摘要:

ThiopurineS-methyltransferase (TPMT) is a cytosolic enzyme that plays a major role in the metabolism of thiopurine drugs such as mercaptopurine and azathioprine. The interindividual differences in response to thiopurine administration is in part due to the presence of genetic polymorphisms in the gene that regulates TPMT activity.TPMTgenotype correlates well with thein vivoenzyme activity within erythrocytes. Patients with genetically determined decreased TPMT activity develop severe myelosuppression when treated with standard doses of thiopurine drugs because an excess of thioguanine nucleotides accumulates in hematopoietic tissues.TPMTgenotyping provides clinicians with a reliable method for identifying TPMT-deficient patients who can benefit from low doses of thiopurine drugs in order to reduce the risk of developing adverse effects. Moreover, the administration of higher doses of the drug could improve therapeutic response in patients in whom theTPMTgenotyping demonstrates the absence of mutated alleles.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Anorexia nervosa, bulimia nervosa, and binge eating disorder are eating disorders with common clinical and psychological features, potentially shared mechanisms, significant morbidity and, at least for anorexia nervosa, a high mortality rate. Among the numerous risk factors involved, the importance of a genetic vulnerability has been demonstrated, and the heritability, in the broad sense, has being estimated to be between 50 and 70%. Studies have thus focused on different candidate genes.Serotonin transmission and regulation has been extensively studied with regard to its role in core mechanisms such as feeding and fasting, but also in different clinical characteristics of eating disorders. The serotonin transporter (5-HTT), encoded by theSLC6A4gene, may also have an important role in eating disorders, as its availability is decreased in patients with bulimia nervosa and binge eating disorder. The promoter region contains a functional insertion/deletion polymorphism with two common alleles that have been designated the short (*S) and long (*L) alleles. The frequency of theSLC6A4*S allele has been assessed in four independent samples of patients with anorexia nervosa, but gave discrepant results. A meta-analysis was performed, which showed that the *S allele could represent a moderate but significant risk factor that increases the risk of anorexia nervosa (odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.16–1.72).Eating disorders are treated using different types of psychotherapy and pharmacotherapy with antidepressants; serotonin reuptake inhibitors being the most frequently prescribed. High doses of selective serotonin reuptake inhibitors (SSRIs) are usually prescribed in eating disorders. The prevalence of non-responders (roughly one out of two), and the presence of a functional genetic polymorphism in the promotor region ofSLC6A4, emphasizes the potential utility of psychopharmacogenetics in prescribing SSRIs in the treatment of patients with weight-restored anorexia nervosa. Information about genetic variations of cytochrome P450 could also facilitate pharmacotherapy by preventing the administration of high doses in poor metabolizers and identify rapid metabolizes who may require higher doses for efficacy.SLC6A4genotyping would allow physicians to individualize selective serotonin reuptake therapy for their patients.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

The estrogen receptors (ERs), ERα and ERβ, play a central role in mediating the biological effects of estrogen. The transcription rate of estrogen target genes is determined by several parameters including the type of ligand, estrogen receptor subtype and isoform, as well as interactions with receptor-binding cofactor proteins.The ERs regulate gene expression by binding to specific response element sequences in the promoters of estrogen target genes. Alternative pathways have also been described in which the ERs modulate transcription indirectly, via protein : protein interactions. In this regulatory mode, which has been traced to activator protein (AP)-1-, cyclic adenosine monophosphate (cAMP)-, and Sp1-response elements, the ERs appear to be tethered to target gene promoters via heterologous transcription factors. It has been found that ERα and ERβ have opposite effects on transcription mediated via the indirect mode of action. Moreover, recent studies suggest that ERβ may inhibit the stimulatory effects of ERα on cellular proliferation.Estrogen is a key regulatory hormone that affects numerous physiological processes. Estrogen is required for female pubertal development and affects growth, differentiation and function of the female reproductive system. It has recently been suggested that estrogen also has an important role in the male urogenital tract. In addition, estrogens have profound effects in other tissues. For instance, in the skeleton estrogen prevents bone-resorption by inhibition of osteoclast function.Numerous reports have suggested that estrogen has a beneficial effect in the cardiovascular system and in the CNS; however, this has not been confirmed in randomized clinical trials. In fact, a large randomized trial on healthy postmenopausal women receiving oral estrogen plus progestin showed an increased incidence of cardiovascular disease. In addition, this study revealed an increased risk for dementia and impaired cognitive function in the group receiving oral estrogen/progestin. Additional clinical trials are required to determine which hormonal component causes these health risks or whether the effects were due to the combination of estrogen and progestin.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

The post-genomic era of functional genomics and target validation will allow us to narrow the bridge between clinically correlative data and causative data for complex diseases, such as arthritis, for which the etiological agent remains elusive. The availability of human and other annotated genome sequences, and parallel developments of new technologies that allow analysis of minute amounts of human and animal cells (peripheral blood cells and infiltrating cells) and tissues (synovium and cartilage) under different pathophysiological conditions, has facilitated high-throughput gene mining approaches that can generate vast amounts of clinically correlative data. Characterizing some of the correlative/causative genes will require reverting to the hypothesis-driven, low throughput method of complementary experimental biology using genomic approaches as a tool. This will includein silicogene expression arrays, genome-wide scans, comparative genomics using various animal models (such as rodents and zebrafish), bioinformatics and a team of well trained translational scientists and physicians.For the first time, the ‘genomic tools’ will allow us to analyze small amounts of surgical samples (such as needle biopsies) and clinical samples in the context of the whole genome. Preliminary genomic analysis in osteoarthritis has already resurrected the debate on the semantic issues in the definition of inflammation. Further analyses will not only facilitate the development of unbiased hypotheses at the molecular level, but also assist us in the identification and characterization of novel targets and disease markers for pharmacological intervention, gene therapy, and diagnosis.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Small interfering RNA (siRNA) molecules are short sequences of double-stranded RNA 19-27 bp in length, which suppress expression of target genes by inducing the breakdown of the cognate mRNA through mechanisms that are still being elucidated. siRNA molecules can be chemically synthesized or prepared through digestion of larger double-stranded RNA molecules using recombinant dicer or RNAase III enzyme. siRNA molecules can also be encoded by plasmid or virus vectors or expressed in transgenic animals. Design of siRNA sequences that efficiently suppress target genes can sometimes be challenging, although digestion of large double-standed RNA species with recombinant dicer or RNAase III may remove the necessity for testing multiple candidate siRNA. Exogenous siRNA can suppress translation for varying amounts of time depending on the half-life of the protein targeted. Vector-mediated approaches may improve duration but their use can be limited by the permanency and efficiency of transduction. Potential therapeutic targets for siRNA include viral and non-viral pathogens, cancer, neurodegenerative diseases, septic shock and macular degeneration. Suppression of expression via siRNA is also an extremely useful research tool for ascertaining gene function. Looking ahead to clinical applications, it will be important to know the consequences of inadvertent suppression of non-targeted sequences. If safety can be established, siRNA has the potential to significantly impact the field of molecular medicine.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

Microarray technology allows one to measure gene expression levels simultaneously on the whole-genome scale. The rapid progress generates both a great wealth of information and challenges in making inferences from such massive data sets. Bayesian statistical modeling offers an alternative approach to frequentist methodologies, and has several features that make these methods advantageous for the analysis of microarray data. These include the incorporation of prior information, flexible exploration of arbitrarily complex hypotheses, easy inclusion of nuisance parameters, and relatively well developed methods to handle missing data.Recent developments in Bayesian methodology generated a variety of techniques for the identification of differentially expressed genes, finding genes with similar expression profiles, and uncovering underlying gene regulatory networks. Bayesian methods will undoubtedly become more common in the future because of their great utility in microarray analysis.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

BackgroundPrevious studies of vitamin D binding protein (VDBP, also known as group-specific component, Gc, encoded by theGCgene) have implicated two gene variants,GC*2 andGC*1F, as possible contributors with chronic obstructive pulmonary disease (COPD) protection and susceptibility, respectively. The objective of this study was to examine the association of VDBP to different subtypes of COPD.Study designThe association of the variousGCgenotypes to the COPD phenotype was examined in Icelandic COPD patients who were followed by pulmonary physicians at the University Hospital of Iceland.MethodsAll patients were genotyped for the known alleles of theGCgene. The single nucleotide polymorphisms (SNPs) were identified by a restriction fragment length polymorphism procedure. Study power was estimated based on allele frequencies of the variants, and risk ratios were calculated from the prevalence of genotypes in the affected group divided by its prevalence in the control population. Statistical analyses were performed using the 2-tailed Fisher’s Exact Test and χ2test, where appropriate.Patient groupOne hundred and two COPD patients and 183 controls, together with 46 asthma patients and 48 patients with chronic mucous hypersecretion (CMH) were examined.Main outcome measure and resultsThe results demonstrate similar allele and genotype frequencies ofGCin COPD patients overall and healthy controls. However, there was a higher prevalence of genotypes carrying aGC*1F allele and lower prevalence of genotypes with aGC*2 allele in the CMH patients than in controls. This difference was most notable in the homozygous form: 8.3% vs 1.1% for theGC*1F/*1F, and 0.0% vs 7.6% for theGC*2/*2 genotypes, respectively. When controlled for smoking, only the non-smoking CMH patients demonstrated a significantly altered frequency of theGC*1F/*1F genotype (p = 0.0001). The prevalence of theGC*2/*2 genotype was also significantly lower in patients with bronchial hypersecretion with airflow obstruction compared with the control group (2.9% vs 7.6%). Taken together, these results demonstrate that theGC*1F andGC*2 alleles are associated with sputum hypersecretion in individuals who are at increased risk of developing COPD.

ISSN:1175-2203    

出版商:ADIS    

年代:2004

数据来源: ADIS