The Pharmacogenomics Journal (PHARMACOGENOMICS J)

Publications in this journal

• Article: Heterochromatin as an Incubator for Pathology and Treatment Nonresponse: Implication for Neuropsychiatric Illness.

  Sharma RP, Gavin DP, Chase KA
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  ABSTRACT: Heterochromatin is a higher order assembly that is characterized by a genome-wide distribution, gene-repression, durability and potential to spread. In this light, it is an appealing mechanism to interpret the neurobiology of complex brain disorders such as schizophrenia where downregulation of expression appears to be the norm. H3K9 methylation (H3K9me) can initiate the seeding of a heterochromatin assembly on an inactive or poorly coordinated promoter as a consequence of a decline in transactivators either from disuse or from misuse. H3K9me can extend its influence by spatial spreading through the mechanism of recursively recruiting adapters, such as heterochromatin protein 1 (HP1) homodimers. HP1 itself serves as a platform for other repressive proteins such as DNA methyltransferases. In full color, heterochromatin can occupy genome-wide gene networks, tissue specific ontologies and even rearrange the nuclear architecture. Heterochromatin in the brain is modified by small molecule pharmacology and serves a physiological role in the functioning of dopamine neurons and the construction of memory. From a therapeutic perspective, the durable nature of heterochromatin implies that it may require disassembly before the full genomic-potential of standard pharmacotherapies is achieved, especially in treatment resistant patients.
  The Pharmacogenomics Journal 10/2012; 12(5):361-7.
• Article: Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases

  J P Mena, M Salazar-P|[aacute]|ramo, L Gonz|[aacute]|lez-L|[oacute]|pez, J I G|[aacute]|mez-Nava, L Sandoval-Ramirez, J D S|[aacute]|nchez, L E Figuera, F J Mu|[ntilde]|oz-Valle, M Vazquez del Mercado, I P D|[aacute]|valos
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  ABSTRACT: Rheumatoid arthritis (RA) is the prototype of the rheumatic diseases worldwide. Methotrexate (MTX) is the drug of first choice in the treatment of this disease due to its immunosuppressant effect. However, side events are present in 30% of the patients. The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are involved in the metabolism of MTX. Earlier studies reported an association between these polymorphisms and elevation of hepatic enzymes. We analyzed the frequencies of both polymorphisms and the presence of transaminasemia in 70 Mexican patients with rheumatic arthritis treated with MTX. The 19% (13/70) of patients had an increase in the serum level of transaminases. The A1298C polymorphism was associated with elevation of transaminases (P=0.024). The identification of MTHFR genotypes for C677T and A1298C polymorphisms could lead clinicians to identify patients in risk of elevation of transaminases, and give them an individualized treatment, as is a goal of pharmacogenetics.Keywords: methotrexate; transaminases; pharmacogenetics; rheumatoid arthritis; MTHFR
  The Pharmacogenomics Journal 05/2010; 11(4):287-291.
• Article: Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

  T K Bergmann, C Brasch-Andersen, H Gr|[eacute]|en, M Mirza, R S Pedersen, F Nielsen, K Skougaard, J Wihl, N Keldsen, P Damkier, L E Friberg, C Peterson, W Vach, M O Karlsson, K Brosen
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  ABSTRACT: The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h–1 (range 176–726 l h–1). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P=0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P=0.04) and ABCC1 g.7356253C>G (P=0.04).Keywords: CYP2C8; ABCB1; P-glycoprotein; paclitaxel; cremophor; ovarian cancer
  The Pharmacogenomics Journal 04/2010; 11(2):113-120.
• Article: Assessing sources of inconsistencies in genotypes and their effects on genome-wide association studies with HapMap samplesOpen

  H Hong, L Shi, Z Su, W Ge, W D Jones, W Czika, K Miclaus, C G Lambert, S C Vega, J Zhang, [......], S M Lin, N Jafari, K Park, T Ahn, M Chierici, C Furlanello, L Zhang, R D Wolfinger, F Goodsaid, W Tong
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  ABSTRACT: The discordance in results of independent genome-wide association studies (GWAS) indicates the potential for Type I and Type II errors. We assessed the repeatibility of current Affymetrix technologies that support GWAS. Reasonable reproducibility was observed for both raw intensity and the genotypes/copy number variants. We also assessed consistencies between different SNP arrays and between genotype calling algorithms. We observed that the inconsistency in genotypes was generally small at the specimen level. To further examine whether the differences from genotyping and genotype calling are possible sources of variation in GWAS results, an association analysis was applied to compare the associated SNPs. We observed that the inconsistency in genotypes not only propagated to the association analysis, but was amplified in the associated SNPs. Our studies show that inconsistencies between SNP arrays and between genotype calling algorithms are potential sources for the lack of reproducibility in GWAS results.Keywords: repeatability; association; genotype; calling algorithm; intensity; copy number
  The Pharmacogenomics Journal 04/2010; 10(4):364-374.
• Article: Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancerOpen

  B Glimelius, H Garmo, Aring]| Berglund, L A Fredriksson, M Berglund, H Kohnke, P Bystr|[ouml]|m, H S|[oslash]|rbye, M Wadelius
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  ABSTRACT: Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09–13.2), and in patients carrying the UGT1A1*28/*28 genotype, OR=4.43 (95% CI=1.30–15.2). Patients with UGT1A1*28/*28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70–27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01–2.45).Keywords: camptothecin/analogs and derivatives; fluorouracil; glucuronosyltransferase; P-glycoprotein; thymidylate synthase; methylenetetrahydrofolate reductase (NADPH2)
  The Pharmacogenomics Journal 02/2010; 11(1):61-71.
• Article: SNPs in genes coding for ROS metabolism and signalling in association with docetaxel clearance

  H Edvardsen, P F Brunsvig, H Solvang, A Tsalenko, A Andersen, A-C Syvanen, Z Yakhini, A-L B|[oslash]|rresen-Dale, H Olsen, S Aamdal, V N Kristensen
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  ABSTRACT: The dose of docetaxel is currently calculated based on body surface area and does not reflect the pharmacokinetic, metabolic potential or genetic background of the patients. The influence of genetic variation on the clearance of docetaxel was analysed in a two-stage analysis. In step one, 583 single-nucleotide polymorphisms (SNPs) in 203 genes were genotyped on samples from 24 patients with locally advanced non-small cell lung cancer. We found that many of the genes harbour several SNPs associated with clearance of docetaxel. Most notably these were four SNPs in EGF, three SNPs in PRDX4 and XPC, and two SNPs in GSTA4, TGFBR2, TNFAIP2, BCL2, DPYD and EGFR. The multiple SNPs per gene suggested the existence of common haplotypes associated with clearance. These were confirmed with detailed haplotype analysis. On the basis of analysis of variance (ANOVA), quantitative mutual information score (QMIS) and Kruskal–Wallis (KW) analysis SNPs significantly associated with clearance of docetaxel were confirmed for GSTA4, PRDX4, TGFBR2 and XPC and additional putative markers were found in CYP2C8, EPHX1, IGF2, IL1R2, MAPK7, NDUFB4, TGFBR3, TPMT (2 SNPs), (P<0.05 or borderline significant for all three methods, 14 SNPs in total). In step two, these 14 SNPs were genotyped in additional 9 samples and the results combined with the genotyping results from the first step. For 7 of the 14 SNPs, the results are still significant/borderline significant by all three methods: ANOVA, QMIS and KW analysis strengthening our hypothesis that they are associated with the clearance of docetaxel.Keywords: SNPs; docetaxel; clearance; pharmacogenetics; cytochrome P450 system
  The Pharmacogenomics Journal 02/2010; 10(6):513-523.
• Article: Global variation in CYP2C8–CYP2C9 functional haplotypesTPJOpen

  William C Speed, Soonmo Peter Kang, David P Tuck, Lyndsay N Harris, Kenneth K Kidd
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  ABSTRACT: We have studied the global frequency distributions of 10 single nucleotide polymorphisms (SNPs) across 132 kb of CYP2C8 and CYP2C9 in ~2500 individuals representing 45 populations. Five of the SNPs were in noncoding sequences; the other five involved the more common missense variants (four in CYP2C8, one in CYP2C9) that change amino acids in the gene products. One haplotype containing two CYP2C8 coding variants and one CYP2C9 coding variant reaches an average frequency of 10% in Europe; a set of haplotypes with a different CYP2C8 coding variant reaches 17% in Africa. In both cases these haplotypes are found in other regions of the world at <1%. This considerable geographic variation in haplotype frequencies impacts the interpretation of CYP2C8/CYP2C9 association studies, and has pharmacogenomic implications for drug interactions.Keywords: CYP2C8, CYP2C9, paclitaxel, population genetics, haplotypes, evolution
  The Pharmacogenomics Journal 04/2009; 9(4):283-290.
• Article: Association study of tardive dyskinesia and five DRD4 polymorphisms in schizophrenia patients

  C C Zai, A K Tiwari, V Basile, V De Luca, D J M|[uuml]|ller, N King, A N Voineskos, G Remington, H Y Meltzer, J A Lieberman, S G Potkin, J L Kennedy
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  ABSTRACT: Tardive dyskinesia (TD) is a side effect of chronic antipsychotic medication exposure. Abnormalities in dopaminergic activity in the nigro-striatal system have been most often suggested to be involved because the agents that cause TD share in common potent antagonism of dopamine D2 receptors (DRD2). Thus, a number of studies have focused on the association of dopamine system gene polymorphisms and TD, with the most consistent findings being an association between TD and the Ser9Gly polymorphism of the DRD3 gene and the TaqIA site 3′ of the DRD2 gene. The DRD4 gene codes for the third member of the D2-like dopamine receptor family, and the variable number tandem-repeat polymorphism in exon 3 of DRD4 has been associated with TD. However, other polymorphisms have not been thoroughly examined. In this study, we investigated five polymorphisms spanning the DRD4 gene and their association with TD in our European Caucasian sample (N=171). Although the exon 3 variable number tandem repeat was not associated with TD, haplotypes consisting of four tag polymorphisms were associated with TD in males. This study suggests that DRD4 may be involved in TD in the Caucasian population, although further replication studies are needed.Keywords: schizophrenia, tardive dyskinesia, genetics, DRD4, abnormal involuntary movement scale
  The Pharmacogenomics Journal 02/2009; 9(3):168-174.
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  Article: The clinical role of genetic polymorphisms in drug-metabolizing enzymes.

  D Tomalik-Scharte, A Lazar, U Fuhr, J Kirchheiner
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  ABSTRACT: For most drug-metabolizing enzymes (DMEs), the functional consequences of genetic polymorphisms have been examined. Variants leading to reduced or increased enzymatic activity as compared to the wild-type alleles have been identified. This review tries to define potential fields in the therapy of major medical conditions where genotyping (or phenotyping) of genetically polymorphic DMEs might be beneficial for drug safety or therapeutic outcome. The possible application of genotyping is discussed for depression, cardiovascular diseases and thromboembolic disorders, gastric ulcer, malignant diseases and tuberculosis. Some drugs used for relief of these ailments are metabolized with participation of genetically polymorphic DMEs including CYP2D6, CYP2C9, CYP2C19, thiopurine-S-methyltransferase, dihydropyrimidine dehydrogenase, uridine diphosphate glucuronosyltransferase and N-acetyltransferase type 2. Current evidence suggests that taking genetically determined metabolic capacities of DMEs into account has the potential to improve individual risk/benefit relationship. However, more prospective studies with clinical endpoints are needed before the paradigm of 'personalized medicine' based on DME variants can be established.
  The Pharmacogenomics Journal 03/2008; 8(1):4-15.
• Article: Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study.

  K Hirata, H Takagi, M Yamamoto, T Matsumoto, T Nishiya, K Mori, S Shimizu, H Masumoto, Y Okutani
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  ABSTRACT: Genetic risk factors for ticlopidine-induced hepatotoxicity were determined in 22 Japanese patients with ticlopidine-induced hepatotoxicity and 85 Japanese patients who tolerated ticlopidine therapy without experiencing adverse reactions. There was a significant correlation between ticlopidine-induced hepatotoxicity and five human leukocyte antigen (HLA) alleles: HLA-A*3303, HLA-B*4403, HLA-Cw*1403, HLA-DRB1*1302 and HLA-DQB1*0604 (corrected probability (P)-value (Pc)<0.01). In particular HLA-A*3303 was present in 15 (68%) of the 22 patients with ticlopidine-induced hepatotoxicity and in 12 (14%) of the 85 ticlopidine-tolerant patients (odds ratio, 13.04; 95% confidence interval (CI), 4.40-38.59; the corrected P-value (Pc)=1.24 x 10(-5)). HLA-A*3303 was present in 12 (86%) of the 14 patients with ticlopidine-induced cholestatic hepatotoxicity (odds ratio, 36.50; 95% CI, 7.25-183.82, Pc=7.32 x 10(-7)). Ticlopidine-induced severe cholestatic hepatotoxicity occurred more frequently in subjects with HLA-A*3303 and its haplotype in Japanese patients. These findings may explain the high incidence of ticlopidine-induced hepatotoxicity in Japanese patients mediated via an immune-mediated mechanism.
  The Pharmacogenomics Journal 03/2008; 8(1):29-33.
• Article: Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans.

  S E Kimmel, J Christie, C Kealey, Z Chen, M Price, C F Thorn, C M Brensinger, C W Newcomb, A S Whitehead
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  ABSTRACT: Warfarin sodium is a vitamin K antagonist that is plagued by large variability in patient response, including higher dose requirements among African Americans. Polymorphisms in the gene encoding apolipoprotein E (APOE) may partly explain this variability by altering transport of vitamin K to the liver. In a prospective cohort study of 232 individuals (52.2% Caucasian and 47.8% African American) initiating warfarin therapy, the weekly maintenance dose was significantly higher for African Americans than for Caucasians (mean 42.9 versus mean 36.9 mg, P=0.018), and the epsilon4 allele was more common among African Americans (37.8 versus 26.4% for Caucasians). In multivariable analyses, the presence of the epsilon4 allele was associated with a statistically significantly higher warfarin dose among African Americans (median 45.0 mg in epsilon4 carriers versus 35.0 mg in non-epsilon4 carriers, P=0.014) but not Caucasians (38.1 versus 35.0 mg, P=0.60). In addition, warfarin maintenance dose increased among African Americans according to genotype previously associated with differential hepatic chylomicron clearance (epsilon2/epsilon2 or epsilon2/epsilon3: 30.0 mg; epsilon3/epsilon3: 35.0 mg; epsilon3/epsilon4 or epsilon4/epsilon4: 45.0 mg; P=0.012), although the epsilon4/epsilon4 genotype was rare and not clearly associated with higher doses. The association of APOE with warfarin dosing was independent of CYP2C9 and VKORC1 polymorphisms. APOE polymorphisms thus may be important determinants of warfarin maintenance dose and could explain at least some of the observed racial differences in dose requirements.
  The Pharmacogenomics Journal 03/2008; 8(1):53-60.
• Article: Whole genome expression profiling of hepatitis B virus-transfected cell line reveals the potential targets of anti-HBV drugs.

  X R Ding, J Yang, D C Sun, S K Lou, S Q Wang
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  ABSTRACT: Hepatitis B virus (HBV) infection is a major health concern world wide, and few effective treatments have been developed. It has recently been reported that inhibiting host-cell proteins can prevent viral infection. The human genome may contain more genes required for HBV infection and replication than the viral genome. A systematic approach to find these potential antiviral targets is by host gene expression analysis using DNA microarrays. The aim of this study was to identify and validate novel cellular anti-HBV targets. The Human Whole Genome Bioarray was used to analyze differentially expressed genes in HepG2.2.15 cells and HepG2 cells. Altered gene expression in HepG2.2.15 cells was studied following treatment with the anti-HBV drug, lamivudine. Genes that were differentially expressed during HBV infection and reversed with anti-HBV drugs were validated by semiquantitative reverse transcription-PCR. Bioinformatics analysis revealed ABHD2, EREG, ACVR2B, CDC34, KHDRBS3 and RORA as potential cellular anti-HBV targets. Antisense oligodeoxynucleotides were used to test the antiviral activity of these potential targets. Results strongly suggested that inhibition of ABHD2 or EREG significantly blocked HBV propagation in HepG2.2.15 cells. This study demonstrates that ABHD2 and EREG are essential for HBV propagation and provides strong evidence that these proteins could be used as potential targets for anti-HBV drugs.
  The Pharmacogenomics Journal 03/2008; 8(1):61-70.
• Article: Rat survival to anthrax lethal toxin is likely controlled by a single gene.

  S H Nye, A L Wittenburg, D L Evans, J A O'Connor, R J Roman, H J Jacob
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  ABSTRACT: We examined whether survival of different rat strains administered anthrax lethal toxin is genetically determined. A reproducible test population of first filial generation hybrid rats was bred based on the susceptibility of progenitors to anthrax lethal toxin and to maximize genetic diversity across the strains. These rats were then tested with varying doses of anthrax lethal toxin. We found that all 'sensitive' strains died within 2 h following systemic administration of 240 mug/kg lethal toxin, while one strain survived following a five times higher dose (1.4 mg/kg). The ability of lethal toxin to lyse macrophage cultures derived from the bone marrow of these strains corresponded with in vivo results. We conclude that a rat test population can detect strain differences in response to anthrax lethal toxin. Survival is influenced by the host genome background and is likely due to a single gene with a recessive mode of inheritance.
  The Pharmacogenomics Journal 03/2008; 8(1):16-22.
• Article: I have forgotten ever having undergone heart surgery...

  A Palotás
  The Pharmacogenomics Journal 03/2008; 8(1):1-3.
• Article: Megalin genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin.

  L Riedemann, C Lanvers, D Deuster, U Peters, J Boos, H Jürgens, A am Zehnhoff-Dinnesen
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  ABSTRACT: Ototoxicity and nephrotoxicity are dose-limiting side effects of cisplatin. Megalin, a member of the low-density lipoprotein receptor family, is highly expressed in renal proximal tubular cells and marginal cells of the stria vascularis of the inner ear - tissues, which accumulate high levels of platinum-DNA adducts. On the assumption that the mechanisms of cisplatin-induced nephro- and ototoxicity involve megalin we analyzed the incidence of the non-synonymous single nucleotide polymorphisms (SNP) rs2075252 and rs4668123 in 25 patients who developed a distinct hearing loss during cisplatin therapy and in 25 patients without hearing impairment after cisplatin therapy. We found no association between cisplatin-induced ototoxicity and any allele of rs4668123 but observed a higher frequency of the A-allele of rs2075252 in the group with hearing impairment than in the group with normal hearing after cisplatin therapy (0.32 versus 0.14) (chi(2)=5.83, P<0.02; odds ratio: 3.45; 95% confidence interval: 1.11-11.2) indicating that SNPs at the megalin gene might impact the individual susceptibility against cisplatin-induced ototoxicity.
  The Pharmacogenomics Journal 02/2008; 8(1):23-8.
• Article: Variability in human hepatic MRP4 expression: influence of cholestasis and genotype.

  U Gradhand, T Lang, E Schaeffeler, H Glaeser, H Tegude, K Klein, P Fritz, G Jedlitschky, H K Kroemer, I Bachmakov, B Anwald, R Kerb, U M Zanger, M Eichelbaum, M Schwab, M F Fromm
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  ABSTRACT: The multidrug resistance protein 4 (MRP4) is an efflux transporter involved in the transport of endogenous substrates and xenobiotics. We measured MRP4 mRNA and protein expression in human livers and found a 38- and 45-fold variability, respectively. We sequenced 2 kb of the 5'-flanking region, all exons and intron/exon boundaries of the MRP4 gene in 95 patients and identified 74 genetic variants including 10 non-synonymous variations, seven of them being located in highly conserved regions. None of the detected polymorphisms was significantly associated with changes in the MRP4 mRNA or protein expression. Immunofluorescence microscopy indicated that none of the non-synonymous variations affected the cellular localization of MRP4. However, in cholestatic patients the MRP4 mRNA and protein expression both were significantly upregulated compared to non-cholestatic livers (protein: 299+/-138 vs 100+/-60a.u., P<0.001). Taken together, human hepatic MRP4 expression is highly variable. Genetic variations were not sufficient to explain this variability. In contrast, cholestasis is one major determinant of human hepatic MRP4 expression.
  The Pharmacogenomics Journal 02/2008; 8(1):42-52.
• Article: Polymorphisms of norepinephrine transporter and adrenergic receptor alpha1D are associated with the response to beta-blockers in dilated cardiomyopathy.

  S Nonen, H Okamoto, Y Fujio, Y Takemoto, M Yoshiyama, T Hamaguchi, Y Matsui, J Yoshikawa, A Kitabatake, J Azuma
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  ABSTRACT: Recent clinical trials have clearly demonstrated that the administration with beta-blockers decreases the mortality in the patients with chronic heart failure (CHF). However, significant heterogeneity exists in the effectiveness of beta-blockers among individual cases. We focused on 39 polymorphisms in 16 genes related to adrenergic system and investigated their association with the response to beta-blockers among 80 patients with CHF owing to idiopathic dilated cardiomyopathy. The polymorphisms of NET T-182C (P=0.019), ADRA1D T1848A (P=0.023) and ADRA1D A1905G (P=0.029) were associated with the improvement of left ventricular fractional shortening (LVFS) by beta-blockers. Furthermore, combined genotype analysis of NET T-182C and ADRA1D T1848A revealed a significant difference in LVFS improvement among genotype groups (P=0.011). These results suggest that NET (T-182C) and ADRA1D (T1848A and A1905G) polymorphisms are predictive markers of the response to beta-blockers. Genotyping of these polymorphisms may provide clinical insights into an individual difference in the response to the beta-blocker therapy in CHF.
  The Pharmacogenomics Journal 02/2008; 8(1):78-84.
• Article: UGT1A7 polymorphisms in chronic pancreatitis: an example of genotyping pitfalls.

  R H M te Morsche, J P H Drenth, K Truninger, H-U Schulz, A Kage, O Landt, M Verlaan, J Rosendahl, M Macek, J B M J Jansen, H Witt
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  ABSTRACT: UDP-glucuronosyltransferases (UGT) catalyze the glucuronidation of various compounds and thus inactivate toxic substrates. Genetic variations reducing the activity of UGT1A7 have been associated with various gastrointestinal cancers. Most recently, the UGT1A7*3 allele has been reported as a significant risk factor for pancreatic disorders, but we could not confirm these data. This study focused on the possible causes for the noted discrepancy. UGT1A7 genotypes were assessed in 37 samples, which were previously analyzed for UGT1A7 polymorphisms by others. We determined genotypes by melting curve analysis and by DNA sequencing. Additionally, we produced UGT1A7*1 and *3 constructs with or without a mutation at position - 57 of UGT1A7 and analyzed various combinations of these constructs. In 14/37 samples UGT1A7 genotyping results differed. The discrepancy could be explained by polymerase chain reaction bias owing to an unbalanced allelic amplification which was caused by a -57T>G variant located within the sequence of the chosen primer template in previous studies. Our findings indicate that most of the previously reported genetic associations between UGT1A7 and gastrointestinal cancers are based on primer-dependent genotyping errors.
  The Pharmacogenomics Journal 02/2008; 8(1):34-41.
• Article: The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy.

  J A Canter, D W Haas, A R Kallianpur, M D Ritchie, G K Robbins, R W Shafer, D B Clifford, D G Murdock, T Hulgan
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  ABSTRACT: Peripheral neuropathy (PN) due to mitochondrial injury complicates HIV therapy with some nucleoside reverse transcriptase inhibitors (NRTIs). Variation in the mitochondrial genome may influence susceptibility to NRTI toxicities. Two non-synonymous mitochondrial DNA polymorphisms, MTND1*LHON4216C (4216C) and MTND2*LHON4917G (4917G) were characterized in HIV-infected participants exposed to NRTIs in a randomized clinical trial. Among 250 self-identified white, non-Hispanic participants, symptomatic PN (> or = grade 1) developed in 70 (28%). Both 4216C (odds ratio (OR)=1.98 (95% confidence interval (CI) 1.05-3.75); P=0.04) and 4917G (OR=2.93 (95% CI 1.25-6.89); P=0.01) were more frequent in PN cases. These two polymorphisms remained independently associated with PN after adjusting for age, baseline CD4 count, plasma HIV RNA level, and NRTI randomization arm; 4216C (OR=2.0 (95% CI 1.1-4.0) P=0.04) and 4917G (OR=5.5 (95% CI 1.6-18.7) P<0.01). When 4917G individuals were excluded from the analysis, the association with 4216C was no longer seen. The mitochondrial 4917G polymorphism may increase susceptibility to NRTI-associated PN.
  The Pharmacogenomics Journal 02/2008; 8(1):71-7.
• Article: Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans.

  H Ishiguro, S Iwasaki, L Teasenfitz, S Higuchi, Y Horiuchi, T Saito, T Arinami, E S Onaivi
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  ABSTRACT: We tested if cannabinoid type 2 receptor (CB2) in the central nervous system plays a role in alcohol abuse/dependence in animal model and then examined an association between the CB2 gene polymorphism and alcoholism in human. Mice experiencing more alcohol preference by drinking showed reduced Cb2 gene expression, whereas mice with little preference showed no changes of it in ventral midbrain. Alcohol preference in conjunction with chronic mild stress were enhanced in mice treated with CB2 agonist JWH015 when subjected to chronic stress, whereas antagonist AM630 prevented development of alcohol preference. There is an association between the Q63R polymorphism of the CB2 gene and alcoholism in a Japanese population (P=0.007; odds ratio 1.25, 95% CI, (1.06-1.47)). CB2 under such environment is associated with the physiologic effects of alcohol and CB2 antagonists may have potential as therapies for alcoholism.
  The Pharmacogenomics Journal 01/2008; 7(6):380-5.