ABSTRACT
In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.
Subject(s)
Chemical and Drug Induced Liver Injury , Drug-Related Side Effects and Adverse Reactions , Humans , Europe , Forecasting , Databases, FactualABSTRACT
This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.
Subject(s)
Alleles , Genetic Testing/standards , Pharmacogenetics/standards , Terminology as Topic , Genes , Genetic Testing/trends , Genetic Variation , Humans , Pharmacogenetics/trends , Precision MedicineSubject(s)
Genetic Testing/statistics & numerical data , Practice Patterns, Physicians' , Female , Humans , MaleABSTRACT
Observational studies have overwhelmingly shown that variants in the genes CYP2C9 and VKORC1 are significant determinants of individual dose of coumarin anticoagulants needed to maintain a therapeutic international normalized ratio (INR).(1) Until recently, however, few randomized clinical trials had been performed relating to the use of genetic data to predict dosing. Three sucsh clinical trials have now reported their findings.
Subject(s)
Acenocoumarol/administration & dosage , Acenocoumarol/pharmacokinetics , Algorithms , Anticoagulants/administration & dosage , Anticoagulants/pharmacokinetics , Aryl Hydrocarbon Hydroxylases/genetics , Blood Coagulation/drug effects , Genotype , Mixed Function Oxygenases/genetics , Phenprocoumon/administration & dosage , Vitamin K Epoxide Reductases/genetics , Warfarin/administration & dosage , Female , Humans , MaleABSTRACT
BACKGROUND & AIMS: Subtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD. METHODS: PNPLA3 rs738409 genotype was determined by allelic discrimination in 100 European Caucasians with NAFLD-related HCC and 275 controls with histologically characterised NAFLD. RESULTS: Genotype frequencies were significantly different between NAFLD-HCC cases (CC=28, CG=43, GG=29) and NAFLD-controls (CC=125, CG=117, GG=33) (p=0.0001). In multivariate analysis adjusted for age, gender, diabetes, BMI, and presence of cirrhosis, carriage of each copy of the rs738409 minor (G) allele conferred an additive risk for HCC (adjusted OR 2.26 [95% CI 1.23-4.14], p=0.0082), with GG homozygotes exhibiting a 5-fold [1.47-17.29], p=0.01 increased risk over CC. When compared to the UK general population (1958 British Birth Cohort, n=1476), the risk-effect was more pronounced (GC vs. CC: unadjusted OR 2.52 [1.55-4.10], p=0.0002; GG vs. CC: OR 12.19 [6.89-21.58], p<0.0001). CONCLUSIONS: Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis but also of HCC. If validated, these findings suggest that PNPLA3 genotyping has the potential to contribute to multi-factorial patient-risk stratification, identifying those to whom HCC surveillance may be targeted.
Subject(s)
Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/genetics , Lipase/genetics , Liver Neoplasms/etiology , Liver Neoplasms/genetics , Membrane Proteins/genetics , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Case-Control Studies , Cohort Studies , Disease Progression , Female , Gene Frequency , Genetic Association Studies , Homozygote , Humans , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/pathology , Risk Factors , White People/geneticsABSTRACT
Pharmacogenetics/pharmacogenomics has been subject to considerable development during the past 10 years and seems likely to advance even more rapidly in the next decade. Several surveys suggest that initial training for health-care professionals-particularly physicians and pharmacists-frequently includes education in this area, but equipping these professions more generally to deal with ongoing development of the field and to make best use of new knowledge remains an important challenge.
Subject(s)
Education, Medical/trends , Education, Pharmacy/trends , Pharmacogenetics/education , Antineoplastic Agents/therapeutic use , Curriculum , Neoplasms/drug therapy , Neoplasms/genetics , Schools, MedicalABSTRACT
Drug-induced liver injury (DILI) is the most frequent reason cited for the withdrawal of approved drugs from the market and accounts for up to 15% of the cases of acute liver failure. Investigators around the globe have begun to identify and study patients with DILI; several large registries and tissue banks are being established. In order to gain the maximum scientific benefit from these efforts, the definitions and terminology related to the clinical phenotypes of DILI must be harmonized. For this purpose, an international DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that would define and characterize the spectrum of clinical syndromes that constitute DILI. Consensus was established with respect to the threshold criteria for definition of a case as being DILI, the pattern of liver injury, causality assessment, severity, and chronicity. Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases, including autoimmune hepatitis (AIH).
Subject(s)
Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/genetics , Drug-Related Side Effects and Adverse Reactions , Pharmaceutical Preparations/standards , Phenotype , Alanine Transaminase/standards , Animals , Chemical and Drug Induced Liver Injury/enzymology , Diagnosis, Differential , Humans , Pharmaceutical Preparations/blood , Reference Standards , Terminology as TopicABSTRACT
Aim. To examine interaction between history of cancer in first-degree relatives and tobacco smoking in index patients of pancreatic adenocarcinoma. Methods. We carried out a case-control involving 113 patients with pancreatic adenocarcinoma and 110 controls over a 12-month period at the Freeman Hospital, Newcastle upon Tyne, UK. They were all administered a detailed tobacco exposure questionnaire and a family history questionnaire. We calculated cumulative tobacco exposure and risk for pancreas cancer. Results. Both smokers (OR 3.01 (95% CI: 1.73 to 5.24)) and those with a family history of malignancy (OR 1.98 (95% CI: 1.15-3.38)) were more likely to develop pancreatic cancer. Having more than one first-degree relative with cancer did not significantly further increase the risk of pancreatic cancer. Amongst pancreatic cancer cases, cumulative tobacco exposure was significantly decreased (P = .032) in the group of smokers (current and ex-smokers) who had a family history of malignancy [mean (SD): 30.00 (24.77) pack-years versus 44.69 (28.47) pack-years with no such history]. Conclusions. Individuals with a family history of malignancy are at an increased risk of pancreatic cancer. Furthermore, individuals with a family history of malignancy and who smoke appear to require a lesser degree of tobacco exposure for the development of pancreatic cancer.
ABSTRACT
BACKGROUND AND PURPOSE: Fenretinide (4-HPR) is a retinoic acid analogue, currently used in clinical trials in oncology. Metabolism of 4-HPR is of particular interest due to production of the active metabolite 4'-oxo 4-HPR and the clinical challenge of obtaining consistent 4-HPR plasma concentrations in patients. Here, we assessed the enzymes involved in various 4-HPR metabolic pathways. EXPERIMENTAL APPROACH: Enzymes involved in 4-HPR metabolism were characterized using human liver microsomes (HLM), supersomes over-expressing individual human cytochrome P450s (CYPs), uridine 5'-diphospho-glucoronosyl transferases (UGTs) and CYP2C8 variants expressed in Escherichia coli. Samples were analysed by high-performance liquid chromatography and liquid chromatography/mass spectrometry assays and kinetic parameters for metabolite formation determined. Incubations were also carried out with inhibitors of CYPs and methylation enzymes. KEY RESULTS: HLM were found to predominantly produce 4'-oxo 4-HPR, with an additional polar metabolite, 4'-hydroxy 4-HPR (4'-OH 4-HPR), produced by individual CYPs. CYPs 2C8, 3A4 and 3A5 were found to metabolize 4-HPR, with metabolite formation prevented by inhibitors of CYP3A4 and CYP2C8. Differences in metabolism to 4'-OH 4-HPR were observed with 2C8 variants, CYP2C8*4 exhibited a significantly lower V(max) value compared with *1. Conversely, a significantly higher V(max) value for CYP2C8*4 versus *1 was observed in terms of 4'-oxo formation. In terms of 4-HPR glucuronidation, UGTs 1A1, 1A3 and 1A6 produced the 4-HPR glucuronide metabolite. CONCLUSIONS AND IMPLICATIONS: The enzymes involved in 4-HPR metabolism have been characterized. The CYP2C8 isoform was found to have a significant effect on oxidative metabolism and may be of clinical relevance.
Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Fenretinide/metabolism , Glucuronosyltransferase/metabolism , Microsomes, Liver/metabolism , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Aryl Hydrocarbon Hydroxylases/genetics , Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 CYP2C8 , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors , Cytochrome P-450 Enzyme System/genetics , Enzyme Inhibitors/pharmacology , Fenretinide/analogs & derivatives , Glucuronides/metabolism , Glucuronosyltransferase/genetics , Humans , Intestinal Mucosa/metabolism , Intestines/drug effects , Kinetics , Microsomes/drug effects , Microsomes/metabolism , Microsomes, Liver/drug effects , Mutant Proteins/metabolism , Recombinant Proteins/metabolism , Tretinoin/analogs & derivatives , Tretinoin/metabolismABSTRACT
BACKGROUND/AIMS: The aim of this study was to assess the effect of functional ENPP1(ectoenzyme nucleotide pyrophosphate phosphodiesterase 1)/PC-1 (plasma cell antigen-1) and IRS-1 (insulin receptor substrate-1) polymorphisms influencing insulin receptor activity on liver damage in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, whose progression is associated with the severity of insulin resistance. PATIENTS AND METHODS: 702 patients with biopsy-proven NAFLD from Italy and the UK, and 310 healthy controls. The Lys121Gln ENPP1/PC-1 and the Gly972Arg IRS-1 polymorphisms were evaluated by restriction analysis. Fibrosis was evaluated according to Kleiner. Insulin signalling activity was evaluated by measuring phosphoAKT levels by western blotting in a subset of obese non-diabetic patients. RESULTS: The ENPP1 121Gln and IRS-1 972Arg polymorphisms were detected in 28.7% and 18.1% of patients and associated with increased body weight/dyslipidaemia and diabetes risk, respectively. The ENPP1 121Gln allele was significantly associated with increased prevalence of fibrosis stage >1 and >2, which was higher in subjects also positive for the 972Arg IRS-1 polymorphism. At multivariate analysis, the presence of the ENPP1 121Gln and IRS-1 972Arg polymorphisms was independently associated with fibrosis >1 (OR 1.55, 95% CI 1.24 to 1.97; and OR 1.57, 95% CI 1.12 to 2.23, respectively). Both polymorphisms were associated with a marked reduction of approximately 70% of AKT activation status, reflecting insulin resistance and disease severity, in obese patients with NAFLD. CONCLUSIONS: The ENPP1 121Gln and IRS-1 972Arg polymorphisms affecting insulin receptor activity predispose to liver damage and decrease hepatic insulin signalling in patients with NAFLD. Defective insulin signalling may play a causal role in the progression of liver damage in NAFLD.
Subject(s)
Fatty Liver/genetics , Insulin Receptor Substrate Proteins/genetics , Phosphoric Diester Hydrolases/genetics , Pyrophosphatases/genetics , Receptor, Insulin/metabolism , Adult , Fatty Liver/metabolism , Fatty Liver/physiopathology , Female , Genetic Predisposition to Disease , Humans , Insulin Resistance/genetics , Male , Middle Aged , Polymorphism, Single Nucleotide , Severity of Illness Index , Signal Transduction/geneticsABSTRACT
BACKGROUND: The strongest risk factors for pancreatic adenocarcinoma are tobacco smoking and increasing age. However, only a few smokers or elderly individuals develop the disease and genetic factors are also likely to be important. METHODS: The literature on genetic factors modifying susceptibility to cancer was reviewed, with particular regard to the interindividual variation that exists in the development of pancreatic adenocarcinoma. RESULTS: Tobacco-derived carcinogen-metabolizing enzyme gene variants have been the main area of study in stratifying the risk of sporadic pancreatic cancer. Inconsistent results have emerged from the few molecular epidemiological studies performed. CONCLUSION: There is great scope for further investigation of critical pathways and unidentified genetic influences may be revealed. This may eventually allow the identification of individuals at high risk who might be targeted for screening.
Subject(s)
Carcinoma, Pancreatic Ductal/genetics , Genetic Predisposition to Disease/genetics , Pancreatic Neoplasms/genetics , Carcinogens/analysis , DNA Repair , Environment , Humans , Life Style , Pedigree , Prospective Studies , Risk Factors , Smoking/adverse effectsABSTRACT
The objective of this study was to investigate factors affecting steady-state plasma concentrations of thioridazine. A cross-sectional study of patients receiving chronic thioridazine was employed. Common allelic variants of CYP2D6 and CYP2C19, as well as thioridazine and metabolite concentrations and QTc intervals, were determined. In 97 patients, dose-corrected plasma concentrations (C/Ds) of thioridazine and metabolites were correlated with age but not sex or CYP2C19 genotype. Patients with no functional CYP2D6 alleles (n=9) had significantly higher C/D for thioridazine (P=0.017) and the ring sulfoxide metabolite and a significantly higher thioridazine/mesoridazine ratio compared with those with >/=1 functional CYP2D6 allele (n=82). Smokers had significantly lower C/D for thioridazine, mesoridazine, and sulforidazine and significantly lower thioridazine/ring sulfoxide ratios than non-smokers. QTc interval was not significantly affected by CYP2D6 or CYP2C19 genotypes. Plasma concentrations of thioridazine are influenced by age, smoking, and CYP2D6 genotype, but CYP2D6 genotype does not appear to influence on-treatment QTc interval.
Subject(s)
Antipsychotic Agents/adverse effects , Antipsychotic Agents/blood , Heart Conduction System/drug effects , Long QT Syndrome/chemically induced , Thioridazine/adverse effects , Thioridazine/blood , Adult , Age Factors , Aged , Aged, 80 and over , Alleles , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/pharmacokinetics , Aryl Hydrocarbon Hydroxylases/genetics , Aryl Hydrocarbon Hydroxylases/metabolism , Cross-Sectional Studies , Cytochrome P-450 CYP2C19 , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Dopamine Antagonists/adverse effects , Dopamine Antagonists/blood , Female , Genetic Variation , Genotype , Humans , Linear Models , Long QT Syndrome/blood , Long QT Syndrome/physiopathology , Male , Mesoridazine/adverse effects , Mesoridazine/blood , Middle Aged , Mixed Function Oxygenases/genetics , Mixed Function Oxygenases/metabolism , Risk Factors , Schizophrenia/drug therapy , Sex Factors , Smoking/adverse effects , Thioridazine/administration & dosage , Thioridazine/pharmacokinetics , White People/geneticsABSTRACT
Low selenium (Se) status has been associated with increased risk of colorectal cancer (CRC). Se is present as the amino acid selenocysteine in selenoproteins, such as the glutathione peroxidases. Se incorporation requires specific RNA structures in the 3' untranslated region (3'UTR) of the selenoprotein mRNAs. A single nucleotide polymorphism (SNP) occurs at nucleotide 718 (within the 3'UTR) in the glutathione peroxidase 4 gene. In the present study, Caco-2 cells were transfected with constructs in which type 1 iodothyronine deiodinase coding region was linked to the GPx4 3'UTR with either C or T variant at position 718. Higher reporter activity was observed in cells expressing the C variant compared to those expressing the T variant, under either Se-adequate or Se-deficient conditions. In addition, a disease association study was carried out in cohorts of patients with either adenomatous polyps, colorectal adenocarcinomas and in healthy controls. A higher proportion of individuals with CC genotype at the GPx4 T/C 718 SNP was present in the cancer group, but not in the polyp group, compared with the control group (P < 0.05). The present data demonstrate the functionality of the GPx4 T/C 718 SNP and suggest that T genotype is associated with lower risk of CRC.
Subject(s)
Anticoagulants/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Simvastatin/pharmacology , Warfarin/administration & dosage , Aged , Aged, 80 and over , Anticoagulants/pharmacokinetics , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Blood Coagulation/drug effects , Cytochrome P-450 CYP2C9 , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Dose-Response Relationship, Drug , Drug Interactions , Drug Therapy, Combination , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Liver/drug effects , Liver/enzymology , Male , Middle Aged , Simvastatin/administration & dosage , Warfarin/pharmacokineticsABSTRACT
BACKGROUND: Osteoporosis is an important cause of morbidity in patients with Crohn's disease. The pathogenesis of reduced bone mineral density (BMD) is multifactorial. A range of genetic factors have been implicated in other populations of patients with osteoporosis. AIM: To investigate the influence of interleukin 6 (IL-6), collagen type 1alpha1 (COL1A1), and vitamin D receptor gene (VDR) single nucleotide polymorphisms (SNP) on BMD in patients with Crohn's disease. PATIENTS: A cohort of 245 well characterised patients with Crohn's disease were recruited from the inflammatory bowel disease register at the Freeman Hospital and Royal Victoria Infirmary, Newcastle upon Tyne, and the Queen Elizabeth Hospital, Gateshead, UK. METHODS: Patients were genotyped for IL-6 C-174G SNP, COL1A1 Sp1 binding site G T SNP, VDR Taq1, and Fok1 SNPs, and CARD15 R702W, G908R, and L1007fs SNPs. BMD was measured at the lumbar spine (LSP) and hip using dual energy x ray absorptiometry. RESULTS: A total of 158 female and 87 male patients, aged 24-70 years (mean 44), were recruited. There were no significant differences in the distribution of the tested SNPs when analysed for age, body mass index, pre/post-menopausal status, smoking, or steroid use. Two hundred and thirteen patients were genotyped for the IL-6 SNP. LSP and total hip BMD was significantly lower in patients with the GG genotype (48%) than the CC genotype (15%) (p = 0.041, p = 0.014). One hundred and eighty patients were genotyped for the COL1A1 SNP. There was no significant difference in BMD at LSP. Hip BMD was significantly lower in heterozygous patients compared with homozygous wild-types (p = 0.034). There were no significant differences in BMD between genotypes for the two VDR SNPs or the CARD15 genotypes examined. CONCLUSION: IL-6 and COL1A1 gene polymorphisms influence BMD in patients with Crohn's disease but the particular VDR gene polymorphisms studied do not have a major effect.
Subject(s)
Bone Density/genetics , Collagen Type I/genetics , Crohn Disease/genetics , Interleukin-6/genetics , Receptors, Calcitriol/genetics , Adrenal Cortex Hormones/pharmacology , Adult , Aged , Bone Density/drug effects , Collagen Type I, alpha 1 Chain , Crohn Disease/drug therapy , Crohn Disease/physiopathology , Female , Genotype , Hip Joint/physiopathology , Humans , Lumbar Vertebrae/physiopathology , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
Drug metabolism may be perturbed by genetically determined differences in the metabolic activity of cytochrome P450 enzymes. The authors encountered extensive bleeding in a patient receiving warfarin for anticoagulation after the introduction of celecoxib, an anti-inflammatory drug. As the CYP2C9 enzyme metabolises these drugs, it was determined whether variant alleles were responsible for altering warfarin handling. Genetic analysis established that the patient was a compound heterozygote with CYP2C9*2 and *3 variant alleles, which exhibit lower drug metabolising capacity and enhance susceptibility to drug toxicity.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anticoagulants/adverse effects , Aryl Hydrocarbon Hydroxylases/genetics , Hemorrhage/chemically induced , Sulfonamides/adverse effects , Warfarin/adverse effects , Aged , Arthralgia/drug therapy , Celecoxib , Cytochrome P-450 CYP2C9 , Drug Interactions , Female , Humans , International Normalized Ratio , Polymorphism, Genetic , PyrazolesABSTRACT
There is increasing information available on the existence of polymorphisms in genes encoding xenobiotic metabolizing enzymes and the functional significance of many of these. In addition to genes long recognized as being polymorphic, such as CYP2D6, CYP2C19 and CYP2C9, there is now information available on the existence of polymorphisms in other cytochrome P450 genes such as CYP2A6, CYP2B6 and CYP2C8. With respect to phase II metabolism, polymorphisms in GSTM1, GSTT1, NAT2 and TPMT are well understood but information is also emerging on other GST polymorphisms and on polymorphisms in the UDP-glucuronosyltransferases and sulfotransferases. The availability of comprehensive information on the occurrence and functional significance of polymorphisms affecting drug metabolism should facilitate their application to pharmacogenomic profiling.
Subject(s)
Enzymes/genetics , Pharmacogenetics , Polymorphism, Genetic , Xenobiotics/metabolism , Cytochrome P-450 Enzyme System/classification , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Enzymes/metabolism , HumansABSTRACT
The aim of this study was to investigate the association of NAT2 gene polymorphism with bladder cancer using the data derived from the International Project on Genetic Susceptibility to Environmental Carcinogens. Four case control studies conducted in four European countries, plus two case series, one from England and one from Germany, for a total of 1530 cases and 731 controls (all Caucasian) were included. The interaction between NAT2 and bladder cancer considering smoking habits and occupational exposure was studied. There was a significant association between NAT2 and bladder cancer (odds ratio: 1.42, 95% confidence interval: 1.14-1.77), with a slightly significant heterogeneity among studies. However, heterogeneity disappeared when smokers were divided into current and ex-smokers. The risk of cancer was elevated in smokers and occupationally exposed subjects, with the highest risk among slow acetylators. The increase in risk was limited, in fact, to current smokers (odds ratio = 1.74, 95% confidence interval: 0.96-3.15). This analysis confirms that the NAT2 genotype is a risk factor for bladder cancer by interacting with smoking or occupational exposures. Our observation suggests that NAT2 is not a risk factors per se but modulates the effect of carcinogens contained in tobacco smoke (probably arylamines) or associated with occupational exposures.