Three novel thiopurine S-methyltransferase allelic variants (TPMT*20, *21, *22) - association with decreased enzyme function

The genetic polymorphism of the thiopurine S-methyltransferase, TPMT, comprises at least 21 alleles causing three distinct drug metabolism phenotypes termed normal/high, intermediate, and deficient methylators. In consequence, adverse drug reactions may occur if standard doses of thiopurines are applied routinely. Genetic prediction of the methylator phenotype as a basis for dose selection requires the extensive knowledge of single nucleotide polymorphisms occurring naturally in the population. Here we describe three novel missense variants in the TPMT gene which were associated with an intermediate red blood cell TPMT activity in three Caucasians. The following alleles were designated: TPMT*20 (c.712A>G), *21 (c.205C>G), and *22 (c.488G>C). No further genetic variations in remaining coding regions as well as the 5'flanking region of TPMT were identified. These sequence variants are present in highly conserved nucleotide positions of the TPMT gene throughout various mammalian species and in zebra fish, and are predicted to be intolerant when the functional consequences of variations were analyzed using SIFT (Sorting Intolerant From Tolerant) algorithm. In Caucasians the occurrence of these genetic variants appears to be extremely rare since none of these alleles were identified in a randomly selected control population of 1048 individuals.     

Association of the HSPG2 Gene with Neuroleptic-Induced Tardive Dyskinesia

Tardive dyskinesia (TD) is characterized by repetitive, involuntary, and purposeless movements that develop in patients treated with long-term dopaminergic antagonists, usually antipsychotics. By a genome-wide association screening of TD in 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD (non-TD group) and subsequent confirmation in independent samples of 36 treatment-resistant TD and 136 non-TD subjects, we identified association of a single nucleotide polymorphism, rs2445142, (allelic p=2 × 10⁻⁵) in the HSPG2 (heparan sulfate proteoglycan 2, perlecan) gene with TD. The risk allele was significantly associated with higher expression of HSPG2 in postmortem human prefrontal brain (p<0.01). Administration of daily injection of haloperidol (HDL) for 50 weeks significantly reduced Hspg2 expression in mouse brains (p<0.001). Vacuous chewing movements (VCMs) induced by 7-week injection of haloperidol–reserpine were significantly infrequent in adult Hspg2 hetero-knockout mice compared with wild-type littermates (p<0.001). Treatment by the acetylcholinesterase inhibitor, physostigmine, was significantly effective for reduction of VCMs in wild-type mice but not in Hspg2 hetero-knockout mice. These findings suggest that the HSPG2 gene is involved in neuroleptic-induced TD and higher expression of HSPG2, probably even after antipsychotic treatment, and may be associated with TD susceptibility.     

Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1

AIMS

To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects.

METHODS

Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol.

RESULTS

A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h⁻¹. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h⁻¹. Absorption rate constant was estimated at 0.24 h⁻¹ and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed.

CONCLUSIONS

The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol.     

Association analysis between the A118G polymorphism in the OPRM1 gene and treatment response to venlafaxine XR in generalized anxiety disorder

Patients diagnosed with generalized anxiety disorder (GAD) exhibit differential responses to standard antidepressant pharmacotherapy. Mounting evidence demonstrates that genetic differences may be implicated in treatment response in disorders like GAD. In this study, we examined whether the OPRM1 gene, which has been implicated in antidepressant treatment response in major depressive disorder, also has an effect in GAD. In our study, 156 patients diagnosed with GAD received venlafaxine XR treatment as part of an 18‐month relapse prevention study. Genotypes were obtained for the OPRM1 functional variant A118G for the entire sample (n = 151); however, only the European American population was considered (n = 108) for pharmacogenetic analysis. We found no significant association between A118G and antidepressant treatment response in our GAD population. Future studies that include different single nucleotide polymorphisms of the OPRM1 gene as well as larger populations will need to be conducted to further elucidate the pharmacogenetic role of the endogenous opioid system in anxiety disorders. Copyright © 2013 John Wiley & Sons, Ltd.     

Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity

The advances in the drug development that allowed the replacement of many potentially hepatotoxic agents by safer alternatives have been out-weighed by the vast expansion of the total number of agents now available for use. Now, rare adverse reactions to several commonly prescribed medications contribute to the total burden of drug-induced liver injury. Studies involving well-characterised patients with diclofenac-induced hepatotoxicity indicate that multiple steps are involved in the development of liver injury. Individual susceptibility to idiosyncratic hepatotoxicity is determined by the interaction of metabolic and immunological factors. Immunomodulatory and anti-inflammatory cytokines, such as IL-10, may have a protective role in reducing drug-induced liver injury. Understanding the mechanisms of idiosyncratic hepatotoxicity may increase our ability to identify susceptible individuals and hence, prevent serious adverse reactions.     

Pharmacogenomics of multiple sclerosis: in search for a personalized therapy

Background: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that affects young adults and provokes severe disability, imposing a high health and social burden. Current therapies for MS include interferon-β, glatiramer acetate, natalizumab and chemotherapy. These therapies decrease the number of relapses and partially prevent disability accumulation. However, their efficacy is only moderate, they have common adverse effects and impose a high cost to health systems. The identification of biomarkers will allow responders and non-responders to therapy to be identified, increasing the efficacy and adherence to therapy, and the pharmaco-economic profile of theses drugs. Objectives and Conclusion: In this review we examine the pharmacogenetic studies that have evaluated the clinical response to interferon-β, and to a lesser extent, glatiramer acetate and natalizumab. Finally, we discuss how systems biology can be used to integrate biological and clinical data in order to develop personalized medicine for MS.     

Hereditary spastic paraplegia: clinical genomics and pharmacogenetic perspectives

Hereditary spastic paraplegias (HSPs) are a group of single-gene disorders characterised by degeneration of the corticospinal tract axons, leading to bilateral, symmetrical, slowly-progressive spastic paraparesis, predominantly of the lower extremities. So far, ~ 30 different chromosomal HSP loci have been identified by genetic linkage analysis. Defects in intracellular trafficking and transport in myelination and abnormalities of mitochondrial proteins have been involved in HSP pathogenesis. At present, treatment of the HSPs is primarily directed symptomatically toward reducing muscle spasticity. Yet, recent progresses in the identification of HSP mutations are providing formidable tools to pharmacogenetic approaches of drug discovery, validation and prediction of individual response.     

Hepatic CYP2B6 is altered by genetic,physiologic, and environmental factors but plays little role in nicotine metabolism

1. Human cytochrome P4502B6 (CYP2B6) is predominantly expressed in the liver and it plays a major role in the metabolism of several therapeutically important drugs and environmental toxicants.

2. The objective was twofold: (1) to determine the role of genetic, physiological, and environmental factors in predicting hepatic CYP2B6 protein expression; and (2) to investigate the role of CYP2B6 in nicotine C-oxidation.

3. Human livers (n?=?40) were assessed for CYP2B6 protein and genotype.

4. Linear regression analyses indicated that CYP2B6 genotype (10%), gender (14%), and exposure to inducers (21%), but not age, were predictors of CYP2B6 protein amounts. Livers with at least one CYP2B6*5 or *6 allele were associated with lower CYP2B6. Female livers and livers exposed to inducers (phenobarbital and/or dexamethasone) were associated with higher CYP2B6.

5. A weak correlation between CYP2B6 and nicotine C-oxidation activity was observed, which was abrogated when controlling for CYP2A6 protein levels. CYP2B6*6 was not associated with different nicotine kinetics.

6. In summary, CYP2B6 protein expression was associated with genotype, gender, and exposure to inducers, but not with nicotine C-oxidation activity.