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Sökning: WFRF:(Aklillu Eleni)

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  • Aklillu, Eleni, et al. (författare)
  • Association of MAOA gene functional promoter polymorphism with CSF dopamine turnover and atypical depression.
  • 2009
  • Ingår i: Pharmacogenetics and genomics. - 1744-6872. ; 19:4, s. 267-75
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Monoamine oxidase-A (MAO-A) is a key mitochondrial enzyme that metabolizes biogenic amine neurotransmitters such as dopamine and serotonin. Individuals with atypical depression (AD) are particularly responsive to treatment with MAO inhibitors (MAOIs). Biomarker tests are essential for prompt diagnosis of AD, and to identify those with an altered brain neurotransmitter metabolism who may selectively respond to MAOI therapy. METHODS: In a sample of 118 Scandinavian patients with treatment-resistant depression who are naive to MAOI therapy, we investigated the associations between a common MAOA functional promoter polymorphism (MAOA-uVNTR), cerebrospinal fluid (CSF) neurotransmitter metabolites, and AD susceptibility. The metabolites for dopamine (homovanillic acid, HVA), serotonin (5-hydroxyindoleacetic acid) and noradrenaline (3-methoxy-4-hydroxyphenylglycol) were measured in the CSF. RESULTS: AD was associated with the female sex and a higher HVA in CSF (P=0.008). The carriers of the MAOA-uVNTR short allele were significantly overrepresented among women with AD (P=0.005; odds ratio=4.76; 95% confidence interval=1.5-13.1; statistical power=80.0%). Moreover, the MAOA-uVNTR genotype significantly influenced the HVA concentration (P=0.01) and showed a strong trend in relation to 5-hydroxyindoleacetic acid concentration (P=0.057) in women. The mediational statistical analyses showed the CSF-HVA concentration as a key driver of the relationship between MAOA-uVNTR genotype and AD. CONCLUSION: The association of the MAOA-uVNTR with both susceptibility to AD and dopamine metabolite (HVA) concentration lends further biological plausibility for high MAO-A enzyme activity as a mechanistic factor for genetic predisposition to AD through altered dopamine turnover. Our observations provide new evidence on the in-vivo functional significance of the MAOA-uVNTR short allele as a high activity variant.
  • Kishida, Ikuko, et al. (författare)
  • Monoamine metabolites level in CSF is related to the 5-HTT gene polymorphism in treatment-resistant depression.
  • 2007
  • Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - 0893-133X. ; 32:10, s. 2143-51
  • Tidskriftsartikel (refereegranskat)abstract
    • The serotonin (5-hydroxytryptamine) transporter (5-HTT) is considered to affect the pathogenesis of mood disorders. Large number of genetic association studies between 5-HTT functional polymorphisms and vulnerability of mood disorders and therapeutic response to antidepressants has been carried out. We investigated the influence of 5-HTT-linked polymorphic region (5-HTTLPR) and 5-HTT 17 bp variable number of tandem repeat polymorphism (5-HTTVNTR) polymorphisms on concentrations of monoamine metabolites in cerebrospinal fluid (CSF) among treatment-resistant patients with mood disorders. Subjects were 119 Swedish patients with persistent mood disorders and 141 healthy subjects. In 112 of these patients, we measured 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol in CSF. Genotyping for 5-HTT polymorphisms from genomic DNA was carried out by PCR. There was no significant difference in allele/genotype frequency between patients and healthy subjects. In patients with mood disorders, we found significant difference in mean 5-HIAA concentration between 5-HTTLPR genotypes (p=0.03). Although the 5-HIAA concentration showed a tendency to be higher in short (S) carriers than in non-S carriers of the 5-HTTLPR in patients (p=0.06), when considering patients with major depressive disorder (MDD), the 5-HIAA concentration was significantly higher among S carriers than among non-S carriers (p=0.02). Moreover, the 5-HIAA concentration was higher in S/S subjects compared to long (L)/L (p=0.0001) and L/S (p=0.002) subjects in patients with MDD. Similarly, there was higher HVA concentration in S/S subjects compared to L/L (p=0.002) and L/S subjects (p=0.002). There was no effect of 5-HTTVNTR. Our findings show that the 5-HTTLPR polymorphism affects 5-HIAA and HVA concentrations among treatment-resistant patients with mood disorders.
  • Mukonzo, Jackson K, et al. (författare)
  • A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.
  • 2009
  • Ingår i: British journal of clinical pharmacology. - 1365-2125. ; 68:5, s. 690-9
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using NONMEM. METHODS: Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS: Apparent oral clearance (95% confidence interval) was 4 l h l(-1) (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS: The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
  • Mukonzo, Jackson K, et al. (författare)
  • HIV/AIDS Patients Display Lower Relative Bioavailability of Efavirenz than Healthy Subjects.
  • 2011
  • Ingår i: Clinical pharmacokinetics. - 0312-5963. ; 50:8, s. 531-40
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Pharmacokinetic studies of antiretroviral drugs are often conducted in adult healthy subjects, and the results are extrapolated to HIV/AIDS patients. HIV/AIDS, however, is known to cause morphological and physiological changes that may alter the pharmacokinetics of antiretroviral drugs. We examined the effect of HIV/AIDS on the pharmacokinetics of efavirenz in Ugandans. Methods: After a first oral dose of efavirenz 600 mg in treatment-naïve HIV-infected patients, blood samples were collected at nine time points up to 24 hours. The plasma-concentration time data from these patients were merged with previously reported data from adult healthy subjects. Population pharmacokinetic models were fitted to the data, using NONMEM VI software. Covariate analyses were performed to estimate the effects of HIV/AIDS disease, demographic characteristics (sex, bodyweight, age), biochemical variables (serum creatinine, urea, alanine aminotransferase) and pharmacogenetic variation in cytochrome P450 (CYP) 2B6, CYP3A5 and adenosine triphosphate-binding cassette, sub-family B, member 1 (ABCB1) on the population pharmacokinetic parameters. Results: Efavirenz plasma concentration-time data obtained from 29 HIV-1-infected, treatment-naïve patients were merged with previously reported data from 32 adult healthy subjects. The model identified sex and HIV/AIDS disease as statistically significant categorical predictors of efavirenz pharmacokinetics. Females were predicted to have a 2-fold higher volume of distribution of the peripheral compartment after oral administration (V(2)/F) than males (95% CI 1.53, 2.63), while HIV/AIDS patients were found to have 30% lower relative bioavailability (95% CI 18.7, 40.7) than healthy subjects. The increased V(2)/F in females resulted in a 2-fold longer elimination half-life than in males. Conclusion: On the basis of the findings of this analysis, we conclude that, apart from bodyweight-based differences, both HIV/AIDS disease and sex affect efavirenz pharmacokinetics in Ugandans. HIV/AIDS disease is associated with reduced relative bioavailability of efavirenz. We recommend that findings from healthy subject studies be confirmed in HIV/AIDS patients and that caution be applied in direct extrapolation of exposure data to the target patient population.
  • Aklillu, Eleni (författare)
  • Pharmacogenetics of drug metabolizing enzymes with special emphasis on Ethiopians
  • 2003
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Pharmacogenetics of drug metabolising enzymes has been well studied in Caucasians and Asians, but relatively little in Africans. The aim of this thesis was to investigate the molecular genetics of drug metabolising enzymes, in particular CYP2D6, CYP2C19, CYP2C9, CYP1B1, CYP1A2 and XO, with special emphasis on the Ethiopian population. Two different Ethiopian populations were investigated, healthy unrelated subjects living in Ethiopia (n=122) and Ethiopians living in Sweden (n=73). In the first group, it was found that only 1.8% were PMs for debrisoquine, whereas 29 % carried duplicated or multiduplicated CYP2D6 genes, having higher enzyme activity. We identified new haplotypes carrying 4 or 5 CYP2D6*2 gene copies on one allele. We found a significantly lower rate of CYP2D6 but not of CYP2C19-catalyzed reactions in Ethiopians living in Ethiopia as compared to Ethiopians living in Sweden of the same genotypes. We suggest that the dietary habits in Ethiopia have had an inhibitory effect on CYP2D6 and have contributed to dietary related selection for CYP2D6 duplication in Ethiopians. We screened for new SNPs in the CYP1B1 gene and detected 3 novel SNPs one of which (4360C>G in exon 3) was present at a frequency of 7 %, and causes an Ala443Gly (m5) amino acid substitution. In total, 5 missense SNPs were found yielding in total 32 possible CYP1B1 haplotypes. However, we could only find 7 of them carrying 1-4 different missense SNPs. Functional characterization of these revealed that CYP1B1.6 and CYP1B1.7, having the Arg48Gly, Ala119Ser and Leu432Val mutations in common, had significantly decreased Vmax/Km for both the 2- and 4-hydroxylation of 17 b-estradiol whereas the other were similar to the CYP1B1.1 enzyme. It is emphasized that haplotypes rather than single SNPs are to be considered in e.g. molecular epidemiological studies. Ethiopians living in Ethiopia (n=115) or in Sweden (n=73) were phenotyped with caffeine to evaluate any influence of environmental and gender related differences on XO and CYP1A2 activities. XO activity was significantly higher in Ethiopians living in Ethiopia compared with those living in Sweden. We suggest that the dietary habits in Ethiopia might have caused the elevated XO-expression. Genomic DNA sequencing of CYP1A2 gene from 12 subjects revealed the presence of a novel intron 1 SNP, -730C>T. Genotyping and molecular haplotyping methods for the intron 1 SNPs were developed and 4 different haplotypes were identified: CYP1A2*1A (wt for all SNPs); CYP1A2*1F (-164A); CYP1A2*1J (-740G and -164A) and CYP1A2*1K (-730T, -740G and -164A) with frequencies of 39.9, 49.6, 7.5 and 3.0 %, respectively. Subjects with CYP1A2*1K had significantly decreased CYP1A2 activity in vivo (p<0.02) and reporter constructs with this haplotype revealed significantly less inducibility with TCDD in human B16A2 hepatoma cells. EMSA analysis using nuclear extracts from B16A2 cells indicated that the -730 C>T mutation abolishes a binding site for a transcription factor of the Ets family. It is concluded that this polymorphism might be of great importance for individual sensitivity to carcinogen activation and rate of drug metabolism. In conclusion unique novel alleles have been identified in the Ethiopian population and has given light to mechanisms behind their evolution and putative importance in carcinogen and drug metabolism.
  • Ghotbi, Roza, et al. (författare)
  • Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers
  • 2009
  • Ingår i: The Pharmacogenomics Journal. - 1470-269X .- 1473-1150. ; 9:3, s. 208-217
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The basis for interindividual variation in the CYP1A2 gene expression is not fully understood and the known genetic polymorphisms in the gene provide no explanation. We investigated whether the CYP1A2 gene expression is regulated by DNA methylation and displays allele-specific expression (ASE) using 65 human livers. Forty-eight percent of the livers displayed ASE not associated to the CYP1A2 mRNA levels. The extent of DNA methylation of a CpG island including 17 CpG sites, close to the translation start site, inversely correlated with hepatic CYP1A2 mRNA levels (P=0.018). The methylation of two separate core CpG sites was strongly associated with the CYP1A2 mRNA levels (P=0.005) and ASE phenotype (P=0.01), respectively. The CYP1A2 expression in hepatoma B16A2 cells was strongly induced by treatment with 5-aza-2'-deoxycytidine. In conclusion, the CYP1A2 gene expression is influenced by the extent of DNA methylation and displays ASE, mechanisms contributing to the large interindividual differences in CYP1A2 gene expression.</p>
  • Hatta, Fazleen H M, et al. (författare)
  • Differences in CYP2C9 Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine : Role of Ethnicity, Genotype, Smoking, Age, and Sex
  • 2015
  • Ingår i: Omics. - 1536-2310 .- 1557-8100. ; 19:6, s. 346-353
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Global personalized medicine demands the characterization of person-to-person and between-population differences in drug pharmacokinetics and pharmacodynamics. CYP2C9 pharmacokinetic pathway is subject to modulation by both genetic and environmental factors. CYP2C9 genotype-based dose recommendations (e.g., for warfarin) is advocated. However, the overall contribution of genotype for variation in enzyme activity may differ between populations. We evaluated the importance of ethnicity, genotype, smoking, body weight, age, and sex for CYP2C9 enzyme activity. CYP2C9 genotype and phenotype was determined in 148 Swedes and 146 Koreans using losartan as a probe. CYP2C9 enzyme activity was assessed using urinary losartan/metabolite E-3174 ratio. The frequency of CYP2C9 defective variant alleles (*2 and *3) was significantly higher in Swedes (10.8% and 12.5%) than in Koreans (0% and 5.8%). In matched genotypes, CYP2C9 enzyme activity was significantly lower in Swedes compared to Koreans (p&lt;0.0001). In a univariate analysis, age, weight, ethnicity, genotype, and smoking were significant predictors of CYP2C9 phenotype. A stepwise multivariate analysis indicated ethnicity, genotype, and smoking remained as significant predictors of CYP2C9 enzyme activity, accounting for 50% of the total variance. In both study populations, CYP2C9 genotype was a significant predictor of CYP2C9 enzyme activity, but its contribution in explaining the total variance was lower in Koreans (26.6%) than Swedes (40%). In conclusion, we report significantly lower CYP2C9 enzyme activity in Swedes compared to Koreans, partly but not exclusively due to CYP2C9 pharmacogenetic variations. Ethnicity and environment factors need to be considered together with genotype for population-specific dose optimization and global personalized medicine.</p>
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