摘要:

Selective serotonin reuptake inhibitors (SSRIs) are used to treat a number of psychiatric disorders related to mood and anxiety, and variations in the serotonin transporter (5-HTT) gene may be involved in a number of these. A polymorphic site in the promoter region is associated with differences in5-HTTgene expression. Studies suggest that the short allele of the5-HTTpromoter (5-HTTPR) site can adversely influence the antidepressant response to SSRIs, and is associated with anxiety-related traits, depression, and impulsive disorders such as alcohol abuse. Several studies do not replicate these findings; potential confounding factors include age, gender, and population stratification. Other5-HTTpolymorphisms also exist. For example, individuals with the short allele of a variable number of tandem repeats (VNTR) polymorphism, located in the second intron, may have reduced responsiveness to SSRIs, and theSTin2.12allele at this site has been associated with bipolar disorder. Findings both supporting and inconsistent with these conclusions are reviewed. The clinical effects of the polymorphisms may be associated with effects on platelets, neural 5-HTT levels, and indices of serotonergic function.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Asthma is a polygenic disease for which no clear genotype-phenotype relationships have emerged. In contrast, although not associated with the diagnosis of asthmaper se,variant forms of the β2-adrenoceptor (β2-AR) gene (ADRB2) display functional effects that may be clinically relevant. Single nucleotide polymorphisms (SNPs) ofADBR2are common and result in amino acid substitutions at positions 16, 27, and 164 of the receptor as well as position 19 of its 5′ upstream peptide. These SNPs influence receptor functionin vitro, although evidence regarding exact relationships is conflicting. This has raised the possibility that phenotypes such as bronchial hyper-responsiveness (BHR) and responses toβ2-agonist drugs may be genetically determined. To date, no unequivocal relationships between SNPs and phenotype have been identified. In some studies the Gly16allele has been associated with increased BHR and asthma severity. In others, the Arg16allele has been shown to determine acute bronchodilator response and adverse events during long term β2-agonist therapy. The latter may provide the basis for clinical application of this new knowledge. More recently, a small number of frequently occurring, functionally relevantADRB2haplotype pairs have been confirmed. These combinations of alleles may be more important in determining genotype/phenotype relationships than individual SNPs, and may explain why earlier investigations have yielded contrasting results. Future studies will be required to clarify the pharmacodynamic effects ofADRB2haplotypes bothin vitroandin vivo.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Skeletal biology is a complex process involving the developmental commitment and differentiation of chondrocytes and osteoblasts which produce and mineralize cartilage and bone matrix during growth and postnatal life. Several genes are involved in controlling osteogenesis by acting on target cells in a very complex manner. Manipulation of genes in mice and studies of genetic mutations affecting the skeleton in humans have enabled the assessment of the role of transcription factors, bone matrix proteins and regulatory factors involved in the control of chondrocyte and osteoblast differentiation, and have considerably improved our understanding of the bone formation process. Clinical studies and gene polymorphism analyses suggest that the variable expression of particular genes may be linked to clinical osteoporosis. A major challenge in the future will be to develop molecularly targeted approaches to stimulating bone formation and increasing bone mass. The use of mouse strain models and transgenic animals with variable bone density may be useful to identify genetic determinants of bone mass which may serve as a basis for drug discovery and development. On the other hand, the availability of gene microarrays and other emerging genomic techniques are promising tools to identify genes that are distinctly expressed in health and disease. These technologies may also serve to test the mechanisms of action of drugs aimed at increasing bone formation. Genetic studies of the molecular signaling pathways involved in normal and pathological osteogenesis may also help to identify genes that could be targeted for therapeutic intervention. Candidate approaches include selective gene transfection in target cells and the use of drugs acting on gene promoters to selectively enhance gene expression in osteoblasts. The development of these strategies is expected not only to bring new insight into the molecular mechanisms that govern bone formation in normal and pathological situations but, in the long term, may also result in the identification of novel molecular targets for therapeutic interventions for bone formation disorders.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism by channeling one-carbon units between nucleotide synthesis and methylation reactions. Severe enzyme deficiency leads to hyperhomocysteinemia and homocystinuria, with altered folate distribution and a phenotype that is characterized by damage to the nervous and vascular systems. Two frequent polymorphisms in the humanMTHFRgene confer moderate functional impairment of MTHFR activity for homozygous mutant individuals. The C to T change at nucleotide position 677, whose functional consequences are dependent on folate status, has been extensively studied for its clinical consequences. A second polymorphism, an A to C change at nucleotide position 1298, is not as well characterized.Still equivocal are associations betweenMTHFRpolymorphisms and vascular arteriosclerotic or thrombotic disease. Neural tube defects and pregnancy complications appear to be linked to impaired MTHFR function. Colonic cancer and acute leukemia, however, appear to be less frequent in individuals homozygous for the 677T polymorphism.MTHFRpolymorphisms influence the homocysteine-lowering effect of folates and could modify the pharmacodynamics of antifolates and many other drugs whose metabolism, biochemical effects, or target structures require methylation reactions. However, only preliminary evidence exists for gene-drug interactions.This review summarizes the biochemical basis and clinical evidence for interactions between MTHFR polymorphisms and several disease entities, as well as potential interactions with drug therapies. Future investigations of MTHFR in disease should consider the influence of other variants of functionally-related genes as well as the medication regimen of the patients. Animal models for genetic deficiencies in folate metabolism will likely play a greater role in our understanding of folate-dependent disorders.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

During the last decade, hundreds of genes that harbor mutations causing simple Mendelian disorders have been identified using a combination of linkage analysis and positional cloning techniques. Traditional approaches to gene mapping have been largely unsuccessful in mapping genes influencing so-called ‘complex’ genetic diseases, however, because of low power and other factors. Complex genetic diseases do not display simple Mendelian patterns of inheritance, although genes do have an influence and close relatives of probands consequently have an increased risk. These disorders are thought to be due to the combined effects of variation at multiple interacting genes and the environment. Complex diseases have a significant impact on human health because of their high population incidence (unlike simple Mendelian disorders, which tend to be rare). New techniques are being developed aimed specifically at mapping genes conferring susceptibility to complex diseases. A project aimed at mapping genes influencing susceptibility to a complex disease may be undertaken in several stages: establishing a genetic basis for the disease in one or more populations; measuring the distribution of gene effects; studying statistical power using models; carrying out marker-based mapping studies using linkage or association. Quantitative genetic models can be used to estimate the heritability of a complex (polygenic) disease, as well as to predict the distribution of gene effects and to test whether one or more quantitative trait loci (QTLs) exist. Such models can be used to predict the power of different mapping approaches, but are often unrealistic and therefore provide only approximate predictions. Linkage analyses, association studies and family-based association tests are all hindered by low power and other specific problems. Association studies tend to be more powerful but can generate spurious associations due to population admixture. Alternative strategies for association mapping include the use of recent founder populations or unique isolated populations that are genetically homogeneous, and the use of unlinked markers (so-called genomic controls) to assign different regions of the genome of an admixed individual to particular source populations. Linkage disequilibrium observed in a sample of unrelated affected and normal individuals can also be used to fine-map a disease susceptibility locus in a candidate region. New Bayesian strategies make use of an annotated human genome sequence to further refine the position of a candidate disease susceptibility locus.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS

摘要:

Cystic fibrosis (CF) is caused by a mutation in theCFTRgene, encoding a chloride channel. For the most common mutation, ΔF508, the basis of the deficit is the failure of the mutant CFTR channel protein to traffic properly to the apical plasma membrane of the affected epithelial cell. The trafficking failure results in loss of the cyclic adenosine monophosphate (cAMP)-activated chloride channel function of the CFTR protein in the plasma membrane. The lung is the principal site affecting patient morbidity and mortality in CF. The main reason is that the CF airway epithelial cells also secrete high levels of the proinflammatory cytokine interleukin (IL)-8, resulting in massive cellular inflammation, infection, tissue damage and lung destruction. The relationship between the trafficking defect, the loss of chloride channel activity, and inflammation is not known. However, gene therapy of CF lung epithelial cells with the wild-typeCFTRgene can repair the chloride channel defect, as well as suppress the intrinsic hypersecretion of IL-8. Repair of both defective channels and high IL-8 secretion can also be effected by treatment with the candidate CF drug CPX, which is in clinical trials in CF patients. CPX acts by binding to the mutant CFTR protein, and helps the protein to mature and gain access to the plasma membrane. CPX also suppresses the synthesis and secretion of IL-8 from CF epithelial cells, presumably by virtue of its repair of the trafficking defect of mutant CFTR. To guide pharmacogenomic experiments we have therefore hypothesized that the genomic signature of CF epithelial cells treated with CPX should resemble the signature of the same cells repaired by gene therapy. We have developed two algorithms for identifying genes modified by repair of CFTR defects. The GRASP algorithm uses a statistical test to identify the most profoundly changing genes. The GENESAVER algorithm allows us to identify those genes whose pattern of expression changes in-phase or out-of-phase with IL-8 secretion by CF cells. For the latter algorithm we modified IL-8 secretion from CF cells by treatment with wild-typeCFTR, with CPX, or by exposure to bacteria. The results have supported the hypothesis, and have provided a basis for considering the common pharmacogenomic expression signature as a surrogate endpoint for CF drug discovery. Significantly, the nature of the hypothesis, as well as the algorithm developed for this study, can be easily applied to pharmacogenomic studies with other goals.

ISSN:1175-2203    

出版商:ADIS    

年代:2001

数据来源: ADIS