Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 19

Search results for: pharmacogenetics

19 Database of Pharmacogenetics HLA-A*31:01 Allele in Thai Population and Carbamazepine-Induced SCARs

Authors: Watchawin Ekphinitphithaya, Patompong Satapornpong

Abstract:

Introduction: Carbamazepine (CBZ) is one of the most prescribed antiepileptic drugs (AEDs) by neurologists and non-neurologist worldwide. CBZ is usually prescribed along with other drugs, leading to the possibility of severe cutaneous adverse drug reactions (SCARs). The HLA-B*15:02 is strongly associated with CBZ-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS–TEN) in the Han Chinese and other Asian populations but not in European populations, while HLA-A*31:01 allele has been reported to be associated with CBZ-induced SCARs in European population and Japanese. Objective: The aim of this study is to investigate the distribution of pharmacogenetics HLA-A*31:01 marker in a healthy Thai population associated with Carbamazepine-induced SCARs. Materials and Methods: Prospective study, 350 unrelated healthy Thais were recruited in this study. Human leukocyte antigen-A alleles were genotyped using PCR-sequence specific oligonucleotides (PCR-SSOs). Results: The frequency of HLA-A alleles were HLA-A*11:01 (190 alleles, 27.14%), HLA-A*24:02 (82 alleles, 11.71%), HLA-A*02:03 (80 alleles, 11.43%), HLA-A*33:03 (76 alleles, 10.86%), HLA-A*02:07 (58 alleles, 8.29%), HLA-A*02:01 (35 alleles, 5.00%), HLA-A*24:07 (29 alleles, 4.14%), HLA-A*02:06 – HLA-A*30:01 (15 alleles, 2.14%), and HLA-A*01:01 (14 alleles, 2.00%). Particularly, the number of HLA-A*31:01 alleles was 6 of 700 (0.86%) in the healthy Thai population. Many research presented varying distributions of HLA-A*31:01 in Asians, including 2% of Han Chinese, 9% of Japanese and 5% of Koreans. In addition, this allele was found approximately 2-5% in the Caucasian population. Conclusions: Thus, the pharmacogenetics database is vital to support in many populations, especially in Thais, for screening HLA-A*31:01 allele to avoid CBZ-induced SCARs before initiating treatments in each population.

Keywords: Carbamazepine, HLA-A*31:01, Thai population, pharmacogenetics

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18 Genetic and Non-Genetic Factors Affecting the Response to Clopidogrel Therapy

Authors: Snezana Mugosa, Zoran Todorovic, Zoran Bukumiric, Ivan Radosavljevic, Natasa Djordjevic

Abstract:

Introduction: Various studies have shown that the frequency of clopidogrel resistance ranges from 4-40%. The aim of this study was to provide in depth analysis of genetic and non-genetic factors that influence clopidogrel resistance in cardiology patients. Methods: We have conducted a prospective study in 200 hospitalized patients hospitalized at Cardiology Centre of the Clinical Centre of Montenegro. CYP2C19 genetic testing was conducted, and the PREDICT score was calculated in 102 out of 200 patients treated with clopidogrel in order to determine the influence of genetic and non-genetic factors on outcomes of interest. Adverse cardiovascular events and adverse reactions to clopidogrel were assessed during 12 months follow up period. Results: PREDICT score and CYP2C19 enzymatic activity were found to be statistically significant predictors of expressing lack of therapeutic efficacy of clopidogrel by multivariate logistic regression, without multicollinearity or interaction between the predictors (p = 0.002 and 0.009, respectively). Conclusions: Pharmacogenetics analyses that were done in the Montenegrin population of patients for the first time suggest that these analyses can predict patient response to the certain therapy. Stepwise approach could be used in assessing the clopidogrel resistance in cardiology patients, combining the PREDICT score, platelet aggregation test, and genetic testing for CYP2C19 polymorphism.

Keywords: clopidogrel, pharmacogenetics, pharmacotherapy, PREDICT score

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17 Pharmacogenetics of Uridine Diphosphate Glucuronosyltransferase (UGT1A9) Genetic Polymorphism on Sodium Valproate Pharmacokinetics in Epilepsy

Authors: Murali Munisamy, Gauthaman Karunakaran, Mubarak Al-Gahtany, Vivekanandhan Subbiah, M. Manjari Tripati

Abstract:

Background: Sodium valproate is a widely prescribed broad-spectrum anti-epileptic drug. It shows high inter-individual variability in pharmacokinetics and pharmacodynamics and has a narrow therapeutic range. We evaluated the effects of polymorphic uridine diphosphate glucuronosyltransferase (UGT1A9) metabolizing enzyme on the pharmacokinetics of sodium valproate in the patients with epilepsy who showed toxicity to therapy. Methods: Genotype analysis of the patients was made with polymerase chain–restriction fragment length polymorphism (RFLP) with sequencing. Plasma drug concentrations were measured with reversed phase high-performance liquid chromatography (HPLC) and concentration–time data were analyzed by using a non-compartmental approach. Results: The results of this study suggested a significant genotypic as well as allelic association with valproic acid toxicity for UGT1A9 polymorphic enzymes. The elimination half-life (t 1/2=40.2 h) of valproic acid was longer and the clearance rate (CL=937 ml/h) was lower in the poor metabolizers group of UGT1A9 polymorphism who showed toxicity than in the intermediate metabolizers group (t1/2=35.5 h, CL=1042 ml/h) or the extensive metabolizers group (t1/2=26. h, CL=1,302 ml/h). Conclusion: Our findings suggest that the UGT1A9 genetic polymorphism plays a significant role in the steady state concentration of sodium valproate, and it thereby has an impact on the toxicity of the sodium valproate used in the patients with epilepsy.

Keywords: UGT1A9, sodium valporate, pharmacogenetics, polymorphism

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16 Prenatal Use of Serotonin Reuptake Inhibitors (SRIs) and Congenital Heart Anomalies (CHA): An Exploratory Pharmacogenetics Study

Authors: Aizati N. A. Daud, Jorieke E. H. Bergman, Wilhelmina S. Kerstjens-Frederikse, Pieter Van Der Vlies, Eelko Hak, Rolf M. F. Berger, Henk Groen, Bob Wilffert

Abstract:

Prenatal use of SRIs was previously associated with Congenital Heart Anomalies (CHA). The aim of the study is to explore whether pharmacogenetics plays a role in this teratogenicity using a gene-environment interaction study. A total of 33 case-mother dyads and 2 mother-only (children deceased) registered in EUROCAT Northern Netherlands were included in a case-only study. Five case-mother dyads and two mothers-only were exposed to SRIs (paroxetine=3, fluoxetine=2, venlafaxine=1, paroxetine and venlafaxine=1) in the first trimester of pregnancy. The remaining 28 case-mother dyads were not exposed to SRIs. Ten genes that encode the enzymes or proteins important in determining fetal exposure to SRIs or its mechanism of action were selected: CYPs (CYP1A2, CYP2C9, CYP2C19, CYP2D6), ABCB1 (placental P-glycoprotein), SLC6A4 (serotonin transporter) and serotonin receptor genes (HTR1A, HTR1B, HTR2A, and HTR3B). All included subjects were genotyped for 58 genetic variations in these ten genes. Logistic regression analyses were performed to determine the interaction odds ratio (OR) between genetic variations and SRIs exposure on the risk of CHA. Due to low phenotype frequencies of CYP450 poor metabolizers among exposed cases, the OR cannot be calculated. For ABCB1, there was no indication of changes in the risk of CHA with any of the ABCB1 SNPs in the children and their mothers. Several genetic variations of the serotonin transporter and receptors (SLC6A4 5-HTTLPR and 5-HTTVNTR, HTR1A rs1364043, HTR1B rs6296 & rs6298, HTR3B rs1176744) were associated with an increased risk of CHA, but with too limited sample size to reach statistical significance. For SLC6A4 genetic variations, the mean genetic scores of the exposed case-mothers tended to be higher than the unexposed mothers (2.5 ± 0.8 and 1.88 ± 0.7, respectively; p=0.061). For SNPs of the serotonin receptors, the mean genetic score for exposed cases (children) tended to be higher than the unexposed cases (3.4 ± 2.2, and 1.9 ± 1.6, respectively; p=0.065). This study might be among the first to explore the potential gene-environment interaction between pharmacogenetic determinants and SRIs use on the risk of CHA. With small sample sizes, it was not possible to find a significant interaction. However, there were indications for a role of serotonin receptor polymorphisms in fetuses exposed to SRIs on fetal risk of CHA which warrants further investigation.

Keywords: gene-environment interaction, heart defects, pharmacogenetics, serotonin reuptake inhibitors, teratogenicity

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15 Effect of CYP2B6 c.516G>T and c.983T>C Single Nucleotide Polymorphisms on Plasma Nevirapine Levels in Zimbabwean HIV/AIDS Patients

Authors: Doreen Duri, Danai Zhou, Babil Stray-Pedersen, Collet Dandara

Abstract:

Given the high prevalence of HIV/AIDS in sub-Saharan Africa, and the elusive search for a cure, understanding the pharmacogenetics of currently used drugs is critical in populations from the most affected regions. Compared to Asian and Caucasian populations, African population groups are more genetically diverse, making it difficult to extrapolate findings from one ethnic group to another. This study aimed to investigate the role of genetic variation in CYP2B6 (c.516G>T and c.983T>C) single nucleotide polymorphisms on plasma nevirapine levels among HIV-infected adult Zimbabwean patients. Using a cross-sectional study, patients on nevirapine-containing HAART, having reached steady state (more than six weeks on treatment) were recruited to participate. Blood samples were collected after patients provided consent and samples were used to extract DNA for genetic analysis or to measure plasma nevirapine levels. Genetic analysis was carried out using PCR and RFLP or Snapshot for the two single nucleotide polymorphisms; CYP2B6 c.516G>T and c.983T>C, while LC-MS/MS was used in analyzing nevirapine concentration. CYP2B6 c.516G>T and c.983T>C significantly predicted plasma nevirapine concentration with the c.516T and c.983T being associated with elevated plasma nevirapine concentrations. Comparisons of the variant allele frequencies observed in this group to those reported in some African, Caucasian and Asian populations showed significant differences. We conclude that pharmacogenetics of nevirapine can be creatively used to determine patients who are likely to develop nevirapine-associated side effects as well as too low plasma concentrations for viral suppression.

Keywords: allele frequencies, genetically diverse, nevirapine, single nucleotide polymorphism

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14 Distribution of Cytochrome P450 Gene in Patients Taking Medical Cannabis

Authors: Naso Isaiah Thanavisuth

Abstract:

Introduction: Medical cannabis can be used for treatment, including anorexia, pain, inflammation, multiple sclerosis, Parkinson's disease, epilepsy, cancer, and metabolic syndrome-related disorders. However, medical cannabis leads to adverse effects (AEs), which is delta-9-tetrahydrocannabinol (THC). In previous studies, the major of THC metabolism enzymes are CYP2C9. Especially, the variation of CYP2C9 gene consist of CYP2C9*2 on exon 3 (C430T) (Arg144Cys) and CYP2C9*3 on exon 7 (A1075C) (Ile359Leu) to decrease enzyme activity. Notwithstanding, there is no data describing whether the variant of CYP2C9 genes are a pharmacogenetics marker for prediction of THC-induced AEs in Thai patients. Objective: We want to investigate the association between CYP2C9 gene and THC-induced AEs in Thai patients. Method: We enrolled 39 Thai patients with medical cannabis treatment consisting of men and women who were classified by clinical data. The quality of DNA extraction was assessed by using NanoDrop ND-1000. The CYP2C9*2 and *3 genotyping were conducted using the TaqMan real time PCR assay (ABI, Foster City, CA, USA). Results: All Thai patients who received the medical cannabis consist of twenty four (61.54%) patients who were female and fifteen (38.46%) were male, with age range 27- 87 years. Moreover, the most AEs in Thai patients who were treated with medical cannabis between cases and controls were tachycardia, arrhythmia, dry mouth, and nausea. Particularly, thirteen (72.22%) medical cannabis-induced AEs were female and age range 33 – 69 years. In this study, none of the medical cannabis groups carried CYP2C9*2 variants in Thai patients. The CYP2C9*3 variants (*1/*3, intermediate metabolizer, IM) and (*3/*3, poor metabolizer, PM) were found, three of thirty nine (7.69%) and one of thirty nine (2.56%) , respectively. Conclusion: This is the first study to confirm the genetic polymorphism of CYP2C9 and medical cannabis-induced AEs in the Thai population. Although, our results indicates that there is no found the CYP2C9*2. However, the variation of CYP2C9 allele might serve as a pharmacogenetics marker for screening before initiating the therapy with medical cannabis for prevention of medical cannabis-induced AEs.

Keywords: CYP2C9, medical cannabis, adverse effects, THC, P450

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13 Gene Distribution of CB1 Receptor rs2023239 in Thailand Cannabis Patients

Authors: Tanyaporn Chairoch

Abstract:

Introduction: Cannabis is a drug to treat patients with many diseases such as Multiple sclerosis, Alzheimer’s disease, and Epilepsy, where theycontain many active compounds such as delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). Especially, THC is the primary psychoactive ingredient in cannabis and binds to cannabinoid 1 (CB1) receptors. Moreover, CB1 is located on the neocortex, hippocampus, basal ganglia, cerebellum, and brainstem. In previous study, we found the association between the variant of CB1recptors gene (rs2023239) and decreased effect of nicotine reinforcement in patients. However, there are no data describing whether the distribution of CB1 receptor gene is a genetic marker for Thai patients who are treated with cannabis. Objective: Thus, the aim of this study we want to investigate the frequency of the CB1 receptor gene in Thai patients. Materials and Methods: All of sixty Thai patients received the medical cannabis for treatment who were recruited in this study. DNA will be extracted from EDTA whole blood by Genomic DNA Mini Kit. The genotyping of CNR1 gene (rs 2023239) was genotyped by the TaqMan real time PCR assay (ABI, Foster City, CA, USA).and using the real-time PCR ViiA7 (ABI, Foster City, CA, USA). Results: We found thirty-eight (63.3%) Thai patients were female, and twenty-two (36.70%) were male in this study with median age of 45.8 (range19 – 87 ) years. Especially, thirty-two (53.30%) medical cannabis tolerant controls were female ( 55%) and median age of52.1 (range 27 – 79 ) years. The most adverse effects for medical cannabis treatment was tachycardia. Furthermore, the number of rs 2023239 (TT) carriers was 26 of 27 (96.29%) in medical cannabis-induced adverse effects and 32 of 33 (96.96%) in tolerant controls. Additionally, rs 2023239 (CT) variant was found just only one of twenty-seven (3.7%) in medical cannabis-induced adverse effects and 1 of 33 (3.03%) in tolerant controls. Conclusions: The distribution of genetic variant in CNR1 gene might serve as a pharmacogenetics markers for screening before initiating the therapy with medical cannabis in Thai patients.

Keywords: cannabis, pharmacogenetics, CNR1 gene, thai patient

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12 Genetic Variation in CYP4F2 and VKORC1: Pharmacogenomics Implications for Response to Warfarin

Authors: Zinhle Cindi, Collet Dandara, Mpiko Ntsekhe, Edson Makambwa, Miguel Larceda

Abstract:

Background: Warfarin is the most commonly used drug in the management of thromboembolic disease. However, there is a huge variability in the time, number of doses or starting doses for patients to achieve the required international normalised ratio (INR) which is compounded by a narrow therapeutic index. Many genetic-association studies have reported on European and Asian populations which have led to the designing of specific algorithms that are now being used to assist in warfarin dosing. However, very few or no studies have looked at the pharmacogenetics of warfarin in African populations, yet, huge differences in dosage requirements to reach the same INR have been observed. Objective: We set out to investigate the distribution of 3 SNPs CYP4F2 c.1347C > T, VKORC1 g.-1639G > A and VKORC1 c.1173C > T among South African Mixed Ancestry (MA) and Black African patients. Methods: DNA was extracted from 383 participants and subsequently genotyped using PCR/RFLP for the CYP4F2 c.1347 (V433M) (rs2108622), VKORC1 g.-1639 (rs9923231) and VKORC1 c.1173 (rs9934438) SNPs. Results: Comparing the Black and MA groups, significant differences were observed in the distribution of the following genotypes; CYP4F2 c.1347C/T (23% vs. 39% p=0.03). All VKORC1 g.-1639G > A genotypes (p < 0.006) and all VKORC1 c.1173C > T genotypes (p < 0.007). Conclusion: CYP4F2 c.1347T (V433M) reduces CYP4F2 protein levels and therefore expected to affect the amount of warfarin needed to block vitamin k recycling. The VKORC1 g-1639A variant alters transcriptional regulation therefore affecting the function of vitamin k epoxide reductase in vitamin k production. The VKORC1 c.1173T variant reduces the enzyme activity of VKORC1 consequently enhancing the effectiveness of warfarin. These are preliminary results; more genetic characterization is required to understand all the genetic determinants affecting how patients respond to warfarin.

Keywords: algorithms, pharmacogenetics, thromboembolic disease, warfarin

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11 The Pharmacogenetics of Type 1 Cannabinoid Receptor (CB1) Gene Associated with Adverse Drug Reactions in Thai Patients

Authors: Kittitara Chunlakittiphan, Patompong Satapornpong

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Introduction: The variation of genetics affects how our body responds to pharmaceuticals elucidates the correlation between long-term use of medical cannabis and adverse drug reactions (ADRs). Medical cannabis is regarded as the treatment for chronic pain, cancer pain, acute pain, psychological disorders, multiple sclerosis and migraine management. However, previous studies have shown that delta-9-Tetrahydrocannabinol (THC), an ingredient found in cannabis, was the cause of ADRs in CB1 receptors found in humans. Previous research suggests that distributions of the cannabinoid type 1 (CB1) receptor gene and pharmacogenetic markers, which vary amongst different populations, might affect incidences of ADRs. Although there is an evident need to investigate the level of the CB1 receptor gene (rs806365), studies on the distribution of CB1-pharmacogenetics markers in Thai patients are limited. Objective: Therefore, the aim of this study is to investigate the distribution of the rs806365 polymorphism in Thai patients who have been treated with medical cannabis. Materials and Methods: We enrolled 31 Thai patients with THC-induced ADRs and 34 THC-tolerant controls to take part in this study. All patients with THC-induced ADRs were accessed through a review of medical records by physicians. EDTA blood of 3ml was collected to obtain the CNR1 gene (rs806365) and genotyping of this gene was conducted using the real-time PCR ViiA7 (ABI, Foster City, CA, USA) following the manufacturer’s instruction. Results: The sample consisted of 65 patients (40/61.54%) were females and (25/38.46%) were males, with an age range of 19-87 years, who have been treated with medical cannabis. In this study, the most common THC-induced ADRs were dry mouth and/or dry throat, tachycardia, nausea, and arrhythmia. Across the whole sample, we found that 52.31% of Thai patients carried a heterozygous variant (rs806365, CT allele). Moreover, the number of rs806365 (CC, homozygous variant) carriers totaled seventeen people (26.15%) amongst the subjects of Thai patients treated with medical cannabis. Furthermore, 17 out of 22 patients (77.27%) who experienced severe ADRs: Tachycardia and/or arrhythmia, carried an abnormal rs806365 gene (CT and CC alleles). Conclusions: The results propose that the rs806365 gene is widely distributed amongst the Thai population and there is a link between this gene and vulnerability to developing THC-induced ADRs after being treated with medical cannabis. Therefore, it is necessary to screen for the rs806365 gene before using medical cannabis to treat a patient.

Keywords: rs806365, THC-induced adverse drug reactions, CB1 receptor, Thai population

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10 Healthy Thai Population and Distribution of HLA-B*57:01 Linked with Abacavir Hypersensitivity Syndrome

Authors: Boonyavee Uthaisang, Patompong Satapornpong

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Introduction: Abacavir is a nucleoside reverse transcriptase inhibitor (NRTIs) widely used for the treatment of HIV infection. However, abacavir can lead to hypersensitivity reactions with approximately 5% after initiation of treatment. The abacavir hypersensitivity reaction (AHR) is usually manifested within six weeks after initiation of treatment and is clinically characterized by fever, rash, gastrointestinal, neurological, and musculoskeletal symptoms. The mortality rate of AHR is 0.03%. In previous studies, it was found that HLA-B*57:01 has a strong association with AHR (p-value < 0.001) in the Caucasian population. Nevertheless, the pharmacogenetics marker and the distribution of HLA-B alleles might be different in other populations. Objective: This study aims to investigate the distribution of HLA-B*57:01 among the healthy Thai population. Materials and Methods: HLA-B genotypes of three-hundred healthy Thais were determined by the PCR sequence-specific oligonucleotides probe. Results: The frequency of the HLA-B alleles were HLA-B*46:01 (14.70%), HLA-B*58:01 (7.33%), HLA-B*15:02 (7.17%), HLA-B*40:01 (7.00%), and HLA-B*13:01 (5.83%). Among the healthy Thai population, 6 (1.00%) subjects carried HLA-B*57:01 allele. Moreover, the HLA-B*57:01 allele was similarly distributed in the Asian population (0.5-1%) but higher in the Caucasian population (3%) among HIV-infected patients. Conclusions: Screening of HLA-B*57:01 should take place among HIV-infected patients who are diagnosed with abacavir in order to prevent AHR.

Keywords: abacavir, HLA-B*57:01, Thai population, hypersensitivity reactions

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9 Important role of HLA-B*58:01 Allele and Distribution Among Healthy Thais: Avoid Severe Cutaneous Adverse Reactions

Authors: Jaomai Tungsiripat, Patompong Satapornpong

Abstract:

Allopurinol have been used to treat diseases that relating with the reduction of uric acid and be a treatment preventing the severity of, including gout, chronic kidney disease, chronic heart failure, and diabetes mellitus (type 2). However, allopurinol metabolites can cause a severe cutaneous adverse reaction (SCARs) consist of Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson Syndrome(SJS)/Toxic Epidermal Necrolysis (TEN). Previous studies, we found only HLA-B*58:01 allele has a strongly association with allopurinol-induced SCARs in many populations: Han Chinese [P value = 4.7 x 10−24], European [P value <10−6], and Thai [P value <0.001].However, there was no update the frequency of HLA-B alleles and pharmacogenetics markers distribution in healthy Thais and support for screening before the initiation of treatment. The aim of this study was to investigate the prevalence of HLA-B*58:01 allele associated with allopurinol-induced SCARs in healthy Thai population. A retrospective study of 260 individual healthy subjects who living in Thailand. HLA-B were genotyped using sequence-specific oligonucleotides (PCR-SSOs).In this study, we identified the prevalence of HLA-B alleles consist ofHLA-B*46:01 (12.69%), HLA-B*15:02 (8.85%), HLA-B*13:01 (6.35%), HLA-B*40:01 (6.35%), HLA-B*38:02 (5.00%), HLA-B*51:01 (5.00%), HLA-B*58:01 (4.81%), HLA-B*44:03 (4.62%), HLA-B*18:01 (3.85%) and HLA-B*15:25 (3.08%). Therefore, the distribution of HLA-B*58:01 will support the clinical implementation and screening usage of allopurinol in Thai population.

Keywords: allopurinol, HLA-B*58: 01, Thai population, SCARs

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8 Genetic Variations of CYP2C9 in Thai Patients Taking Medical Cannabis

Authors: Naso Isaiah Thanavisuth

Abstract:

Medical cannabis can be used for treatment including pain, multiple sclerosis, Parkinson's disease, and cancer. However, medical cannabis leads to adverse effects (AEs), which is delta-9-tetrahydrocannabinol (THC). In previous studies, the major of THC metabolism enzymes are CYP2C9. Especially, the variation of CYP2C9 gene consist of CYP2C9*2 on exon 3 and CYP2C9*3 on exon 7 to decrease enzyme activity. Notwithstanding, there is no data describing whether the variant of CYP2C9 genes are apharmacogenetics marker for the prediction of THC-induced AEs in Thai patients. We want to investigate the association between CYP2C9 gene and THC-induced AEs in Thai patients. We enrolled 39 Thai patients with medical cannabis treatment who were classified by clinical data. The CYP2C9*2 and *3 genotyping were conducted using the TaqMan real time PCR assay. All Thai patients who received the medical cannabis consist of twenty-four (61.54%) patients were female, and fifteen (38.46%) were male, with age range 27- 87 years. Moreover, the most AEs in Thai patients who were treated with medical cannabis between cases and controls were tachycardia, arrhythmia, dry mouth, and nausea. Particularly, thirteen (72.22%) medical cannabis-induced AEs were female and age range 33 – 69 years. In this study, none of the medical cannabis groups carried CYP2C9*2 variants in Thai patients. The CYP2C9*3 variants (*1/*3, intermediate metabolizer, IM) and (*3/*3, poor metabolizer, PM) were found, three of thirty-nine (7.69%) and one of thirty-nine (2.56%), respectively. Although, our results indicate that there is no found the CYP2C9*2. However, the variation of CYP2C9 allele might serve as a pharmacogenetics marker for screening before initiating the therapy with medical cannabis for the prevention of medical cannabis-induced AEs.

Keywords: CYP2C9, medical cannabis, adverse effects, THC, P450

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7 CYP2D6*4 Allele Frequency and Extrapyramidal Side Effects during Haloperidol Therapy Among Russians and Tatars: A Pilot Study

Authors: Irina S. Burashnikova, Dmitriy A. Sychev, Ruslan Y. Kazakov

Abstract:

Сytochrome P450 CYP2D6 activity affects antipsychotic therapy safety. CYP2D6*4 polymorphism frequency varies among different ethnic groups. We studied CYP2D6*4 polymorphism frequency in Tatar and Russian schizophrenic patients and association of CYP2D6*4 polymorphism and extrapyramidal disorders (EPD) frequency in schizophrenic patients on haloperidol monotherapy in daily doses up to 20 mg. Results: Heterozygous CYP2D6*4 allele carrier frequency among Tatars was lower (23.8% vs 32.4% in Russians), but the differences did not reach statistical significance. CYP2D6*4 allele frequency among Tatars was also lower (11.9% vs 24.3% in Russians), but the difference was not quite significant (p=0.0592). Average daily haloperidol dose in the group without EPD was significantly higher than in the group with EPD (11.35±4.6 vs 13.87±3.3 mg, p=0.0252), but average daily haloperidol dose/weight ratios in the compared groups had no significant differences. Statistically significant association between EPD development and heterozygous CYP2D6*1/*4 genotype and CYP2D6*4 allele carrier frequency was revealed among all schizophrenic patients and among those of Tatar nationality. Further well designed pharmacogenetic studies in different Russian regions are needed to improve psychotropic therapy safety and to establish evidence-based indications for pharmacogenetic testing in clinical practice.

Keywords: antipsychotic, CYP2D6 polymorphism, ethnic differences of CYP2D6*4 allele frequency, extrapyramidal side effects/disorder, schizophrenia, pharmacogenetics, Russians, Tatars

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6 Update on Genetic Diversity for Lamotrigine Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Authors: Natida Thongsima, Patompong Satapornpong

Abstract:

Introduction: Lamotrigine is widely used in the treatment of epilepsy and bipolar disorder. However, lamotrigine leads to adverse drug reactions (ADRs) consist of severe cutaneous adverse reactions (SCARs) include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS). Moreover, lamotrigine-induced SCARs is usually manifested between 2 and 8 weeks after treatment initiation. A previous study, there was found the association between HLA-B*15:02 and lamotrigine-induced cutaneous adverse drug reactions in the Thai population (odds ratio 4.89; 95% CI 1.28–18.66; p-value = 0.014). Therefore, the distribution of pharmacogenetics markers that a major role in predicting the culprit drugs for SCARs in many populations. Objective: In this study, we want to investigate the prevalence of the HLA-B allele, which correlations in lamotrigine-induced SCARs in a healthy Thai population. Materials and Methods: We enrolled 350 healthy Thai individuals and were approved by the ethics committee of Rangsit University. HLA-B alleles were genotyped by the Lifecodes HLA SSO typing kits (Immucor, West Avenue, Stamford, USA). Results: The results presented HLA-B allele frequency in healthy Thai population were 14.71% (HLA-B*46:01), 8.57% (HLA-B*15:02), 6.71% (HLA-B*40:01), 5.86% (HLA-B*13:01), 5.71% (HLA-B*58:01), 5.14% (HLA-B*38:02), 4.86% (HLA-B*18:01), 4.59% (HLA-B*51:01), 3.86% (HLA-B*44:03) and 2.71% (HLA-B*07:05). Especially, the HLA-B*15:02 allele was the high frequency in the Thais (8.57%), Han Chinese (7.30%), Vietnamese (13.50%), Malaysian (6.06%) and Indonesian (11.60%). Notwithstanding, this allele was much lower in other populations, namely, Africans, Caucasians and Japanese. Conclusions: Although the samples size of the healthy Thai population in this research was limited, there were found the frequency of the HLA-B*15:02 allele could predisposition toward lamotrigine-induced SCARs in Thailand.

Keywords: lamotrigine, cutaneous adverse drug reactions, HLA-B, Thai population

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5 Pharmacogenetics Study of Dapsone-Induced Severe Cutaneous Adverse Reactions and HLA Class I Alleles in Thai Patients

Authors: Patompong Satapornpong, Therdpong Tempark, Pawinee Rerknimitr, Jettanong Klaewsongkram, Chonlaphat Sukasem

Abstract:

Dapsone (4, 4’-diaminodiphenyl sulfone, DDS) is broadly used for the treatment of inflammatory diseases and infections such as; leprosy, Pneumocystis jiroveci pneumonia in patients with HIV infection, neutrophilic dermatoses, dermatitis herpetiformis and autoimmune bullous disease. The severe cutaneous adverse drug reactions (SCARs) including, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) are rare but severe life-threatening adverse drug reactions. Dapsone is one of many culprit drugs induced SJS, TEN and DRESS. Notwithstanding, to our knowledge, there are no studies of the association of HLA class I alleles and dapsone-induced SCARs in non-leprosy Thai patients. This investigation was a prospective cohort study, which performed in a total of 45 non-leprosy patients. Fifteen patients of dapsone-induced SCARs were classified as following the RegiSCAR criteria, and 30 dapsone-tolerant controls were exposed to dapsone more than 6 months without any evidence of cutaneous reactions. The genotyping of HLA-A, -B and –C were performed using sequence-specific oligonucleotides (PCR-SSOs). The Ethics Committee of Ramathibodi hospital, Mahidol University, approved this study. Among all HLA class I alleles, HLA-A*24:07, HLA-B*13:01, HLA-B*15:02, HLA-C*03:04 and HLA-C*03:09 were significantly associated with dapsone-induced SCARs (OR = 10.55, 95% CI = 1.06 – 105.04, p = 0.0360; OR = 56.00, 95% CI = 8.27 – 379.22, p = 0.0001; OR = 7.00, 95% CI = 1.17 – 42.00, p = 0.0322; OR = 6.00, 95% CI = 1.24 – 29.07, p = 0.0425 and OR = 17.08, 95% CI = 0.82 – 355.45, p = 0.0321, respectively). Furthermore, HLA-B*13:01 allele had strong association with dapsone-induced SJS-TEN and DRESS when compared with dapsone-tolerant controls (OR = 42.00, 95% CI = 2.88 – 612.31, p = 0.0064 and OR = 63.00, 95% CI = 7.72 – 513.94 and p = 0.0001, respectively). Consequently, HLA-B*13:01 might serve as a pharmacogenetic marker for screening before initiating the therapy with dapsone for prevention of dapsone-induced SCARs.

Keywords: dapsone-induced SCARs, HLA-B*13:01, HLA class I alleles, severe cutaneous adverse reactions, Thai

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4 Polymorphisms of the UM Genotype of CYP2C19*17 in Thais Taking Medical Cannabis

Authors: Athicha Cherdpunt, Patompong Satapornpong

Abstract:

The medical cannabis is made up of components also known as cannabinoids, which consists of two ingredients which are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Interestingly, the Cannabinoid can be used for many treatments such as chemotherapy, including nausea and vomiting, cachexia, anorexia nervosa, spinal cord injury and disease, epilepsy, pain, and many others. However, the adverse drug reactions (ADRs) of THC can cause sedation, anxiety, dizziness, appetite stimulation and impairments in driving and cognitive function. Furthermore, genetic polymorphisms of CYP2C9, CYP2C19 and CYP3A4 influenced the THC metabolism and might be a cause of ADRs. Particularly, CYP2C19*17 allele increases gene transcription and therefore results in ultra-rapid metabolizer phenotype (UM). The aim of this study, is to investigate the frequency of CYP2C19*17 alleles in Thai patients who have been treated with medical cannabis. We prospectively enrolled 60 Thai patients who were treated with medical cannabis and clinical data from College of Pharmacy, Rangsit University. DNA of each patient was isolated from EDTA blood, using the Genomic DNA Mini Kit. CYP2C19*17 genotyping was conducted using the real time-PCR ViiA7 (ABI, Foster City, CA, USA). 30 patients with medical cannabis-induced ADRs group, 20 (67%) were female, and 10 (33%) were male, with an age range of 30-69 years. On the other hand, 30 patients without medical cannabis-induced ADRs (control group) consist of 17 (57%) female and 13 (43%) male. The most ADRs for medical cannabis treatment in the case group were dry mouth and dry throat (77%), tachycardia (70%), nausea (30%) and arrhythmia(10%). Accordingly, the case group carried CYP2C19*1/*1 (normal metabolizer) approximately 93%, while 7% patients carrying CYP2C19*1/*17 (ultra rapid metabolizers) exhibited in this group. Meanwhile, we found 90% of CYP2C19*1/*1 and 10% of CYP2C19*1/*17 in control group. In this study, we identified the frequency of CYP2C19*17 allele in Thai population which will support the pharmacogenetics biomarkers for screening and avoid ADRs of medical cannabis treatment.

Keywords: CYP2C19, allele frequency, ultra rapid metabolizer, medical cannabis

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3 The Association Between CYP2C19 Gene Distribution and Medical Cannabis Treatment

Authors: Vichayada Laohapiboolkul

Abstract:

Introduction: As the legal use of cannabis is being widely accepted throughout the world, medical cannabis has been explored in order to become an alternative cure for patients. Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are natural cannabinoids found in the Cannabis plant which is proved to have positive treatment for various diseases and symptoms such as chronic pain, neuropathic pain, spasticity resulting from multiple sclerosis, reduce cancer-associated pain, autism spectrum disorders (ASD), dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette's disorder. Regardless of all the medical benefits, THC, if not metabolized, can lead to mild up to severe adverse drug reactions (ADR). The enzyme CYP2C19 was found to be one of the metabolizers of THC. However, the suballele CYP2C19*2 manifests as a poor metabolizer which could lead to higher levels of THC than usual, possibly leading to various ADRs. Objective: The aim of this study was to investigate the distribution of CYP2C19, specifically CYP2C19*2, genes in Thai patients treated with medical cannabis along with adverse drug reactions. Materials and Methods: Clinical data and EDTA whole blood for DNA extraction and genotyping were collected from patients for this study. CYP2C19*2 (681G>A, rs4244285) genotyping was conducted using the Real-time PCR (ABI, Foster City, CA, USA). Results: There were 42 medical cannabis-induced ADRs cases and 18 medical cannabis tolerance controls who were included in this study. A total of 60 patients were observed where 38 (63.3%) patients were female and 22 (36.7%) were male, with a range of age approximately 19 - 87 years. The most apparent ADRs for medical cannabis treatment were dry mouth/dry throat (76.7%), followed by tachycardia (70%), nausea (30%) and a few arrhythmias (10%). In the total of 27 cases, we found a frequency of 18 CYP2C19*1/*1 alleles (normal metabolizers, 66.7%), 8 CYP2C19*1/*2 alleles (intermediate metabolizers, 29.6%) and 1 CYP2C19*2/*2 alleles (poor metabolizers, 3.7%). Meanwhile, 63.6% of CYP2C19*1/*1, 36.3% and 0% of CYP2C19*1/*2 and *2/*2 in the tolerance controls group, respectively. Conclusions: This is the first study to confirm the distribution of CYP2C19*2 allele and the prevalence of poor metabolizer genes in Thai patients who received medical cannabis for treatment. Thus, CYP2C19 allele might serve as a pharmacogenetics marker for screening before initiating treatment.

Keywords: medical cannabis, adverse drug reactions, CYP2C19, tetrahydrocannabinol, poor metabolizer

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2 Prevalence of Cyp2d6 and Its Implications for Personalized Medicine in Saudi Arabs

Authors: Hamsa T. Tayeb, Mohammad A. Arafah, Dana M. Bakheet, Duaa M. Khalaf, Agnieszka Tarnoska, Nduna Dzimiri

Abstract:

Background: CYP2D6 is a member of the cytochrome P450 mixed-function oxidase system. The enzyme is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, especially in breast cancer and psychiatric therapy. Different phenotypes have been described displaying alleles that lead to a complete loss of enzyme activity, reduced function (poor metabolizers – PM), hyperfunctionality (ultrarapid metabolizers–UM) and therefore drug intoxication or loss of drug effect. The prevalence of these variants may vary among different ethnic groups. Furthermore, the xTAG system has been developed to categorized all patients into different groups based on their CYP2D6 substrate metabolization. Aim of the study: To determine the prevalence of the different CYP2D6 variants in our population, and to evaluate their clinical relevance in personalized medicine. Methodology: We used the Luminex xMAP genotyping system to sequence 305 Saudi individuals visiting the Blood Bank of our Institution and determine which polymorphisms of CYP2D6 gene are prevalent in our region. Results: xTAG genotyping showed that 36.72% (112 out of 305 individuals) carried the CYP2D6_*2. Out of the 112 individuals with the *2 SNP, 6.23% had multiple copies of *2 SNP (19 individuals out of 305 individuals), resulting in an UM phenotype. About 33.44% carried the CYP2D6_*41, which leads to decreased activity of the CYP2D6 enzyme. 19.67% had the wild-type alleles and thus had normal enzyme function. Furthermore, 15.74% carried the CYP2D6_*4, which is the most common nonfunctional form of the CYP2D6 enzyme worldwide. 6.56% carried the CYP2D6_*17, resulting in decreased enzyme activity. Approximately 5.73% carried the CYP2D6_*10, consequently decreasing the enzyme activity, resulting in a PM phenotype. 2.30% carried the CYP2D6_*29, leading to decreased metabolic activity of the enzyme, and 2.30% carried the CYP2D6_*35, resulting in an UM phenotype, 1.64% had a whole-gene deletion CYP2D6_*5, thus resulting in the loss of CYP2D6 enzyme production, 0.66% carried the CYP2D6_*6 variant. One individual carried the CYP2D6_*3(B), producing an inactive form of the enzyme, which leads to decrease of enzyme activity, resulting in a PM phenotype. Finally, one individual carried the CYP2D6_*9, which decreases the enzyme activity. Conclusions: Our study demonstrates that different CYP2D6 variants are highly prevalent in ethnic Saudi Arabs. This finding sets a basis for informed genotyping for these variants in personalized medicine. The study also suggests that xTAG is an appropriate procedure for genotyping the CYP2D6 variants in personalized medicine.

Keywords: CYP2D6, hormonal breast cancer, pharmacogenetics, polymorphism, psychiatric treatment, Saudi population

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1 Association between G2677T/A MDR1 Polymorphism with the Clinical Response to Disease Modifying Anti-Rheumatic Drugs in Rheumatoid Arthritis

Authors: Alan Ruiz-Padilla, Brando Villalobos-Villalobos, Yeniley Ruiz-Noa, Claudia Mendoza-Macías, Claudia Palafox-Sánchez, Miguel Marín-Rosales, Álvaro Cruz, Rubén Rangel-Salazar

Abstract:

Introduction: In patients with rheumatoid arthritis, resistance or poor response to disease modifying antirheumatic drugs (DMARD) may be a reflection of the increase in g-P. The expression of g-P may be important in mediating the effluence of DMARD from the cell. In addition, P-glycoprotein is involved in the transport of cytokines, IL-1, IL-2 and IL-4, from normal lymphocytes activated to the surrounding extracellular matrix, thus influencing the activity of RA. The involvement of P-glycoprotein in the transmembrane transport of cytokines can serve as a modulator of the efficacy of DMARD. It was shown that a number of lymphocytes with glycoprotein P activity is increased in patients with RA; therefore, P-glycoprotein expression could be related to the activity of RA and could be a predictor of poor response to therapy. Objective: To evaluate in RA patients, if the G2677T/A MDR1 polymorphisms is associated with differences in the rate of therapeutic response to disease-modifying antirheumatic agents in patients with rheumatoid arthritis. Material and Methods: A prospective cohort study was conducted. Fifty seven patients with RA were included. They had an active disease according to DAS-28 (score >3.2). We excluded patients receiving biological agents. All the patients were followed during 6 months in order to identify the rate of therapeutic response according to the American College of Rheumatology (ACR) criteria. At the baseline peripheral blood samples were taken in order to identify the G2677T/A MDR1 polymorphisms using PCR- Specific allele. The fragment was identified by electrophoresis in polyacrylamide gels stained with ethidium bromide. For statistical analysis, the genotypic and allelic frequencies of MDR1 gene polymorphism between responders and non-responders were determined. Chi-square tests as well as, relative risks with 95% confidence intervals (95%CI) were computed to identify differences in the risk for achieving therapeutic response. Results: RA patients had a mean age of 47.33 ± 12.52 years, 87.7% were women with a mean for DAS-28 score of 6.45 ± 1.12. At the 6 months, the rate of therapeutic response was 68.7 %. The observed genotype frequencies were: for G/G 40%, T/T 32%, A/A 19%, G/T 7% and for A/A genotype 2%. Patients with G allele developed at 6 months of treatment, higher rate for therapeutic response assessed by ACR20 compared to patients with others alleles (p=0.039). Conclusions: Patients with G allele of the - G2677T/A MDR1 polymorphisms had a higher rate of therapeutic response at 6 months with DMARD. These preliminary data support the requirement for a deep evaluation of these and other genotypes as factors that may influence the therapeutic response in RA.

Keywords: pharmacogenetics, MDR1, P-glycoprotein, therapeutic response, rheumatoid arthritis

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