C Coutelle

Imperial College London, Londinium, England, United Kingdom

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Publications (138)471.37 Total impact

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    ABSTRACT: Fetal gene therapy has the potential to treat inherited genetic diseases in utero before significant organ damage has occurred. Rapidly expanding stem cell populations may be targeted and the introduction of transgenes to the fetus during development of the immune system could result in immune tolerance and facilitate repeat treatment postnatally. Genetic diseases such as cystic fibrosis, which are life-threatening and for which there are no currently acceptable treatments available, are suggested targets for this therapy. Ultrasound may be a safe method of delivering a therapeutic gene into the fetus, although most studies have used more invasive techniques, even in large animal models. Viral vectors currently offer the most potential. Adenovirus-based vectors are stable, independent of host cell replication, efficient at tissue infection and have been used as a ‘pathfinder’ to test routes of administration. Unfortunately, they are also highly immunogenic and other systems based on retrovirus or adeno-associated virus may offer advantages because of their lower immunogenicity and potential for permanent transgene expression. Our group is developing the fetal sheep model for the investigation of ultrasound-guided gene therapy in utero. This model is suitable since the sheep fetus is tolerant to manipulations, has a consistent gestation period and shows many similarities with human pregnancy. We have demonstrated significant transfection of the fetal liver and adrenal cortex after ultrasound-guided percutaneous injection of the umbilical vein with adenoviral vectors in the late gestation sheep. We are investigating and here discuss alternative routes of administration to target the fetus in early gestation via ultrasound-guided minimally invasive techniques.
    The Ultrasound Review of Obstetrics & Gynecology 12/2011; 1(1). DOI:10.1080/14722240108500417
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    ABSTRACT: The ideal gene therapy vector should enable persistent expression without the limitations of safety and reproducibility. We previously reported that a prototype plasmid vector, containing a scaffold matrix attachment region (S/MAR) domain and the luciferase reporter gene, showed transgene expression for at least 6 months following a single administration to MF1 mice. Following partial hepatectomy of the animals, however, we found no detectable vector replication and subsequent propagation in vivo. To overcome this drawback, we have now developed an in vivo liver selection strategy by which liver cells transfected with an S/MAR plasmid are provided with a survival advantage over non-transfected cells. This allows an enrichment of vectors that are capable of replicating and establishing themselves as extra-chromosomal entities in the liver. Accordingly, a novel S/MAR plasmid encoding the Bcl-2 gene was constructed; Bcl-2 expression confers resistance against apoptosis-mediated challenges by the Fas-activating antibody Jo2. Following hydrodynamic delivery to the livers of mice and frequent Jo2 administrations, we demonstrate that this Bcl-luciferase S/MAR plasmid is indeed capable of providing sustained luciferase reporter gene expression for over 3 months and that this plasmid replicates as an episomal entity in vivo. These results provide proof-of-principle that S/MAR vectors are capable of preventing transgene silencing, are resistant to integration and are able to confer mitotic stability in vivo when provided with a selective advantage.
    Gene therapy 01/2011; 18(1):82-7. DOI:10.1038/gt.2010.116 · 4.20 Impact Factor
  • Cytogenetic and Genome Research 01/2010; 58(3-4):1550-1589. DOI:10.1159/000317224 · 1.91 Impact Factor
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    ABSTRACT: Fetal gene therapy for cystic fibrosis may have advantages over adult treatment. We aimed (1) to develop a percutaneous ultrasound guided technique to inject adenoviral vectors into the fetal sheep trachea and (2) to improve transgene expression with transduction enhancing agents. Adenoviral vectors containing the β-galactosidase gene (2.0×1011–8.3×1011 particles/kg) and transduction enhancing agents were delivered to the trachea via a needle inserted through the thorax of late (n = 3) or mid gestation (n = 15) fetal sheep using ultrasound guidance. Tissues were analysed 48 hours after injection (n = 17) or 12 hours after birth (n = 1) for transgene expression. Transthoracic injection of the trachea was successful in 16 fetuses with 100% survival. Expression of β-galactosidase, as measured by ELISA, was low after delivery of adenoviral vector alone, but increased 10-fold when the vector was complexed with the polycation DEAE dextran. Pretreatment of the fetal airways with sodium caprate, which opens tight junctions to reach the basolateral surface of lung epithelia, resulted in a 90-fold increase in expression. A synergistic effect of the two agents resulted in widespread staining of the trachea, main bronchi and all airways, confirmed by immunohistochemistry for β-galactosidase. Instillation of perflubron following sodium caprate and vector/DEAE dextran complex injection increased transduction of the peripheral small airways at the expense of tracheal and large airways transduction.
    Journal of Obstetrics and Gynaecology 07/2009; 23(s1). DOI:10.1080/718591787 · 0.60 Impact Factor
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    ABSTRACT: An ideal gene therapy vector should enable persistent transgene expression without limitations of safety and reproducibility. Here we report the development of a non-viral episomal plasmid DNA (pDNA) vector that appears to fulfil these criteria. This pDNA vector combines a scaffold/matrix attachment region (S/MAR) with a human liver-specific promoter (alpha1-antitrypsin (AAT)) in such a way that long-term expression is enabled in murine liver following hydrodynamic injection. Long-term expression is demonstrated by monitoring the longitudinal luciferase expression profile for up to 6 months by means of in situ bioluminescent imaging. All relevant control pDNA constructs expressing luciferase are unable to sustain significant transgene expression beyond 1 week post-administration. We establish that this shutdown of expression is due to promoter methylation. In contrast, the S/MAR element appears to inhibit methylation of the AAT promoter thereby preventing transgene silencing. Although this vector appears to be maintained as an episome throughout, we have no evidence for its establishment as a replicating entity. We conclude that the combination of a mammalian, tissue-specific promoter with the S/MAR element is sufficient to drive long-term episomal pDNA expression of genes in vivo.
    Gene therapy 12/2008; 15(24):1593-605. DOI:10.1038/gt.2008.113 · 4.20 Impact Factor
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    ABSTRACT: Due to its early onset and severe prognosis, cystic fibrosis (CF) has been suggested as a candidate disease for in utero gene therapy. In 1997, a study was published claiming that to how transient prenatal expression of CF transmembrane conductance regulator (CFTR) from an in utero-injected adenovirus vector could achieve permanent reversal of the CF intestinal pathology in adult CF knockout mice, despite the loss of CFTR transgene expression by birth. This would imply that the underlying cause of CF is a prenatal defect for which lifelong cure can be achieved by transient prenatal expression of CFTR. Despite criticism at the time of publication, no independent verification of this contentious finding has been published so far. This is vital for the development of future therapeutic strategies as it may determine whether CF gene therapy should be performed prenatally or postnatally. We therefore reinvestigated this finding with an identical adenoviral vector and a knockout CF mouse line (Cftr(tmlCam)) with a completely inbred genetic background to eliminate any effects due to genetic variation. After delivery of the CFTR-expressing adenovirus to the fetal mouse, both vector DNA and transgenic CFTR expression were detected in treated animals postpartum but statistically no significant difference in survival was observed between the Cftr(-/-) mice treated with the CFTR-adenovirus and those treated with the control vector.
    Molecular Therapy 06/2008; 16(5):819-24. DOI:10.1038/mt.2008.26 · 6.43 Impact Factor
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    ABSTRACT: Gene transfer for cystic fibrosis (CF) airway disease has been hampered by the lung's innate refractivity to pathogen infection. We hypothesized that early intervention with an integrating gene transfer vector capable of transducing the lung via the lumen may be a successful therapeutic approach. An HIV-based lentiviral vector pseudotyped with the baculovirus gp64 envelope was applied to the fetal, neonatal or adult airways. Fetal intra-amniotic administration resulted in transduction of approximately 14% of airway epithelial cells, including both ciliated and non-ciliated epithelia of the upper, mid and lower airways; there was negligible alveolar or nasal transduction. Following neonatal intra-nasal administration we observed significant transduction of the airway epithelium (approximately 11%), although mainly in the distal lung, and substantial alveolar transduction. This expression was still detectable at 1 year after application. In the adult, the majority of transduction was restricted to the alveoli. In contrast, vesicular stomatitis virus glycoprotein pseudotyped virus transduced only alveoli after adult and neonatal application and no transduction was observed after fetal administration. Repeat administration did not increase transduction levels of the conducting airway epithelia. These data demonstrate that application at early developmental stages in conjunction with an appropriately pseudotyped virus provides efficient, high-level transgene expression in the murine lung. This may provide a modality for treatment for lung disease in CF.
    Gene therapy 05/2008; 15(16):1167-75. DOI:10.1038/gt.2008.74 · 4.20 Impact Factor
  • Annals of the New York Academy of Sciences 12/2006; 343(1):111 - 132. DOI:10.1111/j.1749-6632.1980.tb47246.x · 4.31 Impact Factor
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    ABSTRACT: Targeting gene therapy vectors to the fetal intestinal tract could provide a novel means toward prevention of the early postnatal intestinal pathology of cystic fibrosis and other conditions, such as congenital enteropathy, that cause intestinal failure. Among these conditions, cystic fibrosis is by far the most common lethal genetic disease. It is caused by a functional absence or deficiency of the cystic fibrosis transmembrane conductance regulator and manifests in the gut as meconium ileus. Prenatal treatment of genetic disease may avoid early-onset tissue damage and immune sensitization, and may target cells that are less accessible in the adult. We investigated gene transfer to the fetal gut, using a minimally invasive injection technique. First-generation replication-deficient adenoviral vectors encoding the beta-galactosidase gene and transduction-enhancing agents were injected into the stomach of early-gestation fetal sheep (n = 8, 60 days of gestation; term, 145 days) under ultrasound guidance. Reporter gene expression was observed 2 days after injection in the villi of the gastrointestinal epithelia after 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining and beta-galactosidase immunohistochemistry of fetal tissues. Expression of beta-galactosidase, as measured by enzyme-linked immunosorbent assay, was enhanced after pretreatment of the fetal gut with sodium caprate, which opens tight junctions, and after adenovirus complexation with DEAE-dextran, which confers a positive charge to the virus. Instillation of the fluorocarbon perflubron after virus delivery resulted in tissue transduction from the fetal stomach to the colon. Using a clinically relevant technique, we have demonstrated widespread gene transfer to the fetal gastrointestinal epithelia.
    Human Gene Therapy 08/2006; 17(7):767-79. DOI:10.1089/hum.2006.17.767 · 3.62 Impact Factor
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    ABSTRACT: To access the fetal sheep trachea by ultrasound-guided transthoracic injection in order to deliver gene therapy vectors or occlude the trachea with a detachable balloon. Fetal sheep were operated on at a mean gestational age of 102 (range, 81-116) days (term = 145 days). Under ultrasound guidance, either a 20-G spinal (for vector delivery) or a 16-G Kellett (for placement of an occlusive balloon) needle was inserted via the fetal thorax into the fetal trachea. Using the 20-G spinal needle the trachea was accessed successfully in 33/36 fetuses, with 97% survival. Failure to inject was related to fetal position and gestational age. Blood vessel damage causing significant morbidity occurred in two fetuses (6%). Tracheal occlusion was achieved by puncturing the trachea with the 16-G needle and advancing an endoluminal balloon in three out of five attempts in a mean time of 17 (range, 16-19) min, with 100% survival. In one case, the balloon became sited within the accessory lobe bronchus and was not inflated. At postmortem examination 21 days later, all balloons remained inflated and occluded the trachea, and the lung-to-body weight ratio and airways morphometric indices were consistent with relative pulmonary hyperplasia in the obstructed lungs. Ultrasound-guided transthoracic tracheal puncture is a reliable technique in fetal sheep, with low morbidity and mortality. Using this technique, a detachable endotracheal balloon can be placed to provoke pulmonary growth. Advances in needle design and balloon size may improve the success rate.
    Ultrasound in Obstetrics and Gynecology 07/2006; 28(1):82-8. DOI:10.1002/uog.2815 · 3.14 Impact Factor
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    ABSTRACT: Immune responses against an introduced transgenic protein are a potential risk in many gene replacement strategies to treat genetic disease. We have developed a gene delivery approach for hemophilia B based on lentiviral expression of human factor IX in purified hematopoietic stem cells. In both normal C57Bl/6J and hemophilic 129/Sv recipient mice, we observed the production of therapeutic levels of human factor IX, persisting for at least a year with tolerance to human factor IX antigen. Secondary and tertiary recipients also demonstrate long-term production of therapeutic levels of human factor IX and tolerance, even at very low levels of donor chimerism. Furthermore, in hemophilic mice, partial functional correction of treated mice and phenotypic rescue is achieved. These data show the potential of a stem cell approach to gene delivery to tolerize recipients to a secreted foreign transgenic protein and, with appropriate modification, may be of use in developing treatments for other genetic disorders.
    Gene Therapy 02/2006; 13(2):117-26. DOI:10.1038/sj.gt.3302638 · 4.20 Impact Factor
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    ABSTRACT: Somatic gene delivery in utero is a novel approach to gene therapy for genetic disease based on the hypothesis that prenatal intervention may avoid the development of severe manifestations of early-onset disease, allow targeting of otherwise inaccessible tissues including expanding stem cell populations, induce tolerance against the therapeutic transgenic protein and thereby provide permanent somatic gene correction. This approach is particularly relevant in relation to prenatal screening programmes for severe genetic diseases as it could offer prevention as a third option to families faced with the prenatal diagnosis of a genetically affected child. Most investigations towards in utero gene therapy have been performed on mice and sheep fetuses as model animals for human disease and for the application of clinically relevant intervention techniques such as vector delivery by minimally invasive ultrasound guidance. Other animals such as dogs may serve as particular disease models and primates have to be considered in immediate preparation for clinical trials. Proof of principle for the hypothesis of fetal gene therapy has been provided during the last 2 years in mouse models for Crigler Najjar Disease, Leber's congenital amaurosis, Pompe's disease and haemophilia B showing long-term postnatal therapeutic effects and tolerance of the transgenic protein after in utero gene delivery. However, recently we have also observed a high incidence of liver tumours after in utero application of an early form of third-generation equine infectious anaemia virus vectors with SIN configuration. These findings highlight the need for more investigations into the safety and the ethical aspects of in utero gene therapy as well as for science-based public information on risks and benefits of this preventive gene therapy approach before application in humans can be contemplated.
    Gene Therapy 12/2005; 12(22):1601-7. DOI:10.1038/sj.gt.3302632 · 4.20 Impact Factor
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    ABSTRACT: Intra-amniotic injection of adenovirus allows transduction of the fetal airways following natural fetal breathing movements. This administration method is promising for use in gene therapy for cystic fibrosis and other diseases for which the main target for exogenous gene expression is the lung. Here we have investigated factors that may affect the efficacy of gene transfer to the murine fetal lung. We examined marker compound distribution and transgene expression (from a first-generation adenoviral vector) at different stages of development. This demonstrated that fetal breathing movements at 15-16 days of gestation are of sufficient intensity to carry marker/vector into the fetal lungs. These movements can be significantly stimulated by the combination of intra-amniotic theophylline administration and postoperative exposure of the dam to elevated CO(2) levels. However, the most important factor for efficient and consistent pulmonary transgene delivery is the dose of adenoviral vector used, as both the degree of transduction and the percentage of lungs transduced increases with escalating viral dose.
    Molecular Therapy 10/2005; 12(3):484-92. DOI:10.1016/j.ymthe.2005.02.020 · 6.43 Impact Factor
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    ABSTRACT: The current approaches to gene therapy of monogenetic diseases into mature organisms are confronted with several problems including the following: (1) the underlying genetic defect may have already caused irreversible pathological changes; (2) the level of sufficient protein expression to ameliorate or prevent the disease requires prohibitively large amounts of gene delivery vector; (3) adult tissues may be poorly infected by conventional vector systems dependent upon cellular proliferation for optimal infection, for example, oncoretrovirus vectors; (4) immune responses, either pre-existing or developing following vector delivery, may rapidly eliminate transgenic protein expression and prevent future effective intervention. Early gene transfer, in the neonatal or even fetal period, may overcome some or all of these obstacles. The mammalian fetus enjoys a uniquely protected environment in the womb, bathed in a biochemically and physically supportive fluid devoid of myriad extra-uterine pathogens. Strong physical and chemical barriers to infection might, perhaps, impede the frenetic cell division. The physical support and the biochemical support provided by the fetal-maternal placental interface may, therefore, minimize the onset of genetic diseases manifest early in life. The fetal organism must prepare itself for birth, but lacking a mature adaptive immune system may depend upon more primordial immune defences. It is the nature of these defences, and the vulnerabilities they protect, that are poorly understood in the context of gene therapy and might provide useful information for approaches to gene therapy in the young, as well as perhaps the mature organism.
    Gene Therapy 11/2004; 11 Suppl 1:S92-7. DOI:10.1038/sj.gt.3302375 · 4.20 Impact Factor
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    ABSTRACT: Chronic alcohol consumption is associated with an increased risk for breast cancer, even if consumed in moderate doses. Since acetaldehyde is a carcinogenic factor associated with chronic alcohol consumption, individuals with the alcohol dehydrogenase 1C*1 allele (ADH1C*1 allele) seem to be at particular risk, since this allele encodes for a rapidly ethanol metabolizing enzyme leading to increased acetaldehyde levels. Since recent epidemiological studies demonstrated an increased risk for breast cancer for individuals with the ADH1C*1 allele, we have investigated here ADH1C genotypes in moderate alcohol consumers. Furthermore, estradiols are also known risk factors for breast cancer and acute alcohol ingestion in high doses results in increased serum estradiol concentrations. Thus, in the present study, we tested the effect of low ethanol doses on estrogen serum concentrations. We analyzed the ADH1C genotype in 117 moderate alcohol consumers with breast cancer and in 111 age-matched women with alcohol associated diseases without cancer (74 cirrhotics, 22 patients with pancreatitis and 15 alcohol dependent patients). In addition, 107 healthy controls were studied. Genotyping of the ADH1C-locus was performed using polymerase chain reaction-based restriction fragment length polymorphism methods on leukocyte DNA. To study the effects of ethanol on estradiol levels, ethanol in a dose of 0.225 g/kg body weight was given orally to 8 premenopausal women at various time points of their menstrual cycle. Thereafter estradiol serum concentrations were measured over time. The allele frequency of the ADH1C*1 allele was found to be significantly increased in moderate alcohol consumers with breast cancer as compared to age-matched alcoholic controls without cancer (62% vs. 41.9%, p=0.0035). Women with the ADH1C*1,1 genotype were found to be 1.8 times more at risk for breast cancer than those with another genotype (95% CI 1.431-2.330, p<0.001). Oral ethanol increased serum estradiol levels significantly by 27-38%. The data demonstrate that moderate alcohol consumers with the ADH1C*1 allele have an increased risk to develop breast cancer and even small amounts of alcohol increase serum estradiol levels significantly in premenopausal women especially in the midphase of the menstrual cycle.
    International Journal of Oncology 11/2004; 25(4):1127-32. · 2.77 Impact Factor
  • Alcoholism Clinical and Experimental Research 08/2004; 28. DOI:10.1097/00000374-200408002-00045 · 3.31 Impact Factor
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    ABSTRACT: Gene therapy for Duchenne muscular dystrophy has so far not been successful because of the difficulty in achieving efficient and permanent gene transfer to the large number of affected muscles and the development of immune reactions against vector and transgenic protein. In addition, the prenatal onset of disease complicates postnatal gene therapy. We have therefore proposed a fetal approach to overcome these barriers. We have applied beta-galactosidase expressing equine infectious anaemia virus (EIAV) lentiviruses pseudotyped with VSV-G by single or combined injection via different routes to the MF1 mouse fetus on day 15 of gestation and describe substantial gene delivery to the musculature. Highly efficient gene transfer to skeletal muscles, including the diaphragm and intercostal muscles, as well as to cardiac myocytes was observed and gene expression persisted for at least 15 months after administration of this integrating vector. These findings support the concept of in utero gene delivery for therapeutic and long-term prevention/correction of muscular dystrophies and pave the way for a future application in the clinic.
    Gene Therapy 08/2004; 11(14):1117-25. DOI:10.1038/sj.gt.3302268 · 4.20 Impact Factor
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    ABSTRACT: Current concerns over insertional mutagenesis by retroviral vectors mitigate investigations into alternative, potentially persistent gene therapy vector systems not dependent on genomic integration, such as Sendai virus vectors (SeVV). Prenatal gene therapy requires efficient gene delivery to several tissues, which may not be achievable by somatic gene transfer to the adult. Initially, to test the potential and tropism of the SeVV for gene delivery to fetal tissues, first-generation (replication- and propagation-competent) recombinant SeVV, expressing beta-galactosidase was introduced into late gestation immunocompetent mice via the amniotic and peritoneal cavities and the yolk sac vessels. At 2 days, this resulted in very high levels of expression particularly in the airway epithelium, mesothelium and vascular endothelium, respectively. However, as expected, substantial vector toxicity was observed. The efficiency of gene transfer and the level of gene expression were then examined using a second-generation SeVV. The second generation was developed to be still capable of cytoplasmic RNA replication and therefore high-level gene expression, but incapable of vector spread due to lack of the gene for viral F-protein. Vector was introduced into the fetal amniotic and peritoneal cavities, intravascularly, intramuscularly and intraspinally; at 2 days, expression was observed in the airway epithelia, peritoneal mesothelia, unidentified cells in the gut wall, locally at the site of muscle injection and in the dorsal root ganglia, respectively. Mortality was dramatically diminished compared with the first-generation vector.
    Gene Therapy 05/2004; 11(7):599-608. DOI:10.1038/sj.gt.3302205 · 4.20 Impact Factor
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    ABSTRACT: Cystic fibrosis is a common lethal genetic disease caused by functional absence of the cystic fibrosis transmembrane conductance regulator (CFTR). Although a candidate disease for in utero gene therapy, demonstration of potentially therapeutic levels of transgene expression in the fetal airways after minimally invasive gene delivery is a mandatory prerequisite before application of this approach in humans can be considered. We report here on the delivery of a beta-galactosidase expressing adenovirus directly to the airways of fetal sheep in utero using ultrasound-guided percutaneous injection of the trachea in the fetal chest. Injection of adenoviral particles to the fetal airways was not associated with mortality and resulted in low-level expression in the peripheral airways. However, complexation of the virus with DEAE dextran, which confers a positive charge to the virus, and pretreatment of the airways with Na-caprate, which opens tight junctions, increased transgene expression, and a combination of these two enhancers resulted in widespread and efficient gene transfer of the fetal trachea and bronchial tree. Using a percutaneous ultrasound-guided injection technique, we have clearly demonstrated proof of principle for substantial transgene delivery to the fetal airways providing levels of gene expression that could be relevant for a therapeutic application of CFTR expressing vectors.
    Gene Therapy 02/2004; 11(1):70-8. DOI:10.1038/sj.gt.3302130 · 4.20 Impact Factor
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    ABSTRACT: The objectives were to study the association between metabolic genes involved in alcohol metabolism (CYP2E1 RsaI, CYP2E1 DraI, ADH1C, NQO1) and alcohol consumption in a large sample of healthy controls. Healthy subjects were selected from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). Subjects with information on both alcohol consumption and at least one of the studied polymorphisms were included in the analysis (n=2224). Information on the amount of alcohol consumption was available for a subset of subjects (n=844). None of the studied genes was significantly associated with drinking habits. A significant heterogeneity with age was observed when studying the association between CYP2E1 RsaI and alcohol drinking. CYP2E1 RsaI polymorphism was significantly associated with being a never drinker at older ages (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.2-4.8; at ages above 68 years), while the association was reversed at ages below 47 years (OR 0.5, 95% CI 0.2-1.4). For subjects with detailed information on alcohol intake, no association between alcohol quantity and polymorphisms in metabolic genes was observed; subjects carrying the NQO1 polymorphism tended to drink more than subjects carrying the wild-type alleles. Therefore, no significant association between CYP2E1 RsaI, CYP2E1 DraI, ADH1C, NQO1 polymorphisms and alcohol consumption was observed in healthy controls.
    Biomarkers 01/2004; 9(2):180-9. DOI:10.1080/13547500410001728381 · 2.52 Impact Factor

Publication Stats

3k Citations
471.37 Total Impact Points


  • 1993–2009
    • Imperial College London
      • • Molecular Medicine
      • • Section of Molecular Genetics & Genomics
      • • Division of Cell and Molecular Biology
      Londinium, England, United Kingdom
  • 1998–2004
    • Université Victor Segalen Bordeaux 2
      Burdeos, Aquitaine, France
  • 1991–2004
    • University of Bordeaux
      Burdeos, Aquitaine, France
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1996
    • St. Mary’s Hospital for Children
      New York City, New York, United States
  • 1994–1995
    • Imperial College Healthcare NHS Trust
      Londinium, England, United Kingdom
  • 1992–1994
    • Max-Delbrück-Centrum für Molekulare Medizin
      Berlín, Berlin, Germany
  • 1981–1991
    • Institute of Molecular Biology
      Mayence, Rheinland-Pfalz, Germany
  • 1988
    • Deen Dayal Rustagi College
      Khandela, Rajasthan, India
  • 1974
    • Humboldt State University
      ACV, California, United States
  • 1971
    • Институт молекулярной биологии им. В.А. Энгельгардта Российской академии наук
      Moskva, Moscow, Russia