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1. |
Prothrombotic genetic risk factors and heparin‐induced thrombocytopenia |
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Pharmacogenetics,
Volume 13,
Issue 5,
2003,
Page 245-246
Theodore Warkentin,
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ISSN:0960-314X
出版商:OVID
年代:2003
数据来源: OVID
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2. |
Pharmacogenetics of oral anticoagulants |
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Pharmacogenetics,
Volume 13,
Issue 5,
2003,
Page 247-252
Ann Daly,
Barry King,
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摘要:
&NA;There is wide interindividual variation in oral anticoagulant dose requirement, which is partly genetically determined. Several cytochrome P450s contribute to oxidative metabolism of oral anticoagulants. The most important of these is CYP2C9, which hydroxylates theS‐enantiomers of warfarin, acenocoumarol and phenprocoumon with high catalytic activity. In at least eight separate clinical studies, possession of theCYP2C9*2orCYP2C9*3variant alleles, which result in decreased enzyme activity, has been associated with a significant decrease in a mean warfarin dose requirement. Several studies also suggest that possession of a CYP2C9 variant allele is associated with an increased risk of adverse events, such as bleeding. Possession of theCYP2C9*3variant also appears to be associated with a low acenocoumarol dose requirement. Other genetic factors, such as polymorphisms in the cytochromes P450 that metabolize theR‐enantiomers of warfarin and acenocoumarol, may also be relevant to anticoagulant dose. The molecular basis of anticoagulant resistance where a higher than normal dose of anticoagulant is required remains unclear, but could be due to unusually high CYP2C9 activity (pharmacokinetic resistance) or to an abnormality in the target enzyme vitamin K epoxide reductase (pharmacodynamic resistance).
ISSN:0960-314X
出版商:OVID
年代:2003
数据来源: OVID
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3. |
Platelet receptor and clotting factor polymorphisms as genetic risk factors for thromboembolic complications in heparin‐induced thrombocytopenia |
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Pharmacogenetics,
Volume 13,
Issue 5,
2003,
Page 253-258
Lena Carlsson,
Norbert Lubenow,
Carmen Blumentritt,
Reiner Kempf,
Stephanie Papenberg,
Winnie Schröder,
Petra Eichler,
Falko Herrmann,
Sentot Santoso,
Andreas Greinacher,
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摘要:
&NA;Heparin‐induced thrombocytopenia (HIT) is an immune mediated adverse reaction to heparin treatment often associated with limb‐ and/or life‐threatening thromboembolic complications (TECs). Presently, no prognostic marker has been identified that allows differentiation between mildly (isolated thrombocytopenia) and severely (TECs) affected patients. This study assesses the impact of platelet glycoprotein‐ and clotting factor polymorphisms in HIT‐patients with isolated thrombocytopenia compared to HIT‐patients with TECs. Sixty‐three HIT‐patients with isolated thrombocytopenia and 79 HIT‐patients with HIT‐related TECs were genotyped for GPIIb‐IIIa polymorphisms (HPA‐1, HPA‐3), GPIa‐IIa polymorphisms (HPA‐5, GPIaC807T), GPIb‐IX‐V polymorphisms (HPA‐2, Kozak‐5, VNTR), and clotting factor polymorphisms (FV‐Leiden R506Q, prothrombin PT‐G20210A and MTHFR C677T). Women more often presented with TECs than men (P= 0.04). No differences in genotype frequencies could be seen on comparing HIT‐patients with and without TECs. Analysing men and women separately, the C allele of the Kozak polymorphism was overrepresented in men who developed TECs (P= 0.034). The enhanced risk of women to develop HIT‐associated TECs remains unexplained but it is potentially important in view of recent data on sex‐hormone related changes of haemostasis. There was no correlation between platelet glycoprotein‐ and clotting factor polymorphisms and the risk to develop HIT‐associated TECs. An association between the development of TECs and the Kozak‐5C allele could be seen among male patients. However, this would need to be assessed in further larger studies. Most likely, the high levels of thrombin generation during acute HIT are so procoagulant that less pronounced risk factors such as polymorphisms are overshadowed.
ISSN:0960-314X
出版商:OVID
年代:2003
数据来源: OVID
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4. |
Polymorphism in the P‐glycoprotein drug transporter MDR1 genea possible link between environmental and genetic factors in Parkinson's disease |
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Pharmacogenetics,
Volume 13,
Issue 5,
2003,
Page 259-263
Marek Droździk,
Monika Białecka,
Katarzyna Myśliwiec,
Krystyna Honczarenko,
Jan Stankiewicz,
Zbigniew Sych,
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摘要:
&NA;P‐glycoprotein is a membrane protein encoded by theMDR1gene, which demonstrates functional polymorphism. It is present in endothelial cells of the blood‐brain barrier, thus limiting accumulation of its substrates in the central nervous system. Many epidemiological studies suggest an association between pesticides, which are substrates for P‐glycoprotein, and Parkinson's disease. It was hypothesized that polymorphism of theMDR1gene could modulate interindividual susceptibility for the disease in subjects exposed to pesticides. In a pilot case‐control study involving 107 Parkinson's disease patients (30 early onset and 77 late onset patients; 59 exposed to pesticides and 48 non‐exposed) and 103 controls, C3435T polymorphism of the gene was analysed. No statistically significant correlation betweenMDR1gene polymorphism and Parkinson's disease was found. The 3435TT genotype was noted more frequently, but not significantly, in patients with early onset compared to late onset disease (23.3% versus 10.4%, respectively). A significant association between patients with parkinsonism exposed to pesticides and C3435T polymorphism of theMDR1gene was found. Comparing the exposed and non‐exposed patients, a statistically higher frequency of heterozygous subjects was observed (72.9% versus 47.9%, respectively). This genotype was associated with a significant, almost three‐fold increased risk of disease. Similarly, a higher frequency of 3435TT subjects was revealed in exposed subjects (15.5%) compared to non‐exposed patients (12.5%). In exposed versus non‐exposed subjects, patients carrying at least one 3435T allele (i.e. homozygous and heterozygous) had a significant, five‐fold higher risk of Parkinson's disease. Thus, it appears that mutation of the MDR1 gene predisposes to damaging effects of pesticides, and possibly other toxic xenobiotics transported by P‐glycoprotein, leading to Parkinson's disease.
ISSN:0960-314X
出版商:OVID
年代:2003
数据来源: OVID
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5. |
Frequency of butyrylcholinesterase gene mutations in individuals with abnormal inhibition numbersan Italianpopulation study |
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Pharmacogenetics,
Volume 13,
Issue 5,
2003,
Page 265-270
Giuliana Lando,
Andrea Mosca,
Roberto Bonora,
Franco Azzario,
Silvana Penco,
Alessandro Marocchi,
Mauro Panteghini,
Maria Patrosso,
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摘要:
ObjectivesMore than 30 genetic variants of serum cholinesterase (butyrylcholinesterase, BChE) have been described. Some of them (the atypical and the fluorideresistant variants) are well known because carriers are prone to develop prolonged apnea following the administration of the muscle relaxant succinylcholine. Genotype characterization is therefore important in order to prevent such episodes. Genetic studies have so far focused on selected individuals or families rather than on the random population.MethodsFrom a large group of healthy blood donors (n=2609), we selected all the 58 individuals with low serum cholinesterase activity: among them 28 subjects had abnormal dibucaine and fluoride inhibition numbers. Twenty‐five mutations in the coding region of the human cholinesterase gene were analyzed.ResultsAll individuals with abnormal inhibition numbers were homozygotes or double heterozygotes in several mutations. Asp70Gly (Atypical variant) and Ala539Thr (K variant) were the most frequently observed amino acid substitutions. The majority of subjects with low BChE activity but normal dibucaine and fluoride number presented only the K form. We analyzed 106 randomly chosen subjects for K and atypical variants. Carriers of these alleles were at risk of low BChE activity (OR = 9.55, 95%CI, 5.61‐16.26 and OR = 30.33, 95%CI, 7.05‐130.52 respectively).ConclusionsData obtained from this study help to better define the etiology of low BChE activity and the role of the rather common K allele. It is the first time that such a large population has been screened for so many mutations. BChE is also implicated in detoxifying cocaine; therefore genetic analysis could be useful in cases of cocaine toxicity in Italian subjects.
ISSN:0960-314X
出版商:OVID
年代:2003
数据来源: OVID
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6. |
A microsatellite repeat in the promoter of the N‐methyl‐D‐aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia |
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Pharmacogenetics,
Volume 13,
Issue 5,
2003,
Page 271-278
Masanari Itokawa,
Kazuo Yamada,
Kiyoshi Yoshitsugu,
Tomoko Toyota,
Toshiro Suga,
Hisako Ohba,
Akiko Watanabe,
Eiji Hattori,
Hiromitsu Shimizu,
Tetsuo Kumakura,
Mitsuru Ebihara,
Joanne Meerabux,
Michio Toru,
Takeo Yoshikawa,
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摘要:
&NA;Hypofunction of theN‐methyl‐D‐aspartate (NMDA) receptor has been hypothesized to underlie the pathophysiology of schizophrenia, based on the observation that non‐competitive antagonists of the NMDA receptor, such as phencyclidine, induce schizophrenia‐like symptoms. Mice lacking the NR2A subunit of the NMDA receptor complex are known to display abnormal behaviour, similar to schizophrenic symptoms. The expression of NR2A starts at puberty, a period corresponding to the clinical onset of schizophrenia. This evidence suggests that the NR2A (GRIN2A) gene may play a role in the development of schizophrenia and disease phenotypes. In this study, we performed a genetic analysis of this gene in schizophrenia. Analysis of theGRIN2Agene detected four single nucleotide polymorphisms, and a variable (GT)nrepeat in the promoter region of the gene. A case‐control study (375 schizophrenics and 378 controls) demonstrated evidence of an association between the repeat polymorphism and the disease (P= 0.05, Mann‐Whitney test), with longer alleles overly represented in patients. An in‐vitro promoter assay revealed a length dependent inhibition of transcriptional activity by the (GT)nrepeat, which was consistent with a receptor binding assay in postmortem brains. Significantly, the score of symptom severity in chronic patients correlated with repeat size (P= 0.01, Spearman's Rank test). These results illustrate a genotype‐phenotype correlation in schizophrenia and suggest that the longer (GT)nstretch may act as a riskconferring factor that worsens chronic outcome by reducing GRIN2A levels in the brain.
ISSN:0960-314X
出版商:OVID
年代:2003
数据来源: OVID
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7. |
Role of theeNOSGlu298Asp variant on theGNB3825T allele dependent determination of &agr;‐adrenergic coronary constriction |
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Pharmacogenetics,
Volume 13,
Issue 5,
2003,
Page 279-284
Christoph Naber,
Dietrich Baumgart,
Gerd Heusch,
Winfried Siffert,
Olaf Oldenburg,
Johannes Huesing,
Raimund Erbel,
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摘要:
&NA;The 825T allele of a polymorphism atGNB3,encoding the G protein &bgr;3subunit, is associated with an enhanced coronary blood flow (CBF) reduction in response to &agr;2‐, but not to &agr;1‐adrenoceptor activation. Because the regulation of vascular tone by &agr;2‐adrenoceptors includes direct vasoconstriction as well as vasodilatation by endothelial release of nitric oxide, the eNOS Glu298Asp variant might further contribute to explain the variability of CBF reduction in response to &agr;‐adrenoceptor activation. Genotyping at theGNB3and theeNOSgene was performed on 48 individuals receiving either the &agr;1‐adrenoceptor agonist methoxamine (5 mg i.c.) and/or the &agr;2‐adrenoceptor agonist BHT 933 (5 mg i.c.). CBF was calculated from quantitative coronary angiography and intracoronary Doppler flow velocity measurement. To analyse the impact of genotypes and coronary artery disease, a linear regression model was used, including cholesterol levels, heart rate, smoking and mean aortic blood pressure. An initial, univariate analysis suggested an impact of theeNOSGlu298Asp variant on &agr;2‐adrenoceptor‐induced coronary constriction (CBF reduction 53.4 ch006 .1 TT/TG versus 30.7 ch006 .9% GG;P= 0.003). However, multifactorial analysis showed that the GNB3825T allele was associated exclusively with the CBF reduction on &agr;2‐adrenoceptor activation (58.2 ± 4.4% TT/TC versus 27.9 ± 4.3% CC;P< 0.0001). Contrary to the initial analysis, the Glu298Asp variant of theeNOSgene provides no additional information on the genetic basis of &agr;2‐adrenoceptor‐induced coronary vasoconstriction, which appears exclusively associated to the 825T allele atGNB3.Analysis of modifying genes appears crucial for the understanding of genetic associations.
ISSN:0960-314X
出版商:OVID
年代:2003
数据来源: OVID
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8. |
NAT2 slow acetylator function as a risk indicator for agerelated cataract formation |
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Pharmacogenetics,
Volume 13,
Issue 5,
2003,
Page 285-289
David Meyer,
Donald Parkin,
Heine Seifart,
J. Maritz,
Albertus Engelbrecht,
Cedric Werely,
Paul van Helden,
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摘要:
ObjectivesTo show that the slow arylamineN‐acetyltransferase type 2 (NAT2) catalysed acetylator function is associated with the development of age‐related cataracts.MethodsBoth the acetylator phenotype and genotype of 139 patients with age‐related cataracts were determined, and the distribution of the acetylator subtypes in the cased population was compared with the distribution in the general (control) population. The genotype was determined by restriction‐enzyme analysis of DNA, and the phenotype was determined using the elimination characteristics of isoniazid as discriminant.ResultsThe frequency of alleles coding for slow acetylator characteristics was higher in the patients than in the controls, and the difference was significant (P = 0.013).ConclusionsSlow acetylators are at higher risk of developing age‐related cataracts than fast acetylators and we suggest that exogenous factors, which can be detoxified by acetylation, are aetiological agents for cataract formation. Identification of and avoidance of such (environmental) agents should reduce the incidence of age‐related cataracts.
ISSN:0960-314X
出版商:OVID
年代:2003
数据来源: OVID
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9. |
Novel paraoxonase (PON1) nonsense and missense mutations predicted by functional genomic assay of PON1 status |
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Pharmacogenetics,
Volume 13,
Issue 5,
2003,
Page 291-295
Gail Jarvik,
Rachel Jampsa,
Rebecca Richter,
Chris Carlson,
Mark Rieder,
Deborah Nickerson,
Clement Furlong,
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摘要:
&NA;Paraoxonase (PON1) has been termed an environmental response enzyme for its function in the detoxification of organophosphate pesticides, nerve agents and pharmaceuticals such as glucocorticoids and statins, as well as its cardioprotective role in breaking down oxidized LDL.PON1192genotype can be predicted with high accuracy from an examination of the two‐dimensional plot of paraoxon and diazoxon hydrolysis rates [1]. Individuals for whom this functional genomic assay failed to predictPON1192genotype, or who had a low PON activity relative to others with the same genotype, were predicted to have genetic alterations that explained the inconsistency. Sequencing of the PON1 region of 23 Caucasian individuals detected a nonsense mutation changing amino acid 194 from a Trp to a stop codon (PON1Trp194stop). It was predicted that subjects who genotyped asPON1192QRbut phenotyped asPON1192QQorPON1192RRmight carry the protein truncation mutation for which the defective product failed to be detected by the phenotyping assay. Screening of the five discordant subjects resulted in the detection of a single Caucasian carrying the stop codon, and determined its phasing on thePON1192Rallele. Sequencing confirmed the change and revealed an additional subject with a likely deletion of the 5′ end of thePON1gene.Additional sequencing of 25 subjects with low PON1 activities identified two additional previously undescribedPON1mutations, which may affect PON1 function:PON1Pro90Leuassociated with thePON1192Qallele andPON1Asp124misspliceassociated with thePON1192Rallele.
ISSN:0960-314X
出版商:OVID
年代:2003
数据来源: OVID
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10. |
Functional characterization in yeast of genetic variants in the human equilibrative nucleoside transporter, ENT1 |
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Pharmacogenetics,
Volume 13,
Issue 5,
2003,
Page 297-301
Douglas Osato,
Conrad Huang,
Michiko Kawamoto,
Susan Johns,
Doug Stryke,
Joanne Wang,
Thomas Ferrin,
Ira Herskowitz,
Kathleen Giacomini,
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摘要:
&NA;The human equilibrative nucleoside transporter, ENT1, appears to play a critical role in the disposition of nucleosides and nucleoside analogs used clinically as anti‐viral and anti‐cancer drugs. Recently, we identified variants ofENT1in an ethnically diverse DNA sample set from 247 individuals, focusing primarily on the coding region. The goal of the present study was to analyse the haplotype structure and functionally characterize the variants of ENT1. We observed that a single haplotype,ENT1*1,accounted for 91.3% of the 494 chromosomes. Functional analysis inSaccharomyces cerevisiaerevealed no differences in the kinetics of uptake of nucleosides and nucleoside analogs by the two non‐synonymous variant transporters, ENT1‐I216T and ENT1‐E391K, and the reference ENT1. These results, together with the observation that there are few haplotypes of ENT1, indicate that coding region variants of ENT1 do not contribute to inter‐individual differences in response to nucleoside analog drugs. Pharmacogenetics
ISSN:0960-314X
出版商:OVID
年代:2003
数据来源: OVID
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