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At least 1,297 records · Page 72Linked to original sources
PubMed2005

Genetic variation in G-protein-coupled receptors--consequences for G-protein-coupled receptors as drug targets.

G-protein-coupled receptors (GPCRs), including 'orphan' GPCRs whose natural ligands are unknown, comprise the largest membrane receptor superfamily and are the most commonly used therapeutic targets. GPCR genetic loci harbour numerous variants, such as DNA insertions or deletions and single nucleotide polymorphisms that alter GPCR expression and function, thereby contributing to inter-individual differences in disease susceptibility/progression and drug responses. In this article, the authors review examples of GPCR genetic variants that influence transcription, translation, receptor folding and expression on cell surface (by affecting receptor trafficking, dimerisation, desensitisation/downregulation), or perturb receptor function (by altering ligand binding, G-protein coupling and receptor constitutive activity). In spite of such effects, assessment for genetic variants is not currently applied to the drug development and approval process or in the clinical use of GPCR drugs. Further insights will, the authors believe, alter drug discovery/development, therapeutics and likely provide new GPCR drug targets.

Drug Delivery Systems↗
PubMed1974

Genetic variation in coumarin hydroxylase activity in the mouse (Mus musculus).

Basal and phenobarbital-induced rates of hepatic metabolism of coumarin to 7-hydroxycoumarin are markedly higher in DBA/2J mice than they are in the AKR/J, C57BL/6J, and C3H/HeJ strains. Intermediate coumarin hydroxylase activity in F(1) hybrids of mating between DBA/2J and the other three strains indicates an additive mode of inheritance.

Animals↗
PubMed2002

CYP2A6 genetic variation and potential consequences.

Human cytochrome P450 2A6 (CYP2A6) has been shown to have large interindividual and interethnic variability in levels of expression and activity. This is thought to be largely due to genetic polymorphisms. In recent years, 13 genetic variants (CYP2A6*1-*11 and the gene duplication, *1 x 2) of CYP2A6 have been identified and a number of these have been shown to result in altered CYP2A6 enzyme activity. For example, there are alleles which result in variants that are in inactive (e.g. due to a gene deletion), have decreased activity (e.g. altered enzyme structure or transcriptional activity) or have increased activity (e.g. due to gene duplications). The resulting interindividual variation in metabolic activity may affect the metabolism of CYP2A6 substrates including nicotine, cotinine (the major metabolite of nicotine), several tobacco-specific procarcinogens, coumarin and many toxins. The frequencies of the CYP2A6 alleles vary considerably among different ethnic populations, which may partially explain the interethnic variability found in CYP2A6-related metabolic activity (e.g. nicotine metabolism), behaviors (i.e. smoking) and disease (i.e. lung cancer). Investigations of the genetic variation of CYP2A6 and its resulting effects on metabolism and health consequences are still fairly early; this review summarizes what is presently known about CYP2A6, its genetic variants and their clinical consequences.

Aryl Hydrocarbon Hydroxylases↗
PubMed2006

Effects of heavy metal pollution on genetic variation and cytological disturbances in the Pinus sylvestris L. population.

This isoenzymatic and cytogenetic study has shown significant differences in genetic composition between two groups of Pinus sylvestris trees: tolerant and sensitive to heavy metal pollution. Total and mean numbers of alleles and genotypes per locus were higher in the pollution-sensitive group of trees, but heterozygosity (Ho) was lower in this group. Fixation index (F) indicates that trees tolerant for pollution were in the Hardy-Weinberg equilibrium, while the sensitive group had a significant excess of homozygosity. Cytological analyses demonstrated numerous aberrations of chromosomes in meristematic root tissue of seedlings developed from seeds collected from trees in the polluted area. The aberrations included chromosome bridges and stickiness, laggards, retarded and forward chromosomes, and their fragments. The mitotic index was markedly lower in this group of seedlings, as compared to the control. Both isoenzymatic and cytological analyses showed a significant influence of heavy metal ions on the genetic structure of the Pinus sylvestris population.

Chromosome Aberrations↗
PubMed1993

Estimation of the genetic variation in complement activity of common carp (Cyprinus carpio L.).

The complement status of hybrid, laboratory raised carp was determined by an in vitro approach of the alternate complement activity (ACH50) and total haemolytic activity (CH50), and by measurement of serum C3 levels. The lysis of target sheep red blood cells (RBC) in the haemolytic assay for CH50 activity depended, amongst others, on the haemolysin concentration in the assay. Rocket electrophoresis showed a mean serum C3 concentration of 0.95 mg ml-1. The variation for both ACH50 and CH50 haemolytic activity was approximately 30%. The degree of genetic determination of the parameters was investigated by estimation of their repeatabilities, which were relatively high for CH50 (0.71) and ACH50 activity (0.72), but lower for C3 levels (0.54). Correlations between ACH50 values and C3 levels were significant, but moderate (0.54-0.58).

Animals↗
PubMed1991

Genetic variation in related cytolytic toxins produced by different species of Aeromonas.

Comparative analyses were performed at the immunological, biological, and genetic level to establish the degree of relatedness of a group of four cytotoxic enterotoxins and aerolysins produced by different isolates of Aeromonas: SSU [16], Ah1 [13], Ah2 [18], and Ah65 [21]. Results obtained from Western blot analysis, neutralization studies, and Southern blot analysis indicated that although the members of this group of toxins displayed structural similarities they also differed from each other at the immunological, biological and genetic level.

Aeromonas↗
PubMed2006

Genetic variations of HLA-DRB1 and susceptibility to Kawasaki disease in Taiwanese children.

Although some previous studies have reported that genetic and immunologic factors play important roles in the pathogenesis of Kawasaki disease (KD), the etiologic factors of this enigmatic pediatric disease are still poorly understood. The purpose of this study was to investigate whether polymorphisms of the human leukocyte antigen DRB1 (HLA-DRB1) gene are associated with KD and the development of coronary artery lesions (CAL) in Taiwanese children. Genomic DNA was extracted from whole blood samples from 145 children with KD and 331 healthy controls. The HLA-DRB1 gene was genotyped by polymerase chain reaction (PCR) and sequence-based typing assays. We found that the distribution of HLA-DRB1 allele families and alleles in children with KD did not differ from that in healthy controls. Stratified analysis did not demonstrate any association between particular HLA-DRB1 allele families or alleles and the development of CAL in children with KD. These findings suggest that susceptibility to KD and CAL is not associated with the HLA-DRB1 gene in a Taiwanese population. If immunogenetic determinants are involved in this disease and its complications in Taiwanese children, they must involve genes other than HLA-DRB1.

Child↗
PubMed2002

Patterns of genetic variation at a chromosome 4 locus of Drosophila melanogaster and D. simulans.

DNA sequence surveys of Drosophila melanogaster populations show a strong positive correlation between the recombination rate experienced by a locus and its level of nucleotide polymorphism. In particular, surveys of the fourth chromosome gene ci(D) show greatly reduced levels of nucleotide variation; this observation was originally interpreted in terms of selective sweeps occurring on the nonrecombining fourth chromosome. Subsequent theoretical work has, however, uncovered several other selective processes that can reduce variation. In this study, we revisit the Drosophila fourth chromosome, investigating variation in 5-6 kb of the gene ankyrin in D. melanogaster and D. simulans. Silent nucleotide site diversity is approximately 5 x 10(-4) for both species, consistent with the previous observations of low variation at ci(D). Given the observed frequency spectra at ankyrin, coalescent simulations indicate that reduced diversity in the region is unlikely to be due to a selective sweep alone. We find evidence for recombinational exchange at this locus, and both species appear to be fixed for an insertion of the transposable element HB in an intron of ankyrin.

Animals↗
PubMed2002

Serotonin transporter genetic variation and the response of the human amygdala.

A functional polymorphism in the promoter region of the human serotonin transporter gene (SLC6A4) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.

Adult↗
PubMed1985

Biochemical properties, homology, and genetic variation of Drosophila "nonspecific" esterases.

The biochemical properties and tissue distribution of two major, soluble "nonspecific" esterases have been studied in Drosophila melanogaster, D. pseudoobscura, and related species. The "alpha-like" activity is due to a monomer enzyme (MW congruent to 60 kd) having a nonspecific tissue distribution, which was inhibited by p-hydroxymercuribenzoate (5 X 10(-4)M) plus eserine (1 X 10(-5)M) and was relatively unstable during polyacrylamide gel electrophoresis. Electrophoretograms of this enzyme could be enhanced by treating gels with beta-mercaptoethanol before staining. This procedure allowed the identification of a new alpha-esterase (Est-4) in D. pseudoobscura. The "beta-like" esterase activity (EC 3.1.1.1) is due to a dimer (MW congruent to 120 kd) in most Drosophila species. D. melanogaster and its siblings (D. simulans and D. mauritiana) were exceptions in which this enzyme had an unusual tissue distribution (increased activity in the male reproductive system) and was a monomer (MW congruent to 60 kd). Differences in the genetic variability of these esterases are discussed and interpreted by a population expansion model rather than by differences in biochemical properties of enzyme forms.

Animals↗
PubMed1994

Further observations on the evolution of additive genetic variation with mutation.

Two mutation models, LH by Lynch and Hill and CT by Cockerham and Tachida, utilized for a neutral quantitative character caused by genes with additive effects undergoing mutation and drift, were compared for the genetic variances within, sigma w2, and between sigma b2, replicate small populations initiated from an almost fixed founder population. The two models give results that are very similar for sigma w2 and it is only after a very long time (too long for experimental verification) that they can be distinguished for sigma b2. The CT model also accommodates small replicate populations initiated from a very large equilibrium founder population. This provides information on the additive variance in the large equilibrium population. Results from both types of founder populations provide information on the average mutation rate. Formulations for monoecy for the CT model are shown to be satisfactory for separate sexes with the substitution of the appropriate effective population size.

Alleles↗