Pharmacogenetic Polymorphisms Research Articles

Genetic Polymorphisms in CYP2 Gene Family in Bulgarian Individuals and their Clinical Implications

Abstract The cytochrome P450 superfamily consists of hemeproteins involved in the detoxication of different xenobiotics, including drugs. The CYP2 gene family is responsible for the metabolism of 80% of the drugs in clinical use. There are considerable interindividual and interethnic variabilities in the rate of drug metabolism as a result of genetic polymorphisms. The goal of our study was to determine the frequency of 10 genetic polymorphisms in CYP2 family genes to give light on the pharmacogenetic defects of the main CYPs, involved in drug metabolism, in Bulgarian individuals. We detected high allele frequency for CYP2D6*10 (0.27), CYP2D6*4 (0.22), and CYP2B6*9 (0.24), followed by CYP2C19*2 (0.14), CYP2C9*3 (0.11) and CYP2C9*2 (0.09). The genotype frequencies were also determined for all investigated variants. In total 47.2% of the analyzed individuals carried CYP2D6 genetic polymorphisms – 5.6% carried a single variant and 41.6% were found to have two or more such variants. Homozygotes for CYP2D6 variants were established among 14% of Bulgarian individuals. Determination of the prevailing pharmacogenetic polymorphisms of the CYPs, most responsible for drug metabolism, will lead to a lower risk of drug toxicity, increased drug efficacy, and drug dose optimization.

Pharmacogenetic predictors of variability in efavirenz pharmacokinetics in an admixed Brazilian HIV cohort

To investigate the influence of pharmacogenetic polymorphisms on efavirenz (EFV) exposure and metabolism in HIV-infected Brazilians under treatment with EFV-containing antiretroviral (ART) regimens. HIV-positive adults (n =82) on stable ART regimens containing 600 mg EFV once daily for at least 6 months were recruited at 2 university hospitals. Blood samples collected at mid-dose interval were used to quantify the plasma concentrations of EFV (denoted [EFV]), its major metabolite 8-OH-EFV ([8-OH-EFV]) and [8-OH-EFV]/[EFV] metabolic ratio, and to genotype single nucleotide polymorphisms in CYP2B6 (rs3745274, c.516G > T; rs28399499, c.983 T > C) and ABCB1 (rs3842, c.4036G > A). CYP2B6 metabolic phenotypes were inferred from the CYP2B6 diplotypes. Linear regression modelling was applied to identify sociodemographic, clinical and pharmacogenetic predictors of [EFV] and [8-OH-EFV]/[EFV] metabolic ratio. Wide (50-fold) interindividual variation in [EFV], [8-OH-EFV] and [8-OH-EFV]/[EFV] was observed; 69.5% of participants had [EFV] within the nominal therapeutic range (1000-4000 ng/mL), while 19.5 and 11.0% had [EFV] below and above this range, respectively. Multiple regression modelling retained only CYP2B6 metabolic phenotypes or the combined rs3745274 and rs28399499 genotypes, as significant predictors of [EFV] and [8-OH-EFV]/[EFV]. EFV exposure and disposition varied widely among HIV-infected Brazilians under stable treatment with EFV-containing ART regimens. About 1/10 of the participants had [EFV] exceeding nominal supratherapeutic concentration (4000 ng/mL), but reported tolerance to the ARV regimens, while 1/5 of participants had nominal subtherapeutic [EFV] (<1000 ng/mL) but adequate virological response. Genotype for the 2 CYP2B6 single nucleotide polymorphisms studied explained 48% of variation in [EFV] and 35% of variation in [8-OH-EFV]/[EFV].

Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa.

Plasma bedaquiline clearance is reportedly more rapid with African ancestry. Our objective was to determine whether genetic polymorphisms explained between-individual variability in plasma clearance of bedaquiline, its M2 metabolite, and clofazimine in a cohort of patients treated for drug-resistant tuberculosis in South Africa. Plasma clearance was estimated with nonlinear mixed-effects modeling. Associations between pharmacogenetic polymorphisms, genome-wide polymorphisms, and variability in clearance were examined using linear regression models. Of 195 cohort participants, 140 were evaluable for genetic associations. Among 21 polymorphisms selected based on prior genome-wide significant associations with any drug, rs776746 (CYP3A5∗3) was associated with slower clearance of bedaquiline (P = .0017) but not M2 (P = .25). CYP3A5∗3 heterozygosity and homozygosity were associated with 15% and 30% slower bedaquiline clearance, respectively. The lowest P value for clofazimine clearance was with VKORC1 rs9923231 (P = .13). In genome-wide analyses, the lowest P values for clearance of bedaquiline and clofazimine were with RFX4 rs76345012 (P = 6.4 × 10-7) and CNTN5 rs75285763 (P = 2.9 × 10-8), respectively. Among South Africans treated for drug-resistant tuberculosis, CYP3A5∗3 was associated with slower bedaquiline clearance. Different CYP3A5∗3 frequencies among populations may help explain the more rapid bedaquiline clearance reported in Africans. Associations with RFX4 and CNTN5 are likely by chance alone.

Relevance of pharmacogenetic polymorphisms with response to docetaxel, cisplatin, and 5-fluorouracil chemotherapy in esophageal cancer.

Docetaxel, cisplatin, and 5-fluorouracil (DCF) have high response rates, but severe neutropenia is frequently observed. The occurrence of neutropenia is associated with high histological response in solid tumors, and it might be associated with tumor shrinkage after DCF therapy. This study aimed to determine the genetic polymorphisms involved in the clinical response to preoperative DCF therapy in esophageal cancer patients. We included 56 patients with measurable lesions who received preoperative DCF therapy for esophageal cancer. Twenty-one genetic polymorphisms were analyzed, and univariate logistic regression analysis was used to evaluate the association between genetic polymorphisms and tumor shrinkage. A multivariate logistic regression analysis adjusted for T category and tumor location and a univariate analysis for potential genetic factors with P values < 0.05 were performed to explore the predictive factors and to estimate odds ratios and their 95% confidence intervals. No patient achieved a complete response, whereas 20 patients achieved a partial response, 31 patients had stable disease, and 5 patients had progressive disease. Although no association was found between pharmacokinetic-related gene polymorphisms, XRCC3 rs17997944 was extracted as the only genetic factor that affected tumor shrinkage (P = 0.033) by univariate analysis. The multivariate analysis adjusted for T category and tumor site also showed that XRCC3 rs1799794: AA was a predictive factor that affected tumor shrinkage (odds ratio, 0.243; 95% confidence interval, 0.065-0.914; P = 0.036). XRCC3 rs1799794, which is involved in homologous recombination, is a genetic factor that affects clinical responses to DCF therapy.

Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health.

Both safety and efficacy of medical treatment can vary depending on the ethnogeographic background of the patient. One of the reasons underlying this variability is differences in pharmacogenetic polymorphisms in genes involved in drug disposition, as well as in drug targets. Knowledge and appreciation of these differences is thus essential to optimize population-stratified care. Here, we provide an extensive updated analysis of population pharmacogenomics in ten pharmacokinetic genes (CYP2D6, CYP2C19, DPYD, TPMT, NUDT15 and SLC22A1), drug targets (CFTR) and genes involved in drug hypersensitivity (HLA-A, HLA-B) or drug-induced acute hemolytic anemia (G6PD). Combined, polymorphisms in the analyzed genes affect the pharmacology, efficacy or safety of 141 different drugs and therapeutic regimens. The data reveal pronounced differences in the genetic landscape, complexity and variant frequencies between ethnogeographic groups. Reduced function alleles of CYP2D6, SLC22A1 and CFTR were most prevalent in individuals of European descent, whereas DPYD and TPMT deficiencies were most common in Sub-Saharan Africa. Oceanian populations showed the highest frequencies of CYP2C19 loss-of-function alleles while their inferred CYP2D6 activity was among the highest worldwide. Frequencies of HLA-B*15:02 and HLA-B*58:01 were highest across Asia, which has important implications for the risk of severe cutaneous adverse reactions upon treatment with carbamazepine and allopurinol. G6PD deficiencies were most frequent in Africa, the Middle East and Southeast Asia with pronounced differences in variant composition. These variability data provide an important resource to inform cost-effectiveness modeling and guide population-specific genotyping strategies with the goal of optimizing the implementation of precision public health.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00439-021-02385-x.

Pharmacogenetic approach to methotrexate-related toxicity prediction in psoriasis

Methotrexate is a highly effective for psoriasis, but the use of methotrexate may be limited by its adverse effects. Approximately 1030% of patients treated with methotrexate experience adverse drug reactions, leading to the therapy discontinuation. Patient genetics can play a significant role in the interindividual variability of drug response. There is a growing body of literature on allelic variants of various genes that are assosiated with methotrexate toxicity. Pharmacogenetic studies may establish how patients genotype affect the safety of methotrexate. Treatment Data shows that to predict the risk of methotrexate-induced toxicity it is necessary to take into account the interindividual variability in methotrexate pharmacokinetics, which may be determined by the presence of single-nucleotide polymorphisms of genes encoding methotrexate carrier proteins and enzymes of its biotransformation. The activity of transporter proteins affects the drugs in the blood plasma and peripheral tissues, thereby determining its toxicity. The review was aimed is to summarize the current knowledge on pharmacogenetic polymorphisms that may affect the variability of methotrexate-related toxicity. Evaluation of such promising candidates for predictors of methotrexate-related toxicity risk could be used in psoriasis treatment personalization.

Pharmacogenetic polymorphisms affecting bisoprolol response

β-blockers are commonly prescribed to treat multiple cardiovascular (CV) diseases, but, frequently, adverse drug reactions and intolerance limit their use in clinical practice. Interindividual variability in response to β-blockers may be explained by genetic differences. In fact, pharmacogenetic interactions for some of these drugs have been widely studied, such as metoprolol. But studies that explore genetic variants affecting bisoprolol response are inconclusive, limited or confusing because of mixed results with other β-Blockers, different genetic polymorphisms observed, endpoint studied etc. Because of this, we performed a systematic review in order to find relevant genetic variants affecting bisoprolol response. We have found genetic polymorphism in several genes, but most of the studies focused in ADRB variants. The ADRB1 Arg389Gly (rs1801253) was the most studied genetic polymorphism and it seems to influence the response to bisoprolol, although studies are inconclusive. Even, we performed a meta-analysis about its influence on systolic/diastolic blood pressure in patients treated with bisoprolol, but this did not show statistically significant results. In conclusion, many genetic polymorphisms have been assessed about their influence on patients´ response to bisoprolol and the ADRB1 Arg389Gly (rs1801253) seems the most relevant genetic polymorphism in this regard but results have not been confirmed with a meta-analysis. Our results support the need of further studies about the impact of genetic variants on bisoprolol response, considering different genetic polymorphisms and conducting single and multiple SNPs analysis, including other clinical parameters related to bisoprolol response in a multivariate study.

Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis.

The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6months when combined with pyrazinamide in the first 2months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600mg (8-12mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600mg. Rifampicin maximum (peak) concentration (Cmax) > 8.2μg/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8µg/mL. A higher rifampicin Cmax is required for severe forms TB such as TB meningitis, with Cmax ≥ 22 μg/mL and area under the concentration-time curve (AUC) from time zero to 6h (AUC6) ≥ 70μg·h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35mg/kg were found to be safe and well-tolerated over a period of 12weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC.

TRANSITIONING PATIENTS WITH MAJOR NEUROCOGNITIVE DISORDERS FROM ANTIPSYCHOTIC MEDICATIONS TO CITALOPRAM - A PHARMACOGENETICALLY-INFORMED CASE SERIES

Introduction The successful and safe psychopharmacologic management of older adults suffering with major neurocognitive disorders with behavioral disturbances and has remained a challenging therapeutic dilemma – despite recently published guidelines on the topic. Available guidelines would suggest that individuals with severe agitation, violence, or distress related to their agitation or psychosis should receive pharmacotherapy in addition to behavioral and social management. Citalopram and other SSRIs have shown promise in treating agitation and psychosis in the context of major neurocognitive disorders, however treatment with antipsychotics for this indication has not appreciably declined on the national stage despite the increased risk of morbidity and mortality associated with these medications. While the literature has given much thought to the initial choice of medication for these patients, an important question remains as to whether there are patients whom might benefit from a transition to citalopram after an antipsychotic has already been initiated. Given the high potential for symptom recurrence when transitioning from an antipsychotic, methodology that would allow some measure of individualized response prediction would be of clinical value. Interestingly, low expression alleles of the SLC6A4 (serotonin transporter) gene have been linked to decreased response to citalopram in major neurocognitive disorders. Methods Three cases from the ambulatory Center of Excellence for Alzheimer's Disease at SUNY Downstate are presented in which patients suffering with major neurocognitive disorders and associated neuropsychiatric symptoms were transitioned from antipsychotic medications to citalopram. Case histories and scores on the neuropsychiatric inventory and CGI scales are presented for review. Pharmacogenetic testing results are presented for the final case in which transition to citalopram was not successful. Results Two of three cases were successfully transitioned from antipsychotic medications to citalopram, resulting in near total remission of psychosis and agitation on the CGI Agitation and Psychosis scales. The third case offers a compelling explanation for the treatment failure – pharmacogenetic polymorphisms that impacted both the metabolism (CYP2D6 ultrarapid metabolizer, CYP2C19 intermediate metabolizer) of citalopram and its effectiveness (homozygous for the short promoter of the serotonin transporter gene - SLC6A4). Conclusions This case series presents an important treatment approach for older adults with major neurocognitive disorders that have already been started on antipsychotics for their neuropsychiatric symptoms. Transitioning from an antipsychotic to citalopram was effective in two out of three cases, limiting their exposure to a class of medications with a higher risk profile. The third case, while unsuccessful, highlights the complexities of treatment choice and the importance of a personalized approach to medicine. Given previous reports that low expression alleles of the SLC6A4 gene may be linked to decreased response to citalopram, further controlled study evaluating the transition from antipsychotic medications to citalopram utilizing pharmacogenetic testing to personalize treatment could potentially improve treatment choice in this vulnerable population. This research was funded by This study received no outside support.

Genetic Polymorphisms and In Silico Mutagenesis Analyses of CYP2C9, CYP2D6, and CYPOR Genes in the Pakistani Population.

Diverse distributions of pharmacogenetically relevant variants of highly polymorphic CYP2C9, CYP2D6 and CYPOR genes are responsible for some varied drug responses observed across human populations. There is limited data available regarding the pharmacogenetic polymorphisms and frequency distributions of major allele variants in the Pakistani population. The present in silico mutagenesis study conducted on genotype pharmacogenetic variants and comparative analysis with a global population aims to extend the currently limited pharmacogenetic available evidence for the indigenous Pakistani population. Extracted genomic DNA from 244 healthy individuals’ venous blood samples were amplified for distinct variant loci in the CYP2C9, CYP2D6 and CYPOR genes. Two-way sequencing results were compared with standard PubMed data and sequence variant loci confirmed by Chromas. This study revealed significant variations in CYP2C9 (rs1799853, rs1057910 and rs72558189), CYP2D6 (rs16947 and rs1135840), and CYPOR (rs1057868, rs781919285 and rs562750402) variants in intraethnic and interethnic frequency distributions. In silico mutagenesis and three-dimensional protein structural alignment analysis approaches clearly exposed the possible varied impact of rare CYPOR (rs781919285 and rs562750402) single nucleotide polymorphisms (SNPs) and confirmed that the influences of CYP2C9 and CYP2D6 variants are consistent with what was found in earlier studies. This investigation highlighted the need to study pharmacogenetic relevance loci and documentation since evidence could be utilized to elucidate genetic backgrounds of drug metabolism, and provide a basis for future pharmacogenomic studies and adequate dose adjustments in Pakistani and global populations.

Frequency of 14 genetic variants associated with breast cancer risk and treatment in a Colombian population

Introducción: las variaciones genéticas se han relacionado con el riesgo y la eficacia del tratamiento. Es sabido que muchos polimorfismos en cáncer de mama influyen en la susceptibilidad, el riesgo de cáncer y el resultado del tratamiento. Los polimorfismos varían entre las poblaciones, y por tanto, es necesario realizar estudios locales.Objetivo: establecer la frecuencia de polimorfismos asociados al riesgo de cáncer de mama y la farmacogenómica del tratamiento en un grupo de individuos colombianos.Métodos: los datos de los perfiles de microarreglos, incluidos los polimorfismos genéticos asociados con el tratamiento del cáncer de mama, se obtuvieron de forma retrospectiva (Pathway Genomics®). Se estudiaron la frecuencia del marcador CYP2D6 rs3892097 y un panel de cáncer de mama (CAS8 rs1045485, CHEK21100delC, ESR1 rs2046210, FGFR2 rs1219648, intergenic_2q35rs13387042, intergenic_8q24 rs13281615, MSRP30 rs10941679, TNRC9 rs3803662, AKAP9 rs6964587, LSP1 rs3817198, MAP3K1rs889312, PALBS1592 delT, ESR1 rs3020314).Resultados: se analizaron los datos de microarreglos de 68 hombres y 92 mujeres. Todos los polimorfismos siguieron el equilibrio Hardy-Weinberg. Las frecuencias fenotípicas de CYP2D6 rs3892097 C/T, CAS8 rs1045485 G/C, y aquellas de los genes incluidos en un panel de cáncer de mama (CAS8 rs1045485, CHEK21100delC, FGFR2rs1219648, intergenic_2q35rs13387042, intergenic_8q24 rs13281615, MSRP30 rs10941679, TNRC9 rs3803662, LSP1 rs3817198, MAP3K1rs889312, PALBS1592 del T, ESR1rs3020314) no difirieron significativamente de los datos publicados previamente. ESR1 rs2046210, con frecuencias alélicas de C = 0,04 y T = 0,02, y AKAP9 rs6964587, con una frecuencia de A = 0,005, se determinaron como raras.

Influence of pharmacogenetic polymorphisms and demographic variables on metformin pharmacokinetics in an admixed Brazilian cohort.

To identify pharmacogenetic and demographic variables that influence the systemic exposure to metformin in an admixed Brazilian cohort. The extreme discordant phenotype was used to select 106 data sets from nine metformin bioequivalence trials, comprising 256 healthy adults. Eleven single-nucleotide polymorphisms in SLC22A1, SLC22A2, SLC47A1 SLC47A2 and in transcription factor SP1 were genotyped and a validated panel of ancestry informative markers was used to estimate the individual proportions of biogeographical ancestry. Two-step (univariate followed by multivariate) regression modelling was developed to identify covariates associated with systemic exposure to metformin, accessed by the area under the plasma concentration-time curve, between 0 and 48h (AUC0-48h ), after single oral doses of metformin (500 or 1000mg). The individual proportions of African, Amerindian and European ancestry varied widely, as anticipated from the structure of the Brazilian population The dose-adjusted, log-transformed AUC0-48h 's (nghml-1 mg-1 ) differed largely in the two groups at the opposite ends of the distribution histogram, namely 0.82, 0.79-0.85 and 1.08, 1.06-1.11 (mean, 95% confidence interval; P=6.10-26 , t test). Multivariate modelling revealed that metformin AUC0-48h increased with age, food and carriage of rs12208357 in SLC22A1 but was inversely associated with body surface area and individual proportions of African ancestry. A pharmacogenetic marker in OCT1 (SLC22A1 rs12208357), combined with demographic covariates (age, body surface area and individual proportion of African ancestry) and a food effect explained 29.7% of the variability in metformin AUC0-48h .

Pharmacogenetics and Genetic Polymorphism of CYP Enzymes in Indian Population: A Clinical Review

Pharmacogenetic polymorphism results from the mutations in a Cytochrome P450 (CYP) gene leading to functional alterations, such as increased or decreased activity and occurs at a frequency of at least one percent in a population. At present clinical situation drug clearance and inter-individual variation in drug response is a usual and complex problem. In this clinical review there is a fast update on pharmacogenetics and genetic polymorphism of CYP enzymes in Indian population.

Genetic polymorphisms of cytochrome P450 enzymes: CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in the Croatian population.

Data on the frequency of pharmacogenetic polymorphisms in the Croatian population are limited. We determined and analyzed frequencies for the most important CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 genetic variants in the Croatian population. 2637 subjects were included. Genotyping was performed by real-time polymerase chain reaction (PCR) using TaqMan® DME or TaqMan® SNP Genotyping Assays, and by PCR, and PCR-RFLP analysis. For CYP2C9, allele frequencies of *2 and *3 variant were 14.5% and 7.6%, respectively. Among them, 3.98% of subjects were predicted to be poor metabolizers. For CYP2C19, the most frequent variant alleles were *2 (14.8%), and *17 (23.7%), while 2.4% of subjects were predicted to be poor metabolizers, and 5.39% were homozygous carriers of *17 predicted to be ultrarapid metabolizers (UM). For CYP2D6, the frequencies of tested variant alleles were *3 (2.2%), *4 (17.4%), *5 (1%), *6 (1.1%), and *41 (10.8%). Out of these, 5.59% were predicted to be poor metabolizers, 3.19% were classified as UM while 1.0% were carriers of variant alleles duplications (undefined phenotype). For CYP3A4 allele frequencies of *1B and *22 variants were 1.4% and 2.7%, respectively. Allele frequency of CYP3A5*3 was 95.5%. Analyzing CYP3A cluster according to the combination of CYP3A4*22 and CYP3A5*3 revealed 5.34% of subjects to be poor metabolizers, while 8.66% were classified as extensive metabolizers. The frequency of the CYP allelic variants, genotypes, and predicted phenotypes in the Croatian population is in accordance with the other European populations, between the values of published data for Middle European and Mediterranean populations.

Pharmacogenetic polymorphism as an independent risk factor for frequent hospitalizations in older adults with polypharmacy: a pilot study.

Pharmacogenetic testing identifies genetic biomarkers that are predictive of individual sensitivity to particular drugs. A significant proportion of medications that are widely prescribed for older adults are metabolized by enzymes that are encoded by highly polymorphic genes. Pharmacogenetic testing is increasingly used to optimize the medication regimen; however, its potential in older adults with polypharmacy has not been systematically explored. Following the initial case–series study, this study hypothesized that frequently hospitalized older adults with polypharmacy have higher frequency of pharmacogenetic polymorphism as compared to older adults with polypharmacy who are rarely admitted to a hospital. To test this hypothesis, a nested case–control study was conducted with pharmacogenetic polymorphism as an exposure and hospitalization rate as an outcome. In this study, frequently hospitalized older adults (≥65 years of age) with polypharmacy were matched with rarely hospitalized older adults with poly-pharmacy by age, gender, race, ethnicity, and chronic disease score. Average age and number of prescription drugs did not differ in cases and controls (77.2±5.0 and 78.3±5.1 years, 14.3±5.3 and 14.0±2.9 medications, respectively). No statistically significant difference in sociodemographic, clinical, and behavioral characteristics that are known to affect hospitalization risk was found between the cases and controls. Major pharmacogenetic polymorphism defined as presence of at least one allelic combination resulting in poor or rapid metabolizer status was identified in all the cases. No major pharmacogenetic polymorphisms were detected in controls. Based on the exact McNemar’s test, the difference in major pharmacogenetic polymorphism frequency between cases and controls was statistically significant (p<0.05). In 50% of cases, more than one major pharmacogenetic polymorphism was found. The frequency of CYP2C19 rapid metabolizer, CYP3A4/5 poor metabolizer, VKORC1 low sensitivity, and CYP2D6 rapid metabolizer status in cases was 67%, 33%, 33%, and 17%, respectively, which significantly exceeded respective prevalence in general population. The mean number of major gene–drug interactions found in cases was 2.8±2.2, whereas no major drug–gene interactions were identified in controls. The difference in the number of major drug–gene interactions between cases and controls was statistically significant (p<0.05). The pilot data supported the hypothesis that pharmacogenetic polymorphism may represent an independent risk factor for frequent hospitalizations in older adults with polypharmacy. Due to small sample size, the results of this proof-of-concept study cannot be conclusive. Further work on the utility of pharmacogenetic testing for optimization of medication regimens in this vulnerable group of older adults is warranted.

Evaluation of the Prevalence of Pharmacogenetic Polymorphisms in Pediatric Neurology Patients with Whole Exome Sequencing (P5.153)

Evaluation of the Prevalence of Pharmacogenetic Polymorphisms in Pediatric Neurology Patients with Whole Exome Sequencing (P5.153)

Evaluation of the Prevalence of Pharmacogenetic Polymorphisms in Pediatric Neurology Patients with Whole Exome Sequencing (I14.012)

Evaluation of the Prevalence of Pharmacogenetic Polymorphisms in Pediatric Neurology Patients with Whole Exome Sequencing (I14.012)

POLYMORPHISMS OF DRUG-METABOLIZING ENZYMES CYP1A2, CYP2D6, GST, NAT2 AND TRANSPORTER MDR1 IN POPULATION OF BELARUS: COMPARISON WITH SELECTED EUROPEAN AND ASIAN POPULATIONS

Drug therapeutic efficiency and development of unfavorable pharmacologic responses as well as the disease predisposition are caused first of all by patient’s genetic features. Genetic variations in genes encoding drug-metabolizing enzymes and transporter proteins are essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity of drugs. For that reason, it is necessary to establish the normative frequency distribution of genotypes and alleles of these genes in a particular population. Data on frequency of pharmacogenetic polymorphisms in the of Belarus population are limited. The goal of our investigation was to analyze the frequency distribution of genotypes and alleles of genes encoding drug-metabolizing enzymes (CYP1А2, CYP2D6 – I phase; GSTs, NAT2 – II phase) and transporter protein MDR1 in the population of Belarus and comparisons with other ethnic populations. Our results indicate that clinically important genes are genetically highly variable and differ considerably between populations. Differences in allele frequencies across continents should be considered when designing clinical trials of new drugs continents should be considered when designing clinical trials of new drugs.

Pharmacogenetic Polymorphisms in a Portuguese Gypsy Population

Background: It is well-documented that though living in the same geographical area, European Roma and their host populations have distinct genetic ancestries. Nevertheless, there are very few studies addressing diversity of pharmacogenetic significance in Roma groups. The main goal of the present study was to characterise the Portuguese Gypsies for a selected battery of SNPs located in genes known to influence the response to drugs (TPMT, CYP2C9, CYP2C19, NAT2, and VKORC1) in comparison to their host population. Methods: The DNA of 116 Portuguese Gypsies and 70 Portuguese non-Gypsies individuals was genotyped using a multiplex PCR-minisequencing assay for the following SNPs: TPMT*2, TPMT*3B, TPMT*3C, TPMT*8, CYP2C9*2, CYP2C9*3, CYP2C19*2, NAT2*5, NAT2*13, and VKORC1 c.-1639G>A. Comparative analyses were performed and extended to other populations for which allelic frequencies were available from the literature. Results: Comparisons between Portuguese Gypsies and non-Gypsies only revealed significant differences for CYP2C9*2. In the worldwide geographical context, both samples fitted well the pattern of pharmacogenetic diversity found in Europe. However, in the Euro-Indian framework, Gypsies revealed to be closer to Indian populations, especially from North India, than did the Portuguese non-Gypsies. Conclusion: From the pharmacogenetic point of view, the Gypsies from Portugal do not seem to raise additional public health concerns comparatively to other Portuguese. This study illustrates how important signs of the demographic past of a population can be captured by the fraction of pharmacogenetically relevant genetic diversity. Keywords: Genotyping, Gypsy population, pharmacogenetics, population genetics, Roma, SNP.

The impact of glutathione S–transferase genotype and phenotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases

Azathioprine (AZA) is a thiopurine prodrug which is widely used in patients with inflammatory bowel disease (IBD). However, the use is limited in one–third of patients because of adverse drug reactions (ADRs) or a lack of clinical response. It has been considered that the polymorphic enzyme thiopurine S–methyltransferase (TPMT) plays an important role in the in vivo process of AZA and the occurrence of its myelotoxicity. Glutathione S–transferase (GST) mutation is another pharmacogenetic polymorphism which is probably involved in AZA metabolism and tolerance. The aim of this study was to investigate the association among GST polymorphism, enzyme activity and AZA–related ADRs in Chinese Han patients with IBD.We found that the patients who became neutropenic had a significantly higher GSTs activity when compared with of the patients who did not develop ADRs (analysis of variance, P < 0.001). There was also a significant underrepresentation of GSTP1*–105V allele among patients developing ADRs (odds ratio [OR] = 0.125, 95% confidence interval [CI] = 0.022–0.709, P = 0.0012).The patients with higher GST activity constituted a pharmacogenetic high risk group for leucopenia during AZA treatment. GST–P1 Ile105/Ile105 genotype appeared to be a promising marker indicating predisposition to AZA–related ADRs.