摘要:

Thiopurine drug metabolism is a quintessential case of pharmacogenetics. A wealth of experimental and clinical data on polymorphisms in the thiopurine metabolizing enzyme thiopurine methyl transferase (TPMT) has been generated in the past decade. Pharmacogenetic testing prior to thiopurine treatment is already being practiced to some extent in the clinical context, and it is likely that it will be among the first pharmacogenetic tests applied on a regular basis.We analyzed the published TPMT data and identified some lessons to be learned for the future implementation of pharmacogenetics for thiopurines as well as in other fields. These include the need for comprehensive and unbiased data on allele frequencies relevant to a broad range of populations worldwide. The nature and frequency ofTPMTgene polymorphisms in some ethnic groups is still a matter of speculation, as the vast majority of studies onTPMTallele distribution are limited to only a small subset of alleles and populations. Secondly, an appreciation of the limits of pharmacogenetics is warranted, as pharmacogenetic testing can help in avoiding some, but by far not all adverse effects of drug therapy. An analysis of six clinical studies correlating adverse thiopurine effects andTPMTgenotype revealed that an average of 78% of adverse drug reactions were not associated withTPMTpolymorphisms. Pharmacogenetic testing will thus not eliminate the need for careful clinical monitoring of adverse drug reactions. Finally, a careful approach toward dose increases for patients with high enzyme activity is necessary, as TPMT-mediated methylation of thiopurines generates a possibly hepatotoxic byproduct.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

The glutathione-S-transferase (GST) super family comprises multiple isozymes (Alpha, Mu, Pi, Omega, Theta, and Zeta) with compelling evidence of functional polymorphic variation. Over the last two decades, a significant body of data has accumulated linking aberrant expression of GST isozymes with the development and expression of resistance to cancer drugs. Clinical correlation studies show that genetic differences within the human GST isozymes may play a role in cancer susceptibility and treatment.The initial confusion was presented by the fact that not all drugs used to select for resistance were substrates for thioether bond catalysis by GSTs. However, recent evidence that certain GST isozymes possess the capacity to regulate mitogen activated protein kinases presents an alternative explanation. This dual functionality has contributed to the recent efforts to target GSTs with novel small molecule therapeutics.While the ultimate success of these attempts remains to be shown, at least one drug is in late-stage clinical testing. In addition, the concept of designing new drugs that might interfere with protein:protein interactions between GSTs and regulatory kinases provides a novel approach to identify new targets in the search for cancer therapeutics.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Voltage-gated sodium channels (VGSCs) are critical transmembrane proteins responsible for the rapid action potential upstroke in most excitable cells. Recently discovered mutations in VGSCs, which underlie idiopathic clinical disease, have emphasized the importance of these channels in tissues such as skeletal muscle, nervous system, and myocardium. Mutations in the gene encoding the cardiac sodium channel isoform (SCN5A) have been linked to at least three abnormal phenotypes: variant 3 of the Long QT syndrome (LQT-3); Brugada’s syndrome (BrS); and isolated cardiac conduction disease (ICCD). Mutations inSCN5Amanifest as one or more of these clinical phenotypes – the precise distinction between these diseases is increasingly subtle.Clinical management of LQT-3 and diagnosis of BrS with the local anesthetic flecainide has proven promising. Channels associated with LQT-3 (D1790G) and BrS (Y1795H) both show more sensitivity to flecainide than wild-type (WT) channels, while lidocaine sensitivity is unchanged. One plausible explanation for differential drug sensitivity is that mutant channels may allow more access to a receptor site compared with WT through altered protein allosteric changes during an action potential. The high affinity binding site for local anesthetic block has been identified in the pore region of the channel. This region is not water accessible during the closed state, thus requiring channel opening for charged drug (flecainide and mexiletine) access and block. Channel mutations which disrupt inactivation biophysics lead to increased drug binding by altering the time the binding site is accessible during an action potential.Neutral drugs (lidocaine) which are not dependent on channel opening for binding site access will not be sensitive to mutations that alter channel inactivation properties. Interestingly another LQT-3 mutant (Y1795C) shows no change in flecainide sensitivity, suggesting that although drug effects ofSCN5Amutations cross disease boundaries, clinical management with flecainide will be beneficial to patients in a mutation-specific manner.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Predicting which patients with rheumatoid arthritis (RA), at presentation, are likely to suffer a severe disease course based on genotype data would be a major clinical advance. It would ensure that patients at highest risk of a severe outcome could be targeted with early aggressive therapies. With a better understanding of interactions between genotype and drug response it would be possible to prescribe treatments most likely to be efficacious and safe for specific patient subgroups. While a clear genetic component has been demonstrated in RA severity, the identification of genetic factors poses a challenge to researchers in the field.Initiatives such as the SNP Consortium and advances in genotyping technology have facilitated the investigation of genetic factors in both disease susceptibility and severity. However, several other factors, such as the availability of suitable longitudinal cohorts, definition of outcome measures, study design, selection of genetic markers, and statistical power, will all contribute to the likely success of genetic studies.Several strategies that have been applied in the pursuit of genetic predictors of clinical outcome in RA. While some encouraging results have been generated, it has so far been difficult to quantify the predictive value of genetic markers and extrapolate the results from genetic studies to clinic patients. Establishing high quality prospective inception cohorts, a more systemic approach to defining suitable outcome measures, and understanding the effects of treatment, will be critical to the eventual identification of good predictive genetic markers.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Although it is well known that genetic factors contribute significantly to the expression of systemic lupus erythematosus (SLE) it was only recently realized, through genome-wide searches, that the number of involved genes is rather large. The published information hints at two facts: first, the number of genomic loci identified in various diverse cohorts is large and not necessarily overlapping; and second, certain loci may be preferentially linked with specific clinical manifestations. The latter may ultimately lead to a better understanding of the nature of the clinical entity that we know as SLE, and identification of groups of patients prone to respond better to treatment or to develop significant adverse effects. Advances attained regarding the nature of the biochemical and molecular defects that underwrite the aberrant function of immune cells parallel the progress made on the genetic origin of the disease. The genetic links need to be connected with aberrant function of their products to validate their significance. It is expected that correction of molecular aberrations either medicinally or by gene therapy will provide the needed specific treatment for patients with SLE.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Human biological material is recognized as an important tool in research, and the demand for collections that combine samples and data is increasing. For-profit companies have assumed a leading role in assembling and managing these collections. The emergence of commercial biobanks has raised significant ethical and legal issues.The growing awareness of the importance of human biological material in research has been accompanied by a growing awareness of the deficiencies of existing archives of tissue. Commercial biobanks are attempting to position themselves as a, if not the, solution to problems that include a lack of public trust in researchers and lack of financial resources to support the prospective creation of collections that meet the highest scientific and ethical standards in the non-profit sector.Broad social and policy questions surrounding the operation of commercial biobanks have been raised however. International documents, in particular, suggest discomfort with the idea of gain from the mere transfer or exchange of human genetic material and information. Commercial involvement in the development of useful products from tissue is generally not condemned, so long as there is attention to scientific and social norms. Views on the acceptability of commercial biobanks vary.Specific issues that arise when commercial biobanks are permitted – in the areas of consent, recruitment, confidentiality, and accountability – are also relevant to the operation of public and private, non-profit biobanks. Although many uncertainties remain, consensus seems to be forming on a number of issues. For example, there appears to be agreement that blanket consent to future unspecified research uses, with no conditions, is unacceptable. Indeed, many of the leading commercial biobanks have been attentive to concerns about consent, recruitment, and confidentiality. Unfortunately, the binding nature of assurances in these areas is unclear, especially given the risk of insolvency. Hence, accountability may be the most important area of concern in relation to commercial biobanks. A few countries have enacted general legislation providing for comprehensive regulation of biobanks, for example, through licensure. Efforts to achieve harmonization of standards at the international level, and cautions against an approach that focuses on biobanking for genetic research alone, are to be applauded.

ISSN:1175-2203    

出版商:ADIS    

年代:2003

数据来源: ADIS