Iran were examined. A peripheral blood sample was obtained from each patient to determine the presence of *3, *4, *10 and *17 single nucleotide polymorphisms of the CYP2D6 gene by polymerase chain reaction-based restriction fragment-length polymorphism analysis. Of the four genotypes assessed, CYP2D6*4 was the most common variant and was identified in 41 (48.8%) patients as heterozygous (G/A) and 3 (3.6%) as homozygous (A/A) alleles. CYP2D6*10 heterozygous mutated alleles (C/T) were also a common genotype that presented in 22 (26.2%) of the study subjects. Variant *17 was less common and was detected only as heterozygous (C/T) in 3 patients (3.6%). No CYP2D6*3 heterozygous or homozygous mutated alleles were observed. In conclusion, the frequency of the CYP2D6 nonfunctional alleles *4 and *10 appeared relatively high in Iranian patients with hormone-sensitive breast cancer. This finding may affect the selection of an optimal hormone therapy, as patients with low CYP2D6 pathway activity may not sufficiently convert tamoxifen to its active metabolite endoxifen.

Türk popülasyonunda Polisitemia vera hastalarında CYP 2D6*4 polimorfizmi

Objective: Many studies have shown the association ofsusceptibility to several cancers with gene encoding enzymes’polymorphisms which engage in xenobiotics’ biotransformation.In this study, the main purpose is to search the relation betweencytochrome P450 (CYP) 2D6* 4 polymorphisms and Polycythemiavera (PV) incidence in Turkish population.Materials and Methods: In this research article, 80Polycthemia vera (PV) cases and 76 control samples have beenused for the analysis of CYP 2D6* 4 polymorphism. The researchhas been performed by the methods of polymerase chain reaction(PCR)-restriction fragment length polymorphism (RFLP).Results: As a result, when patients and controls werecompared in terms of CYP 2D6* 4 poor metabolizer (PM) andheterozygous extensive metabolizer (HEM) genotype frequency,it has been found that the patients have 1.35% PM and 32.43%HEM frequency, and controls have 2.63% PM and 21.05% HEMfrequency. The correlation between the results of CYP 2D6genotype analysis and the risk of disease in patients and controlswas examined. We found that PM, HEM and extensive metabolizer(EM) genotypes were unrelated with the risk of PV (OR 0.51, 95%CI 0.04-5.71, OR 1.80, 95% CI 0.86-3.75, χ2 1.93, P: 0.164, OR0.61, 95% CI 0.30-1.24, χ2 1.40, P: 0.235).Conclusion: Our results suggested that the CYP 2D6*4 polymorphism, in the studied population, does not play animportant role in PV etiology.