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PubMed1991

An F41-K88-related genetic determinant of bovine septicemic Escherichia coli mediates expression of CS31A fimbriae and adherence to epithelial cells.

A genetic determinant related to that encoding the F41 fimbrial adhesin was cloned from a bovine septicemic isolate of Escherichia coli. This determinant was found to mediate expression of morphologically distinct fimbriae in E. coli HB101. The gene encoding the fimbrial subunit protein was identified, and the nucleotide sequence was determined. Homology with the amino-terminal amino acid sequence of CS31A (J. Girardeau, M. Der Vartanian, J. Ollier, and M. Contrepois, Infect. Immun. 56:2180-2188, 1988) was observed, suggesting that this determinant encodes expression of the CS31A fimbrial antigen. The CS31A subunit gene was found to share extensive homology in its signal sequence to the subunit genes encoding the F41 and K88 adhesins. No apparent homology between the mature F41 and CS31A subunits was identified. However, substantial relatedness to the K88 fimbrial subunit was observed. Analysis of the protein products encoded by the CS31A, F41, and K88 determinants in maxicells established that despite extensive genetic similarities between the determinants, each encodes a distinct profile of proteins. E. coli HB101 harboring the cloned CS31A determinant was found to adhere to epithelial cells in a tissue culture assay, suggesting a role for CS31A in adherence. A CS31A-specific DNA hybridization probe detected homologous sequences among enterotoxigenic as well as septicemic E. coli isolates from calves.

Amino Acid Sequence↗
PubMed2004

Is benign rolandic epilepsy genetically determined?

Benign rolandic epilepsy (BRE) is considered to be a genetically determined idiopathic partial epilepsy. We studied twins with BRE and compared the concordance with a twin sample of idiopathic generalized epilepsy (IGE). All eight BRE pairs (six monozygous [MZ], two dizygous [DZ]) were discordant. MZ pairwise concordance was 0 (95% confidence interval [CI], 0-0.4) for BRE compared with 0.7 (95% CI, 0.5-0.9) for 26 IGE MZ pairs. Our data suggest that conventional genetic influences in BRE are considerably less than for IGE, and other mechanisms need to be explored.

Adolescent↗
PubMed1985

Genetically determined resistance to listeriosis is associated with increased accumulation of inflammatory neutrophils and macrophages which have enhanced listericidal activity.

The C57BL/6 and A/J inbred strains of mice differ markedly in their resistance to the facultative intracellular bacterium Listeria monocytogenes. One possible explanation for this genetically determined resistance is that phagocytes from Listeria-resistant strains of mice can kill L. monocytogenes more effectively than phagocytes from Listeria-susceptible strains of mice. We report here that inflammatory neutrophils and macrophages from Listeria-resistant mice (C57BL/6) exhibit a slight but significantly enhanced ability to kill L. monocytogenes in vitro as compared to inflammatory phagocytes from Listeria-susceptible mice (A/J). More importantly, however, Listeria-resistant mice recruited more inflammatory neutrophils and macrophages to the peritoneal cavity in response to i.p. injection of heat-killed Listeria than did Listeria-susceptible mice. These data suggest that genetically determined resistance to listeriosis is dependent on the enhanced inflammatory responsiveness of Listeria-resistant mice. Further support for this hypothesis was provided by experiments in which the passive transfer to A/J mice (C5-deficient) of plasma from C57BL/6 mice (C5-sufficient) enhanced the ability of the recipient A/J mice both to recruit inflammatory neutrophils to the peritoneal cavity in response to i.p. injection of heat-killed Listeria, and to clear L. monocytogenes from the spleen after a sublethal challenge of viable Listeria.

Animals↗
PubMed2003

Genetic determinants of arterial thrombosis.

Arterial thrombosis is a complex disorder that involves multiple genetic and environmental factors interacting to produce the characteristic phenotype. In the past decades, investigators have focused on the molecular genetics of arterial vascular disorders and have identified numerous polymorphisms and mutations in genes related to the hemostatic system and to enzymes involved in the synthesis and bioavailability of nitric oxide (NO); however, the relation between most polymorphisms and the risk of coronary artery disease, ischemic stroke, and peripheral vascular disease remains highly controversial. In this review, we describe the most common genetic variations involved in the pathogenesis of arterial thrombosis, their functional implications, and their association with disease risk. Specifically, we consider polymorphisms in coagulation factors (fibrinogen, prothrombin, FV Leiden, FVII, and FXIII); fibrinolytic factors (tissue-type plasminogen activator, plasminogen activator inhibitor-1, and thrombin-activatable fibrinolysis inhibitor); platelet surface receptors; methylenetetrahydrofolate reductase; endothelial NO synthase; and the antioxidant enzymes paraoxonase and plasma glutathione peroxidase. Overall, there seems to be a modest contribution of individual genetic variants in the hemostatic and antioxidant systems to the risk of arterial thrombosis. Thus, future research ought to focus on identifying novel genetic determinants and on the interaction of these genetic risk factors with each other and the environment to understand better the pathobiology and susceptibility to arterial thrombotic disease.

Animals↗
PubMed1986

Organization and expression of genetic determinants for synthesis and assembly of type 51 R bodies.

Type 51 R bodies are produced by all bacterial endosymbionts (Caedibacter taeniospiralis) of Paramecium tetraurelia that confer the hump-killer trait upon their hosts. Type 51 R-body synthesis by C. taeniospiralis is required for expression of the hump-killer trait. The genetic determinants for type 51 R-body synthesis by C. taeniospiralis 47 have been cloned and expressed in Escherichia coli. In this communication we describe three species of polypeptides required for R-body synthesis and the organization of their genetic determinants. Each polypeptide species is controlled by a separate gene that is expressed as an independent transcriptional unit possessing regulatory signals that are recognized by E. coli. Two polypeptide species of 10 and 18 kilodaltons are required for R-body synthesis but apparently are not structural subunits. The third polypeptide species (13 kilodaltons) is the major structural subunit. R-body assembly involves polymerization reactions that result in high-molecular-mass polypeptide complexes, primarily composed of the 13-kilodalton polypeptide species, that appear to be the result of covalent cross-linking between structural subunits. The results presented here have been suggested to apply to the assembly and structure of all type 51 R bodies, but not necessarily to other R-body types.

Animals↗
PubMed1990

Genetic determinants modulating the pathogenic phenotype of tick-borne orbiviruses.

Genetic studies have been carried out on orbiviruses in the Great Island (GI) antigenic subgroup of the Kemerovo serogroup (Orbivrus, Reoviridae) to elucidate the functions of the 10 genomic double-stranded RNA segments. Such studies have shown that segment 4 is the major genetic determinant of neurovirulence (P.A. Nuttall, S.R. Moss, L.D. Jones, and D. Carey, 1989, Virology 172, 428-434), whereas segment 5 of Wexford (WEX) virus and segment 6 of GI virus are the major determinants of serotype specificity (S.R. Moss, C.M. Ayres, and P.A. Nuttall, 1987, Virology 157, 137-144; S.R. Moss, C.M. Ayres, and P.A. Nuttall, 1988, J. Gen. Virol. 69, 2721-2727). In studies with reassortants isolated following dual infection of cell cultures with WEX and GI viruses, the gene combination W4G6 (i.e., viruses deriving segment 4 from WEX virus and segment 6 from GI virus) resulted in nonpathogenic reassortants. Unlike the parental viruses, the avirulent reassortants did not produce clinical evidence of infection in inoculated 2-day-old mice although, suprisingly, they replicated in the brains of the mice. The alternate heterotypic gene combination, G4W5, resulted in typical neurovirulent reassortants. The results indicate that segment 6 of GI virus is able to modulate the phenotypic expression of segment 4 of WEX virus, but not vice versa. Modulation probably results from interactions between the products of these two genomic segments, possibly at the level of virion structure.

Animals↗
PubMed1983

Inhibition of pentylenetetrazol induced genetically-determined stereotypic convulsions in tottering mutant mice by diazepam.

Genetically-determined stereotypic behavioral convulsions (GDSC) resulting from the autosomal recessive mutation tottering (tg) were studied in C57BL/6J mice. GDSC was found to be reliably induced in (tg/tg) homozygotes with 30 mg/kg pentylenetetrazol (PTZ), a dose that is significantly below the threshold for induction of generalized clonic convulsions in (tg/+) heterozygotes and (+/+) wild type C57BL/6J mice. The effects of anticonvulsant drugs on GDSC were studied in (tg/tg) mice induced by 30 mg/kg PTZ. Ethosuximide (250 mg/kg), phenytoin (25 and 50 mg/kg), sodium phenobarbital (25 and 50 mg/kg), naloxone (6 mg/kg), valproic acid (150 mg/kg), sodium valproate (200 mg/kg) and aminooxyacetic acid (25 mg/kg) were all without effect on PTZ induced GDSC. In contrast to its usual anticonvulsant action, phenytoin caused GDSC in (tg/tg) mice. Diazepam (4 mg/kg) was completely effective in blocking GDSC 2 hr post administration. Ethosuximide (250 mg/kg), which did not protect (tg/tg) mice against GDSC, was able to protect both (tg/tg) and (tg/+) mice against generalized clonic-tonic convulsions induced by 85 mg/kg PTZ. These results suggest a novel mechanism of action for the induction of GDSC by 30 mg/kg PTZ in (tg/tg) mice which may involve benzodiazepine receptors.

Animals↗
PubMed1993

Responsiveness for mouse IgG2b antibodies to the human alpha/beta T-cell receptor/CD3 complex: evidence for genetic determination and low grade antibody cross-linking not mediated by known Fc gamma receptors.

Mouse IgG2a and IgG3 antibodies directed to the human T-cell receptor/CD3 complex stimulate peripheral blood mononuclear cells in almost all individuals. By contrast, responder and non-responder individuals exist for the stimulatory effect of mouse IgG1 and IgG2b antibodies. Whereas responsiveness to IgG1 antibodies is rather frequent (60-70%) and is known to be determined by an Fc gamma RII polymorphism on the accessory cells, little is known about the underlying factors of the rare (6%) IgG2b responsiveness. In this study it is shown that (1) IgG2b responsiveness is genetically determined with a dominant pattern of inheritance; (2) IgG2b responsiveness is determined by a radioresistant feature of responder accessory cells which can be substituted by artificial cross-linking, but not by IL-1 beta or IL-2; (3) stimulation of peripheral blood mononuclear cells of an IgG2b responder by IgG2b antibodies requires rather high antibody concentration compared with stimulation by IgG2a antibodies; (4) the stimulation leads to proliferation and IL-2 receptor expression, but no measurable IL-2 production; (5) antibody binding to known Fc gamma receptors (Fc gamma RI, Fc gamma RII, Fc gamma RIII) is not involved in the stimulatory effect of the IgG2b antibodies in responders. These results demonstrate that responsiveness to IgG2b antibodies against the TcR/CD3 complex depends on a genetically determined feature of accessory cells that is not identical with any of the known Fc gamma receptors. Most likely, the stimulatory effect observed in IgG2b responders is explained by a low grade cross-linking of the antibody by a not yet identified polymorphic structure on the surface of accessory cells.

Animals↗
PubMed2002

Mapping the viral genetic determinants of endothelial cell tropism in human cytomegalovirus.

Endothelial cells are natural sites of infection for human cytomegalovirus (HCMV) and are increasingly recognized to play an important role in viral dissemination, as well as provide access to underlying tissues and organs. However, the viral factors required for endothelial cell tropism are poorly defined. The goals of the project were to develop a system to study endothelial cell infectivity factors in HCMV, and map the viral genetic determinants required for these tropism functions. HCMV infection of primary aortic endothelial cells (AEC) was studied as a means to evaluate aspects relevant to both pathogenesis of acute infection and chronic vascular diseases. A series of HCMV virus strains was screened for endothelial tropism by comparing replication efficiencies on AEC. A virus strain that was efficient for replication (AD169varATCC), and a virus strain that was restricted for replication (Toledo), were selected for further analysis and characterization. We present evidence for a novel HCMV endothelial tropism factor that functioned following viral internalization across the endothelial cell plasma membrane and prior to nuclear entry. This factor may be involved in intracellular transport of the virion capsid-tegument structure. Complementation approaches using pseudotype virus infection of AEC demonstrated that the tropism defective strain could be rescued in trans. This supported the existence of a viral encoded tropism determinant. Using a gain of function approach, endothelial cell infectivity of the non-tropic HCMV strain Toledo was rescued with AD169 cosmid sequences. Tropism-specific viral genetic determinant(s) may be mapped to a region of the AD169 viral DNA encompassing UL48-56.

Aorta↗
PubMedDate not supplied

[Evaluation of the degree of genetically determined reactions of the human cardiorespiratory system to hypoxia and hypercapnia].

Using the twin method (16 pairs of monozygotic and 14 pairs of dizygotic twins), the role of the genotype and environment in the phenotypical variations of cardiorespiratory reactions to increasing hypoxia and hypercapnia was investigated. The process of emergency adaptation to acute hypoxia was shown to be associated with both genetically determined potentialities and acquired abilities. It is suggested that regular training may change sensitivity and emergency mechanisms of adaptation to hypoxia. However, the level of these changes depends on the individual genotype. The variability of hypercapnia sensitivity which is an individual genetically determined constant appears to be very low.

Adaptation, Physiological↗
PubMed1990

The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone.

Propranolol and the sodium-channel-blocking antiarrhythmic agent propafenone share structural features. Although propafenone's beta-blocking actions are readily demonstrable in vitro, clinically significant beta-blockade occurs inconsistently in vivo. In this study, we tested the hypothesis that genetically determined variations in the biotransformation of propafenone to its 5-hydroxy metabolite account for variations in the drug's beta-blocking action. We assessed beta-blockade by measuring the reduction in tachycardia produced by boluses of isoproterenol and treadmill exercise in 14 normal subjects during treatment with placebo and with 150, 225, and 300 mg of propafenone every eight hours for five days each. Nine subjects (with the extensive-metabolizer phenotype) metabolized most of the propafenone to 5-hydroxy propafenone, and five (with the poor-metabolizer phenotype) did not produce this metabolite. At the lower dosages, beta-blockade was present in both groups but was significantly greater in the subjects with poor metabolism, in whom deficient 5-hydroxylation was associated with higher plasma propafenone levels. At the highest dose, a similar degree of beta-blockade was observed in the two groups. Propafenone also had a higher affinity for beta 2 receptors in vitro than either of its major metabolites. We conclude that the degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which is necessary for beta-blockade, and that this action of propafenone is considerably enhanced in patients with deficient 5-hydroxylation of propafenone.

Adrenergic beta-Antagonists↗
PubMed1986

High fetal hemoglobin production in sickle cell anemia in the eastern province of Saudi Arabia is genetically determined.

Homozygous sickle cell disease in the eastern province of Saudi Arabia is clinically mild. Circulating fetal hemoglobin levels of 16.0 +/- 7.4% were found in these anemic patients, but only 1.09 +/- 0.97% in their sickle trait parents. To determine whether these sickle cell anemia patients inherit an increased capacity to synthesize fetal hemoglobin, a radioimmunoassay of fetal and adult hemoglobin was performed on erythroid progenitor (BFU-E)-derived erythroblasts from Saudi Arabian sickle cell patients and their parents. Mean fetal hemoglobin content per BFU-E-derived erythroblast from Saudi Arabian sickle cell patients was 6.2 +/- 2.4 pg/cell or 30.4 +/- 8.6% fetal hemoglobin (normal 1.1 +/- 0.7 pg/cell and 5.1 +/- 1.8%). Linear regression analysis of % HbF in peripheral blood versus % HbF per BFU-E-derived cell showed a positive correlation with an r of 0.65. The variance of the intrinsic capacity to produce HbF may account for almost 40% (r2) of the variance of circulating fetal hemoglobin but other factors, particularly selective survival of F cells, must also contribute significantly. Despite virtually normal HbF levels in sickle trait parents of these Saudi patients, mean fetal hemoglobin production per BFU-E-derived erythroblast in these individuals was elevated to 3.42 +/- 1.79 pg/cell or 16.1 +/- 6.4% fetal hemoglobin, and the magnitude of fetal hemoglobin production found in parents correlated with that of the patients. These data indicate that the high fetal hemoglobin in Saudi sickle cell disease is genetically determined but expressed only during accelerated erythropoiesis. Further evidence of such genetic determination was provided by analysis of DNA polymorphisms within the beta-globin gene cluster on chromosome 11. This revealed a distinctive 5' globin haplotype (+ + - + +) on at least one chromosome 11 in all high F SS and AS tested. The precise relationship of this haplotype to HbF production in this population remains to be defined.

Anemia, Sickle Cell↗
PubMed1997

What is the evidence that osteoarthritis is genetically determined?

Although for many years it was speculated that osteoarthritis was genetically determined, little data were available to support this contention. A major problem with early work was a lack of consistency in the definition of osteoarthritis. Based on a radiographical definition of osteoarthritis, which is currently the optimal method for epidemiological and genetic studies, data from a recent twin study have provided an estimate of the hereditable component of osteoarthritis to be in the order of 50 to 65%. In addition, sophisticated molecular biology techniques are being increasingly used to explore potential genetic abnormalities in cartilage and matrix components in osteoarthritis. These exciting new data are examined as we address the role of genetic factors in osteoarthritis.

Cartilage, Articular↗
PubMed2006

The quest for genetic determinants of human longevity: challenges and insights.

Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress.

Alleles↗
PubMed2001

Genetic determinants of IL-6 expression levels do not influence bone loss in inflammatory bowel disease.

Bone loss in inflammatory bowel disease (IBD) is presumed to be mediated by inflammation. Increased levels of the multifunctional cytokine IL-6 in inflammatory diseases have been proposed to be the link in such "inflammation-mediated osteopenia." A recently described G/C polymorphism with an effect on transcription rate and plasma levels of IL-6 suggests a genetically determined difference in the degree of the IL-6 response to stressful stimuli between individuals. This study aimed to assess the frequency of genotypes and haplotypes of the G/C polymorphism of IL-6 in IBD patients. A further aim was to assess whether carriage of the potentially protective CC genotype is favorable with respect to the development of bone disease in IBD. The IL-6 polymorphism was typed in 105 IBD patients and 113 healthy controls. Bone mineral density was evaluated at baseline and after a prospective 2-year-follow-up. The favorable CC genotype with decreased IL-6 release was not underrepresented in IBD patients compared to healthy controls. Carriage of this genotype was not protective with respect to the development of bone disease, either for the bone mineral density at baseline or for the prospectively observed bone loss. Within the subgroup of patients who did not receive steroids during follow-up, the prospectively observed bone loss was even slightly higher in CC carriers, but differences did not reach significance. Genetically determined differences in the degree of the IL-6 response to stressful stimuli are no major predictors for the degree of bone disease in IBD patients.

Adult↗
PubMed1981

Intraindividual stability and extent of genetic determination of platelet monoamine oxidase activity.

Intraindividual stability and extent of genetic determination of platelet MAO activity with tryptamine as substrate was evaluated. Repeated determinations on the same days as well as during an interval of 1-30 days show a high intraindividual stability of MAO. Reexamination of subjects who had formerly been selected because of either low or high MAO activity led to a "regression to the mean", thus pointing to a certain influence of environmental factors on the enzyme values. Twin and family studies, however, show a remarkable influence of genetic factors.

Blood Platelets↗
PubMed1979

Genetically determined, interferon-dependent resistance to influenza virus in mice.

The genetically determined resistance towards orthomyxoviruses exhibited by mice homozygous (A2G) or heterozygous (A2G X A/J) for the gene Mx was abolished or greatly diminished by treatment with anti-interferon globulin (AIF). AIF induced increased susceptibility to challenge with hepatotropic, neurotropic, and pneumotropic strains of influenza A virus. Hepatotropic virus titers in blood and livers of AIF-treated, Mx-bearing mice were higher by a factor of 10(3)--10(6) than those in untreated mice of the same genotype, and were comparable to those in genetically susceptible (untreated or AIF-treated) mice. Peritoneal macrophages from Mx-bearing untreated mice were resistant to challenge with a macrophage-adapted strain of influenza A virus even in the presence of AIF. However, when macrophages were taken from resistant mice injected with AIF and also cultivated in the presence of AIF, they were as susceptible to the virus as macrophages taken from susceptible mice. We conclude that interferons is an important factor in resistance to orthomyxoviruses governed by the gene Mx.

Animals↗
PubMed1998

Genetic determinants of autoimmune disease and coronary vasculitis in the MRL-lpr/lpr mouse model of systemic lupus erythematosus.

MRL-lpr/lpr (MRL/lpr) mice are a model of human autoimmune disease. They exhibit a number of characteristics of systemic lupus erythematosus, including anti-DNA Abs, anti-cardiolipin Abs, immune complex-mediated vasculitis, lymphadenopathy, and severe glomerulonephritis. Although the autoimmune disorder is mediated primarily by mutation of the Fas gene (lpr), which interferes with lymphocyte apoptosis, MRL/lpr mice also have other predisposing genetic factors. In an effort to identify these additional factors, we have applied quantitative trait locus (QTL) mapping using an intercross between MRL/lpr mice and the nonautoimmune inbred strain BALB/cJ. A complete linkage map spanning the entire genome was constructed for 189 intercross progeny, and genetic loci contributing to features of the autoimmunity were identified using statistical analytic procedures. As expected, the primary genetic determinant of autoimmune disease in this cross was the Fas gene on mouse chromosome 19, exhibiting a lod score of 60. In addition, two novel loci, one on chromosome 2 (lod score, 4.3) and one on chromosome 11 (lod score, 3.1), were found to contribute to levels of anti-DNA Abs. Interestingly, the chromosome 19 and chromosome 11 QTLs, but not the chromosome 2 QTL, also exhibited associations with anti-cardiolipin Abs (lod scores, 38.4 and 2.6). We further examined the effects of these QTLs on the development of coronary vasculitis in the F2 mice. Our results indicate that the QTLs on chromosomes 11 and 19 also control the development of vasculitis, demonstrating common genetic determinants of autoantibody levels and vasculitis.

Animals↗