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PubMed2004

Neural basis of genetically determined visuospatial construction deficit in Williams syndrome.

A unique opportunity to understand genetic determinants of cognition is offered by Williams syndrome (WS), a well-characterized hemideletion on chromosome 7q11.23 that causes extreme, specific weakness in visuospatial construction (the ability to visualize an object as a set of parts or construct a replica). Using multimodal neuroimaging, we identified a neural mechanism underlying the WS visuoconstructive deficit. Hierarchical assessment of visual processing with fMRI showed isolated hypoactivation in WS in the parietal portion of the dorsal stream. In the immediately adjacent parietooccipital/intraparietal sulcus, structural neuroimaging showed a gray matter volume reduction in participants with WS. Path analysis demonstrated that the functional abnormalities could be attributed to impaired input from this structurally altered region. Our observations confirm a longstanding hypothesis about dorsal stream dysfunction in WS, demonstrate effects of a localized abnormality on visual information processing in humans, and define a systems-level phenotype for mapping genetic determinants of visuoconstructive function.

Adult↗
PubMedDate not supplied

Heart size in inbred strains of rats. Part 1. Genetic determination of the development of cardiovascular enlargement in rats.

The heart and aorta weights in 23 strains of rats and the four-way cross generation among the M520/N, SHRSP/N, SHR/N, and WKY/N strains were investigated in relation to their blood pressure in an attempt to characterize cardiovascular enlargement (increased weight of heart and aorta) from a genetic aspect. The distribution of blood pressure in these strains at 10 weeks of age was clearly divided into hypertensive and normotensive groups. In the hypertensive group, heart weight increased in proportion to blood pressure. In contrast, there was no relationship between blood pressure and heart weight in the normotensive group in spite of large strain differences in heart weights. The result of variance analysis exhibited a significant strain difference in heart weight, and the degree of genetic determination was estimated to be 65%-75%. A similar genetic influence was apparent for normotensive strains excluding hypertensive strains. The distribution of blood pressures in the four-way cross generation showed the segregation of three phenotypes consisting of normotensive, intermediate and hypertensive groups. A large variability was seen in heart weight of each group. However, the increase in average heart weight of these three groups was very small. The degree of genetic determination from the cross analysis was estimated to be 45%-65%. These results indicate that heart weight is a highly heritable trait, and that the effect of genetic factors on cardiac enlargement is larger than that of blood pressure. A similar result was obtained for the aorta weight. However, the effect of genetic factors was less important for aorta weight than for heart weight since the degree of genetic determination was estimated to be 45%-65% from the strain comparison and 35%-60% from the cross analysis.

Age Factors↗
PubMed1991

Is preterm delivery genetically determined?

Surprisingly, the genetics of preterm delivery have received very little attention in the literature. Possible explanations are the inability to obtain accurate information on the length of gestation in family studies and the heterogeneous nature of this disorder. In contrast to the many studies which consider the relative contribution of both genetic and environmental variance to the total variance of birthweight, few studies have examined the genetic basis of the duration of gestation in man. It is argued that both genetic and epidemiological approaches are needed to separate the effects of heredity and the environment on the duration of gestation.

Birth Weight↗
PubMed1989

[Plasmids and genetic determinants of antibiotic resistance of gram-negative bacteria].

Distribution of plasmids and genetic determinants of antibiotic resistance was studied in 129 strains of Pseudomonas, Klebsiella, Serratia and Enterobacter isolated from oncological patients. It was shown that 56 isolates contained the plasmids, 9 conjugative plasmids being plasmids with broad bacterial host spectrum. A significant part of the strains contained genes controlling production of APH (3"), type II APH (3'), type I and II DHPS and type type II DHFR. Genetic determinants of tetracycline resistance of classes D and E were detected for the first time in the strains of Klebsiella, Serratia and Pseudomonas aeruginosa.

Anti-Bacterial Agents↗
PubMed1988

Are alpha- and beta-adrenoceptor changes in patients with essential hypertension genetically determined?

In order to find out whether adrenoceptor changes in essential hypertension might be genetically determined, we measured platelet alpha 2- and lymphocyte beta 2-adrenoceptor density in 48 normotensive children with normotensive parents, and 41 normotensive children who had one essential hypertensive parent and thus should have had a genetic predisposition for the development of hypertension. The groups did not differ with regard to blood pressure and heart rate, age, body weight and height, plasma renin activity and catecholamines, and serum electrolytes and creatinine. Lymphocyte beta 2-adrenoceptor density (assessed by 125I-iodocyanopindolol binding) and responsiveness (assessed as 10 mumol/l isoprenaline-induced cyclic AMP increases) did not differ between the groups. Platelet alpha 2-adrenoceptor density (assessed by 3H-yohimbine binding) was significantly higher in children with one essential hypertensive parent. We conclude that platelet alpha 2- but not lymphocyte beta 2-adrenoceptor changes in essential hypertension are genetically determined.

Blood Platelets↗
PubMed2004

Host genetic determinants in hepatitis C virus infection.

In addition to viral and environmental/behavioural factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes in hepatitis C virus (HCV) infection. This paper reviews the literature with respect to studies of host genetic determinants of HCV outcome and attempts to highlight trends and synthesise findings. With respect to the susceptibility to HCV infection, several studies have replicated associations of the HLA class II alleles DQB1(*)0301 and DRB1(*)11 with self-limiting infection predominantly in Caucasian populations. Meta-analyses yielded summary estimates of 3.0 (95% CI: 1.8-4.8) and 2.5 (95% CI: 1.7-3.7) for the effects of DQB1(*)0301 and DRB1(*)11 on self-limiting HCV, respectively. Studies of genetics and the response to interferon-based therapies have largely concerned single-nucleotide polymorphisms and have been inconsistent. Regarding studies of genetics and the progression of HCV-related disease, there is a trend with DRB1(*)11 alleles and less severe disease. Studies of extrahepatic manifestations of chronic HCV have shown an association between DQB1(*)11 and DR3 with the formation of cryoglobulins. Some important initial observations have been made with respect to genetic determinants of HCV outcome. Replication studies are needed for many of these associations, as well as biological data on the function of many of these polymorphisms.

Antiviral Agents↗
PubMed1991

Membranoproliferative glomerulonephritis in dogs with a genetically determined deficiency of the third component of complement.

Renal disease is a common clinical manifestation of genetically determined deficiencies of the complement system in man. Like their human counterparts, dogs with a genetically determined complete deficiency of C3 also develop renal disease. Five of 20 C3-deficient dogs developed clinical evidence of renal failure. However, 14 of the 15 remaining dogs had histological evidence of type I membranoproliferative glomerulonephritis. The lesions were characterized by mesangial cell proliferation, an increase in the mesangial matrix, thickening of the glomerular capillary wall, electron-dense deposits in the mesangium and subendothelial space, and the presence of IgG and IgM. In order to determine the effect of treatment with C3 on the renal disease of C3-deficient dogs, two C3-deficient dogs were infused with normal canine plasma twice weekly for 3 weeks. Their urinary protein excretion rose progressively from less than 200 mg/24 hr to greater than 1000 mg/24 hr; renal function remained normal. Renal biopsies performed 1 week after the last infusion revealed more severe glomerulonephritis and the presence of C3. As controls, a C3-deficient dog was given C3-deficient canine plasma and a normal dog was given normal canine plasma; neither control animal developed proteinuria or changes in their renal biopsy. These observations suggest that renal disease may be more common in humans with complement deficiencies than would be suspected based on clinical assessment. Furthermore, these results suggest that treatment with complement-containing blood products may worsen preexisting renal disease in complement-deficient individuals.

Animals↗
PubMed2004

Genetic determinants of the inflammatory response.

PURPOSE OF REVIEW: Despite substantial advances in our understanding of the biology of sepsis and inflammation, improvements in clinical outcomes have been more sporadic and, with few notable exceptions, are related to improvements in supportive care rather than to specific therapies. As a result, morbidity, mortality, and cost remain high. Investigation into the genetic determinants of this response span a broad spectrum and include those aimed at deciphering the mechanisms and involved pathways on a molecular level, to those aiming to identify how genetic variation may be clinically important. While it is clear that gene sequencing and manipulation of experimental models have provided insight into the biology of the inflammatory response to infection, these technologies and their application to the study of naturally occurring human genetic variation have yet to provide the same insight or clinical benefit. The purpose of this review is to summarize what is known about the genetic determinants of the inflammatory response. We make particular reference to this broad scope of investigation introduced above but with a focus on the present status of studies examining the role of human genetic variation in the risk for and outcome from severe bacterial infection, or sepsis. RECENT FINDINGS: Using the examples of two candidate genes tumor necrosis factor-alpha (TNF-alpha) and toll-like receptor 4 (TLR4), we illustrate the spectrum of studies concerning the genetic determinants of the inflammatory response. We highlight recent literature across this spectrum, focusing on genetic association studies examining the relationships between SNPs in these genes and sepsis risk and outcome. We then review the literature addressing discordant findings in basic experimental observations and studies of clinical association. SUMMARY: Naturally occurring genetic variants in important inflammatory mediators such as TNF-alpha and TLR4 appear to alter inflammatory responses in numerous experimental and a few clinical models of inflammation. However, inconsistencies exist in the literature regarding the association between these genetic variants and disease (eg, sepsis) susceptibility and prognosis. The main limitations relate to the translation of experimental observations into reproducible genotype-phenotype associations. The reasons for these are multifactorial and include deficiencies in study design (insufficient sample size), and the complexities introduced by background genetic heterogeneity.

Genetic Predisposition to Disease↗
PubMedDate not supplied

[The involvement of brain 5-HT(1A)-receptors in genetically determined aggressive behavior].

The hypothesis was tested that one of the critical mechanisms underlying genetically determined aggressiveness involves brain serotonin 5-HT(1A)-receptors. The expression of 5-HT(1A)-receptor mRNA in brain structures and functional correlate for 5-HT(1A)-receptors identified as 8-OH-DPAT-induced hypothermia were studied in Norway rats bred over the course of 59 generations for the low and high affective (defensive) aggressiveness with respect to man and in highly aggressive (offensive) MAO A-knockout mice (Tg8 strain). Considerable differences between the aggressive and the nonaggressive animals were shown. Agonist of 5-HT(1A)-receptor 8-OH-DPAT (0.5 mg/kg for rats and 2.0 mg/kg for mice, i.p.) produced a distinct hypothermic reaction in nonaggressive rats and mice and did not affect significantly the body temperature in aggressive animals. In aggressive rats, a significant reduction of the expression of 5-HT(1A)-receptor mRNA was found in the midbrain. In Tg8 mice, 5-HT(1A)-receptor mRNA level was increased in the frontal cortex and amygdala and not changed in the hypothalamus and the midbrain. The results provide support for the idea that brain 5-HT(1A)-receptors contribute to the genetically determined individual differences in aggressiveness.

Aggression↗
PubMed2002

Genetic determinants of sensitivity to pentobarbital in inbred mice.

RATIONALE: We postulated that genetic determinants of different responses to pentobarbital (PB) in mice would differ from response to response. OBJECTIVES: Mice from 14 standard inbred strains were tested for sensitivity to several effects of acute PB. METHODS: Strains were tested for sensitivity to PB-induced low-dose stimulation and high-dose depression of locomotor activity, reduced rearing, hypothermia, and ataxia assessed on a rotarod, using four doses of PB or saline. RESULTS: Strains differed in sensitivity to PB for all responses. Correlations among strain means indicated that strain sensitivity to a particular effect of PB generalized rather well across doses. Sensitivities to some of the different behavioral responses were also significantly correlated. For example, strains less sensitive to PB-induced enhanced locomotor activity were also significantly more sensitive to the drug's hypothermic effects. Some responses were genetically independent. Brain PB concentrations were also determined, and appeared to be unrelated to inbred strain drug sensitivities. CONCLUSIONS: Overall, these results suggest that there are multiple genetic determinants of behavioral sensitivity to PB effects. That is, genetically influenced sensitivity to PB is not monolithic, but is somewhat specific to the particular response variable studied, a result that also characterizes genetic control of responses to other drugs.

Animals↗
PubMed1976

On genetically determined human serum cholinesterases.

The existence of genetically determined human serum cholinesterase variants (actlcholine acyl-hydrolase; EC 3.1.1.8) has been recognized by the use of a short acting muscle relaxant, suxamethonium. This polymorphism is now explained by at least four alleles belonging to an autosomal locus Ch1 or E1 depending on the nomenclature. These are: the usual gene, the dibucaine-resistant gene, the fluoride-resistant gene and the silent gene. At present, the modes of transmission for the silent genes is confusing and lack proper understanding. Another variant, not an allele of the first group, is recognized by gel electrophoresis, belong to a second locus Ch2 or E2. Evidence has been presented that many more rare serum cholinesterase variants may exist. Besides these genetic variants, normal serum cholinesterase is known to exist in multiple molecular forms. The present article attempts to discuss the polymorphism of human cholinesterase in relation to their chemical and genetic characteristics and their possible function.

Acetylcholinesterase↗
PubMed2006

Genetic determination and correlation of body weight and body mass index (BMI) and cross-sectional geometric parameters of the femoral neck.

INTRODUCTION: This study aimed to examine the genetic determination of body weight, body mass index (BMI) and cross-sectional geometric parameters of the femoral neck including cross-sectional area (CSA), cortical thickness (CT), sectional modulus (Z), and buckling ratio (BR), and to test the genetic correlation between body weight/BMI and the femoral neck geometric parameters. METHODS: A total of 929 healthy subjects from 292 Chinese nuclear families was included. Femoral neck geometric parameters were estimated from bone mineral density (BMD) and bone area which were measured by dual energy X-ray absorptiometry (DXA). RESULTS: The heritability (h(2)) estimate values were 0.643, 0.626, 0.626, 0.674, 0.405, and 0.615 for body weight, BMI, CSA, CT, Z, and BR, respectively. Body weight was significantly correlated with bone geometric parameters (p</=0.001) with genetic correlation (rho(G)) values of 0.551, 0.457, 0.571, and -0.385, and bivariate heritability (rho2G) values of 0.304, 0.209, 0.326, and 0.148 for CSA, CT, Z, and BR, respectively. Similar correlations (p</=0.001) were observed between BMI and bone geometric parameters, with rho(G) values of 0.446, 0.432, 0.334, and -0.362, and (rho2G) values of 0.199, 0.187, 0.112, and 0.131 for CSA, CT, Z, and BR, respectively. CONCLUSION: In summary, our study suggested that body weight, BMI, and femoral neck geometry were under strong genetic determination. The strong genetic correlations suggested that the genetic factors of bone geometry may be overlapped with those of body weight and BMI.

Absorptiometry, Photon↗
PubMed1993

Experimental evidence of genetic determinism in high susceptibility to intestinal pinworm infection in mice: a hybrid zone model.

In the hybrid zone of the two mouse subspecies Mus musculus musculus and Mus musculus domesticus, mice with hybrid genotypes harbour, on the average, more helminth parasites (cestodes and nematodes) than mice of the two parental taxa. In order to determine the roles played by genetic parameters in this phenomenon, mice with recombined and parental genotypes were experimentally infected with the intestinal pinworm Aspiculuris tetraptera, a natural parasite of the house mouse. The results showed that the high susceptibility of the hybrid zone mice is genetically determined. In addition, this study shows the occurrence of variability among resistant parental populations.

Analysis of Variance↗
PubMed2005

[Genetic determinants of osteoporosis].

Osteoporosis is a chronic progressive disease, characterized by higher bone resorption than bone mass accumulation. This leads to reduction of the bone mass, to microarchitectural deterioration of the bone tissue and to the increased risk of bone fracture. Osteoporosis affects predominately postmenopausal females, but it is also diagnosed at elderly males. Although osteoporosis is influenced by various environmental factors (mainly by dietary habits and physical activity), analysis of results obtained from studies with different designs (population-, family-, association- studies) confirmed, that risk of osteoporosis development and risk of osteoporotic fractures are significantly influenced by genetic predispositions. The genetic determination of osteoporosis is not yet completely understood. However, it is clear, that although there are mutations in some genes causing rare form of osteoporosis, osteoporosis is a polygenic disease--it is influenced by common variants (polymorphisms) of several different genes. For example genes for vitamin D receptor, estrogen receptor alpha, collagen type I alpha1, transforming growth factor beta-1 and some others are indicated to play a role in genetic determination of osteoporosis. In this review we summarize our recent knowledge about the genetic determination of osteoporosis.

Female↗
PubMed1998

Study on the genetic determinants responsible for expression and assembly of CS3 fimbriae.

Colonization factor antigens (CFAs) are important virulent factors and protective antigens of enterotoxigenic Escherichia coli (ETEC). Among the known CFAs of human origin, CS3 is a major fimbriae antigen. To study the genes associated with the expression and assembly of CS3 is a key step to delineate the regulating mechanism of expression and assembly of the fimbriae. In this paper we analyzed the restriction map of the CS3 genetic determinant and successfully cloned the CS3 subunit gene and the region encoding the auxiliary proteins. Expression results of the recombinant plasmids in minicells showed that the genetic determinant of CS3 fimbriae encodes six polypeptides with molecular weights 15, 17, 24, 27, 48, and 90 kDa. Western blotting and complementary expression analysis among the different mutants showed that the 15 kDa/17 kDa proteins compose the CS3 subunit and the 17 kDa protein is the precursor. The others may be necessary for the assembly of CS3 fimbriae. The relative locations of various genes of the CS3 genetic determinant were also determined.

Bacterial Proteins↗
PubMed1997

The feline leukemia virus long terminal repeat contains a potent genetic determinant of T-cell lymphomagenicity.

Feline leukemia virus (FeLV) is an important pathogen of domestic cats. The most common type of malignancy associated with FeLV is T-cell lymphoma. SL3-3 (SL3) is a potent T-cell lymphomagenic murine leukemia virus. Transcriptional enhancer sequences within the long terminal repeats (LTRs) of SL3 and other murine retroviruses are crucial genetic determinants of the pathogenicities of these viruses. The LTR enhancer sequences of FeLV contain identical binding sites for some of the transcription factors that are known to affect the lymphomagenicity of SL3. To test whether the FeLV LTR contains a genetic determinant of lymphomagenicity, a recombinant virus that contained the U3 region of a naturally occurring FeLV isolate, LC-FeLV, linked to the remainder of the genome of SL3 was generated. When inoculated into mice, the recombinant virus induced T-cell lymphomas nearly as quickly as SL3. Moreover, the U3 sequences of LC-FeLV were found to have about half as much transcriptional activity in T lymphocytes as the corresponding sequences of SL3. This level of activity was severalfold higher than that of the LTR of weakly leukemogenic Akv virus. Thus, the FeLV LTR contains a potent genetic determinant of T-cell lymphomagenicity. Presumably, it is adapted to be recognized by transcription factors present in T cells of cats, and this yields a relatively high level of transcription that allows the enhancer to drive the requisite steps in the process of lymphomagenesis.

3T3 Cells↗
PubMed2000

Use of a transient assay for studying the genetic determinants of Fv1 restriction.

To probe the genetic determinants controlling the interaction between the retroviral restriction gene Fv1 and its murine leukemia virus target, we set out to develop rapid, transient assays for Fv1 function. Cells were transfected or transduced with Fv1 expression plasmids which can produce green fluorescent protein via an internal ribosome entry site positioned between the Fv1 and green fluorescent protein coding sequences. Fv1 function was then assessed by comparing virus replication in green fluorescent protein-positive and -negative cells, using retroviral vectors encoding a second fluorescent marker, yellow fluorescent protein, or beta-galactosidase. Using this assay, we could show that Fv1 specificities were not as absolute as previously thought, since the Fv1(b) allele was capable of interacting with "nonrestricted" B- and NB-tropic viruses and by shuffling the n- and b-alleles of Fv1, it was possible to generate a Fv1 molecule capable of restricting N-, B-, and NB-tropic viruses equally efficiently. Further, we could show that the presence of nonrestricting Fv1 in the same cell as restrictive Fv1 abrogates restriction, implying competition for binding to the retroviral target.

Animals↗
PubMed2005

Resistance to metal contamination by historically-stressed populations of Ceriodaphnia pulchella: environmental influence versus genetic determination.

Field populations of daphnids historically-stressed by metal contamination may show increased resistance to those contaminants. This study was undertaken aiming to confirm/infirm three main hypotheses: (1) field populations living in historically-impacted environments are more tolerant to metal stress than populations from reference sites; (2) resistance differences are genetically-determined, i.e., differences persist after controlling for environmental and maternal effects, by acclimating cloned lineages to similar conditions; and (3) resistance to stress in field populations living in historically-impacted environments is due to the disappearance of sensitive individuals rather than the appearance of highly resistant ones, i.e., the shift in the central tendency of resistance is linked to a decrease in the range of population resistance and not to an increased upper limit of the population resistance. Three populations of the cladoceran Ceriodaphnia pulchella Sars in Southern Portugal were sampled; one of which has been historically-stressed by acid mine drainage (AMD) from an abandoned cupric-pyrite mine and two from reference sites within the same watershed. To assess if resistance differences were genetically-determined, the three populations were acclimated for at least five generations under the same controlled conditions. Assays with AMD contaminated water samples were performed with both non-acclimated and acclimated individuals from all studied populations. Reproduction results in sub-lethal assays revealed significant differences between the reference and stressed populations. Significant differences in resistance to lethal levels of toxicity were observed for both non-acclimated and acclimated populations, individuals from population I being more resistant than those from reference populations. The existence of genetically-determined sensitivity differences was attested by the presence of significant differences in resistance to lethal levels of toxicity in acclimated individuals from reference and stressed populations. Results from cumulative mortality assays revealed that sensitive individuals were most probably present in the original population, but no conclusion could be draw about the presence of extreme resistant individuals in the historically-stressed population. Finally, it was shown that responses among populations converged from high to low levels of contamination.

Adaptation, Physiological↗