Genetic association analysis of polymorphisms in four cytochrome P450 genes, the MDR1 gene and treatment-outcome in Xhosa schizophrenia patients
Year: 2007
Type: dissertation
Study design: Observational Study
Abstract: Rapidly expanding knowledge of the human genome allows new insight into the interaction between drugs and DNA.The heterogeneic nature of schizophrenia is known to cause different patients to display dissimilar drug responses, reflecting distinct genetic profiles.Resulting adverse side effects include tardive dyskinesia (TD), a movement disorder associated with the long-term use of antipsychotic drugs.The identification of a pharmacogenetic basis of TD may have significant clinical implications in the treatment of schizophrenia, allowing individualised prescription of antipsychotic drugs and eventual elimination of undesirable side effects.The current study focussed on a number of South African Xhosa schizophrenia patients, some of whom have been diagnosed with TD.The investigation sought to establish whether the underlying mechanism causing the disorder to manifest only in some individuals, might be attributed to differences in DNA sequences, i.e. genomic susceptibility.A number of candidate polymorphisms in the CYP and MDR1 genes were evaluated in three separate analyses.(The same approach was followed in each investigation, and only known polymorphisms were selected.)The incidences of the various variants were compared between TD and non-TD patients.In addition, potential predisposing factors, i.e. tobacco and cannabis smoking and anhedonia, were taken into consideration.These were analysed concurrently with DNA data and TD status.The first section of the study evaluated a potential association between selected cytochrome P450 (CYP) gene polymorphisms and TD.These variants included single nucleotide polymorphisms (SNPs) in the CYP1A2 and CYP17α-hydroxylase genes, i.e. -3860G>A (CYP1A2*1C), -163C>A (CYP1A2*1F) and 27T>C (CYP17αhydroxylase).A statistically significant difference in genotypic and allelic distribution (P=0.036 and P=0.031 respectively) was observed between patients with and without TD concerning the CYP17α-hydroxylase variant that can be explored by the known influence of this variant on dopamine release.Cannabis smokers who are carriers of this polymorphism had a pronounced decreased risk for TD.CYP3A4 and CYP3A5 are responsible for the metabolism of several antipsychotic drugs.In the next section of our study the SNPs CYP3A4*1B, CYP3A4*1G, CYP3A4 C23081T, CYP3A5*3 and CYP3A5*6 were tested as susceptibility loci for TD.The findings suggested that presence of the CYP3A5*3 polymorphism might contribute to the development of TD (P=0.038).A haplotype encompassing the CYP3A4*1G and CYP3A5*3 polymorphisms was more common amongst the TD patients than the non-TD patients (P=0.049).Polymorphisms in the MDR1 gene have the ability to alter the human drug transporter P-glycoprotein (P-gp) expression which plays an important role in drug secretion and response.The final section of our analysis aimed to determine whether any of four MDR1 gene SNPs T-129C, C1236T, G2677T/A and C3435T contribute to elevated TD risk.The results indicated that the T-129C and C3435T polymorphisms might be associated with a predisposition to TD. Statistically significant differences (P=0.0015 and P=0.0063 respectively) were revealed between TD and non-TD regarding Hardy-Weinberg equilibrium (HWE) only.The current investigation represents the first to study the influence of some of the above mentioned CYP and MDR1 gene polymorphisms in conjunction with the development of TD.Evidence is provided for a possible association between SNPs in the CYP (CYP17α-Hydroxylase and CYP3A5*3) and the MDR1 (T-129C and C3435T) genes.OPSOMMING Snel toenemende kennis aangaande die mensgenoom bring nuwe insig rakende die wisselwerking tussen DNS en geneesmiddels.Pasiënte reageer verskillend op antipsigotiese medikasie, wat toegeskryf kan word aan verskillende individuele genetiese profiele.Hierdie variasie op DNS vlak, tesame met die komplekse aard van skisofrenie, veroorsaak ongunstige newe-effekte en lei tot tardiewe diskinesie (TD).Sou navorsing 'n farmakogenetiese basis vir TD kon uitlig, sal dit lei tot merkwaardige kliniese implikasies in die behandeling van skisofrenie.Dit sal die weg baan vir geïdividualiseerde medikasie en uiteindelik negatiewe medisinale neweeffekte uitskakel.Die huidige studie konsentreer op Suid-Afrikaanse Xhosa skisofrenie pasiënte, sommige van wie kliniese simptome van TD toon.Die ondersoek poog om vas te stel waarom sommige pasiënte die toestand ontwikkel en ander nie.Dit het ten doel om vas te stel of die ontstaan van hierdie sindroom verklaar kan word aan die hand van verskille in DNS volgorde-samestelling, of te wel genetiese vatbaarheid.Kandidaat polimorfismes in die Sitochroom P450 (CYP) en die MDR1 gene wat reeds gedokumenteer is, is geëvalueer in drie afsonderlike analises.Die voorkoms van die variante is vergelyk tussen pasiënte met of sonder TD.Die bydrae wat bykomende faktore, insluitende tabak en dagga rook en anhedonia, mag lewer in verhoogde risiko vir TD, is ook in ag geneem.Die eerste onderafdeling van die studie toets 'n potensiële verwantskap tussen CYP geen-polimorfismes en TD.Die variante sluit in enkel nukleotied polimorfismes in die CYP1A2 en CYP17α-Hidroksilase gene: -3860G>A (CYP1A2*1C), -163C>A (CYP1A2*1F) en 27T>C (CYP17α-Hidroksilase).Die resultate het 'n statisties betekenisvolle verskil tussen die genotipe-en alleel-frekwensies (P=0.036en P=0.031 onderskeidelik) tussen TD en nie-TD pasiënte opgelewer betreffende die CYP17α-Hidroksilase polimorfisme wat verklaar kan word deur die bekende invloed van hierdie variant op dopamien vrystelling.Individue wat die polimorfisme dra en dagga gerook het, het 'n verlaagde risiko om TD te ontwikkel.CYP3A4 en CYP3A5 metaboliseer verskillende antipsigotiese middels.Die volgende afdeling behels die evaluasie van die enkel nukleotied polimorfismes CYP3A4*1B, CYP3A4*1G, CYP3A4 C23081T, CYP3A5*3 en CYP3A5*6 as moontlike vatbaarheidsloci vir TD.Die bevindinge hier bring na vore dat die CYP3A5*3 polimorfisme betrokke mag wees by 'n verhoogde TD risiko (P=0.038).'n Haplotipe wat die CYP3A4*1G en CYP3A5*3 polymorfismes behels was meer algemeen onder die TD as onder die nie-TD pasiënte (P=0.049).Polimorfismes in MDR1 het die vermoë om die uitdrukking van die menslike Pglikoproteïen (P-gp), te verander wat 'n belangrike rol speel in die uitskeiding van medisynes en die reaksie daarop.Die moontlike betrokkenheid van vier MDR1 geen enkel nukleotied polimorfismes T-129C, C1236T, G2677T/A en C3435T by TD is ondersoek.Die uitslag van die studie vestig die aandag op 'n moontlike verbintenis tussen die T-129C en C3435T polimorfismes en die ontwikkeling van TD.Die TD en nie-TD groepe verskil alleenlik t.o.v.Hardy-Weinberg ekwilibrium (HWE) (P=0.0015en P=0.0063).Die onderliggende invloed van bg.polimorfismes in die CYP en MDR1 gene op die oorsprong van TD is nog nie tevore bestudeer nie.Die studie is die eerste om bewys te lewer dat die ontstaan van TD moontlik verband mag hou met sekere polimorfismes in die CYP (CYP17α-Hydroxylase and CYP3A5*3) en die MDR1 (T-129C and C3435T) gene.2.5.1 Adverse drug reactions…………………………………………………..14 2.6 PHARMACOKINETICS…………………………………………………….15 2.7 SINGLE NUCLEOTIDE POLYMORPHISMS (SNPs)…………………….172.8 GENES INVOLVED IN THE METABOLISM AND TRANSPORT OF ANTIPSYCHOTICDRUGS IN SCHIZOPHRENIA AND TD PATIENTS…………………………………………………………………..18 2.8.1 Cytochrome P450………………………………………………………..18 2.8.1.1Cytochrome P450 1A2………………………………………………19 2.8.1.2Cytochrome P450 17 α-hydroxylase………………………………...20 2.8.1.3Cytochrome P450 3A4………………………………………………20 2.8.1.4Cytochrome P450 3A5………………………………………………21 2.8.2 Multidrug resistance gene (MDR1)………………………………………22 2.8.2.1 Substrates…………………………………………………………….23 2.8.2.2 Polymorphisms………………………………………………………23 Table 6: Haplotype analysis between alleles of the MDR1 gene loci: C1236T, G2677T/A and C3435T (Fig. 3B)………………………………………..76
Author: Erika Truter
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2127021269