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At least 1,027 records · Page 57Linked to original sources
PubMed2006

Polymorphism in the beta2-adrenergic receptor and lipoprotein lipase genes as risk determinants for idiopathic venous thromboembolism: a multilocus, population-based, prospective genetic analysis.

BACKGROUND: Candidate genes in inflammation, thrombosis, coagulation, and lipid metabolism pathways have been implicated in venous thromboembolism (VTE). METHODS AND RESULTS: Using DNA samples collected at baseline in the Physicians' Health Study cohort, we genotyped 92 polymorphisms from 56 candidate genes among 304 individuals who subsequently developed VTE (144 idiopathic, 156 secondary cases) and among 2070 individuals who remained free of reported vascular disease over a mean follow-up of 13.2 years to prospectively determine whether these gene polymorphisms contribute to the risk of VTE. For idiopathic VTE, in addition to the factor V (Leiden) mutation (odds ratio [OR], 5.13; 95% confidence interval [CI], 3.24 to 8.14; P<0.0001; false discovery rate [FDR], P<0.0001), an N291S lipoprotein lipase gene polymorphism (OR, 3.09; 95% CI, 1.56 to 6.09; P=0.001; FDR, P=0.036) and a Q27E beta2-adrenergic receptor gene polymorphism (OR, 1.40; 95% CI, 1.09 to 1.79; P=0.006; FDR, P=0.036) were found to be significantly associated with increased risk. For secondary VTE, a Q360H apolipoprotein A4 gene polymorphism (OR, 0.34; 95% CI, 0.18 to 0.65; P=0.001; FDR, P=0.07) and an I50V interleukin-4 receptor polymorphism (OR, 0.66; 95% CI, 0.52 to 0.84; P=0.0009; FDR, P=0.07) were moderately, but not statistically and significantly, associated with reduced risk after adjustment for multiple comparisons. CONCLUSIONS: These present findings are hypothesis generating and require replication and confirmation in an independent investigation.

Adult↗
PubMed1997

Genetic analysis of discrete reproductive traits in sheep using linear and nonlinear models: I. Estimation of genetic parameters.

Repeated records on fertility, litter size, and ovulation rate of Rambouillet ewes and on fertility and litter size of Finnsheep ewes were used to estimate heritabilities and repeatabilities with linear and nonlinear sire and animal models. Linear sire (LSM) and animal models were used with all traits. Nonlinear models were the threshold, Poisson, and negative binomial. Threshold sire (TSM) and animal models were used with all traits. Litter size and ovulation rate were analyzed also with Poisson sire and animal models and with negative binomial sire and animal models. Variance components for linear models were estimated using REML; in the threshold, Poisson, and negative binomial, they were estimated using approximate marginal maximum likelihood. Poisson and negative binomial analyses yielded results difficult to interpret due to problems in variance component estimation. Animal models resulted in slightly greater estimates of heritability for fertility than did sire models, but ovulation rate heritability estimates from sire models were much greater than estimates form animal models. Differences between sire and animal models for heritability estimates for litter size were not consistent. Threshold models resulted in higher heritability estimates for all traits in both breeds and with both sire and animal models. In general, repeatabilities were consistent across models. For example, LSM (TSM) repeatabilities were .10 (.14) for fertility, .20 (.25) for litter size, and .25 (.29) for ovulation rate in the Rambouillet, and .17 (.17) for fertility and .11 (.13 for litter size in the Finnsheep.

Aging↗
PubMed1998

Genetic analysis of the U5-PBS of a novel HIV-1 reveals multiple interactions between the tRNA and RNA genome required for initiation of reverse transcription.

A novel HIV-1 genome that stably utilizes tRNA(His) rather than tRNA(Lys,3) to initiate reverse transcription was used to study features for the interaction between the tRNA and viral RNA genome. In addition to a primer binding site (PBS) complementary to tRNA(His), this virus contains a six-nucleotide sequence in U5 complementary to the anticodon-loop of tRNA(His) and three additional substitutions: U174-to-G, G181-to-A, and U200-to-C [HXB2(His-AC-GAC)]. Mutations in these three nucleotides resulted in viruses with three different genotypes: one group maintained a PBS complementary to tRNA(His) with restored G174A181C200 or G174A181U200 configurations, one group reverted to a PBS complementary to tRNA(Lys,3), and one group contained two or more PBSs complementary to different tRNAs on the same viral genome. Characterization of a previously identified virus with additional C152-to-A and C160-to-U substitutions [HXB2(His-AC-A152U160-GAC)] revealed that this virus maintained a PBS complementary to tRNA(His), whereas a mutant HXB2(His-AC-U152A160-GAC) reverted after culture to contain dual PBS complementary to tRNA(Lys,3) and tRNA(His), respectively. Our results demonstrate that regions in U5 act in concert with the PBS to promote use of the tRNA primer for initiation of reverse transcription. These results are discussed with respect to structural models for the U5-PBS interactions with tRNA.

Anticodon↗
PubMed1999

Genetic analysis of multiplex rheumatoid arthritis families.

To examine the genetic contribution of HLA and non-HLA genes in the etiopathogenesis of rheumatoid arthritis (RA), 60 Caucasian multiplex families were identified and DNA analyzed for over 52 markers including DRB1, DQA1 and DQB1 alleles. Many of the markers were chosen because of close proximity to candidate genes suggested by previous studies or models of pathogenesis. Sibling pair analysis (SIBPAL), relative pair analysis (RELPAL) and linkage studies using two different models of inheritance suggested linkage for the MHC and two additional chromosomal regions: chromosome 2 (D2S443 near CD8 and IGk; 2p13-2p11.1), and chromosome 15 (CYP19-estrogen synthase; 15q15). No support was found for two chromosomal regions, 1p36 and 3q13, recently suggested by other studies. We used transmission disequilibrium testing (TDT), conditional logistic regression, and segregation analysis to study the contributions that the shared epitope and TNF-c have in contributing to risk for RA. These studies provide additional evidence that the association of HLA alleles in RA patients from multiplex families is similar to that observed in sporadic disease, suggest candidate regions for further analysis and find additional support for an association of TNF-c alleles with RA susceptibility.

Adult↗
PubMed2006

Genetic analysis of the stress-responsive adrenocortical axis.

The underlying genetic components contributing to individual variability in functions of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis are poorly understood. To determine genetic loci mediating three aspects of the adrenocortical function, we conducted a quantitative trait locus (QTL) analysis in the segregating F2 generation of a Wistar Kyoto (WKY) x Fischer 344 (F344) cross, two inbred rat strains that differ in several HPA axis measures. The following three components of adrenocortical function are known to be regulated by different mechanisms that are mediated via suprahypothalamic, hypothalamic, pituitary, and intra-adrenal influences: basal plasma corticosterone (Cort) levels, plasma Cort response to a 10-min restraint stress, and adrenal weight. Genome scans identified a complex genetic architecture for the basal Cort phenotype, including sex and maternal lineage effects. Pairwise interactions were also identified for this trait. We identified three significant and two suggestive QTLs for stress Cort, along with two pairs of interacting loci for this trait. Four highly significant and two suggestive loci were identified for adrenal weight, with no interacting loci. In contrast to basal Cort, no sex- or lineage-dependent QTL were identified for stress Cort or adrenal weight, despite the large sex differences in these phenotypes. We identified three nucleotide alterations in an obvious candidate gene mapped to the most significant QTL for stress Cort, Cort-binding globulin (CBG), one of which is known to alter CBG binding. This analysis confirms that three separate traits regulated by the HPA axis are controlled by multiple, but mainly nonoverlapping, QTLs.

Adrenal Glands↗
PubMed1986

A genetic analysis of nicotine effects on open field activity.

The genetics of the effects of nicotine on the open field activity of mice were studied using a 5 by 5 diallel cross. The five inbred strains used were: A, BALB, C57BL, DBA, and C3H. These strains differ both in basal open field activity as well as activity after injection of nicotine. Analysis of the results of baseline activity indicated that both additive and dominance variance affected the activity of the animals. The dominance was non-directional. Likewise, the responses observed after injection of 0.75 mg/kg nicotine displayed both additive and dominance components. However, after correcting the results for differences in basal activity, the dominance item was primarily directional. This directional dominance was towards a more intense response to the effects of the drug, that is, a decrease in open field activity.

Animals↗
PubMed1993

Evolutionary divergence of pobA, the structural gene encoding p-hydroxybenzoate hydroxylase in an Acinetobacter calcoaceticus strain well-suited for genetic analysis.

The pobA gene encoding p-hydroxybenzoate hydroxylase (PobA) from Acinetobacter calcoaceticus has been developed as a genetic tool for the analysis of structure-function relationships in this enzyme. By exploiting the favorable genetic system of A. calcoaceticus strain ADP1, it is possible both to select and to map mutations which disturb PobA activity; characterization and sequence determination of mutants derived in this manner may complement site-directed studies with the homologous Pseudomonas aeruginosa gene. We have determined the nucleotide (nt) sequence of A. calcoaceticus pobA and performed a systematic comparison of the deduced amino acid (aa) sequence with that of the PobA enzyme from Pseudomonas fluorescens, for which the three-dimensional structure is known. Despite a 26% difference in the G+C content of the homologous genes, constraints against structural divergence of the proteins were revealed by an overall identity of 62.4% in the aligned aa sequences of PobA. Clusters of identical sequence occur at previously identified sites of ligand binding and at regions associated with subunit-subunit interaction. Based on the conservation of specific residues involved in flavin binding, we have assembled a consensus sequence for nicotinamide-flavoprotein monooxygenases which differs from that of the oxidoreductase class of flavoproteins. In addition to the conserved regions shared by the two PobA homologs, there are isolated pockets of divergence. The nt sequence divergence in one such region within the A. calcoaceticus gene can be attributed to the acquisition of short nt sequence repetitions.

4-Hydroxybenzoate-3-Monooxygenase↗
PubMed2004

Genetic analysis of cholesterol gallstone formation: searching for Lith (gallstone) genes.

The genetics of cholesterol cholelithiasis is complex because a number of interacting genes regulate biliary cholesterol homeostasis. Quantitative trait locus (QTL) analysis is a powerful method for identifying primary rate-limiting genetic defects and discriminating them from secondary downstream lithogenic effects caused by mutations of the primary genes. The subsequent positional cloning of such genes responsible for QTLs may lead to the discovery of pathophysiologic functions of Lith (gallstone) genes. In this review, we present a map of candidate genes for Lith genes that may determine gallstone susceptibility in mice. The physical-chemical, pathophysiologic, and genetic studies of Lith genes in bile, liver, gallbladder, and intestine will be crucial for elucidating the genetic mechanisms of cholesterol gallstone disease in mice and in humans. Because exceptionally close homology exists between mouse and human genomes, the orthologous human LITH genes can often be recognized after mouse genes are identified.

Animals↗
PubMed1991

Genetic analysis of dystocia in dairy cattle.

Breeding values and genetic parameters for dystocia were estimated in Normande and Holstein breeds. Dystocia scores were related to an underlying continuous variable via a threshold model. The underlying linear model included the effects of calving season, sex of calf by parity of dam, sire of calf, grandsire of calf, dam within maternal grandsire and herd-year effects. Typical results were found for the environmental effects, with a strong influence of dam parity on dystocia, a strong influence of sex of calf, and a small effect of calving season. Herd-year variances were 32 and 40% of the residual variance in the Normande and Holstein breeds, respectively. Heritabilities for the Normande (Holstein) breed were .08 (.07) for direct effects and .11 (.07) for maternal effects. Correlations between sire and grandsire effects were .51 and .36 for the Normande and Holstein breeds, respectively. The corresponding correlations between direct and maternal effects were .15 and -.09. The results of this study show that a complete model for dystocia including the threshold concept and maternal effects can be applied for routine evaluation of dairy AI bulls. Maternal effects are important, and they should be considered in dystocia analysis, especially if nonrandom mating is present. Selection for reducing dystocia in calf and cow effects are not antagonistic.

Animals↗
PubMed1998

Clinical and genetic analysis of a distinct autosomal dominant spinocerebellar ataxia.

OBJECTIVE: To characterize a distinct form of spinocerebellar ataxia (SCA) clinically and genetically. BACKGROUND: The SCAs are a genetically heterogeneous group of neurodegenerative disorders affecting the cerebellum and its connections. The mutations for SCA1, 2, 3, 6, and 7 have been identified and shown to be due to expansion of a CAG repeat in the coding region of these genes. Two additional SCA loci on chromosomes 16 and 11 have been designated SCA4 and SCA5. However, up to 20% of individuals with autosomal dominant forms of ataxias cannot be assigned any of these genotypes, implying the presence of other unidentified genes that may be involved in the development of ataxia. METHODS: We ascertained and clinically characterized a six-generation pedigree segregating an autosomal dominant trait for SCA. We performed direct mutation analysis and linkage analysis for all known SCA loci. RESULTS: The mutation analysis excludes SCA1, 2, 3, 6, and 7, and genetic linkage analysis excludes SCA4 and SCA5 (multipoint location scores < -2 across the candidate region). Clinical analysis of individuals in this family shows that all affected members have dysarthria, gait and limb ataxia, and nystagmus. No individuals have major brainstem or long-tract findings. Analysis of age at disease onset through multiple generations suggests anticipation. CONCLUSION: This pedigree represents a genetically distinct form of SCA with a phenotype characterized by predominantly cerebellar symptoms and signs.

Adult↗
PubMed2005

Genetic analysis of dog rabies viruses circulating in Bangkok.

The genetic diversity of the rabies virus glycoprotein (G) gene isolated from individual rabid dogs (inter-hosts) and within a single infected dog (intra-host) has been analyzed in an effort to better understand selective pressures and population shifts among rabies viruses circulating in Bangkok. Comparison of individual master sequences among inter-hosts revealed that the dog virus isolates circulating in Bangkok were phylogenetically closely related. The ectodomain of the glycoprotein was highly conserved among the virus isolates. Furthermore, the genetic diversity of the G gene within an intra-host was assessed by comparing the cloned sequences in the virus population. The comparisons revealed that rabies virus circulating in an intra-host consisted of closely related heterogenous populations with minor substitutions at nucleotide (0.19%) and amino acid levels.

Amino Acid Sequence↗
PubMed2002

Genetic analysis of rabies virus isolates in the Philippines.

To determine the genetic characteristics of the rabies virus in the Philippines, 59 rabies virus isolates were obtained from domestic rabid dogs and their partial nucleotide sequences of nucleoprotein (N) gene were compared. Based on comparison with reported sequences, phylogenetic analysis revealed that all isolates from the Philippines had close genetic relations and formed two subgroups. The Philippines isolates belonged to a different lineage from other Asian isolates but were closer to them than to terrestrial isolates and laboratory strains. Several specific nucleotide and amino acid substitutions were observed among the Philippines isolates. Our results suggest that rabies viruses in the Philippines might have a characteristic evolution.

Amino Acid Sequence↗
PubMed1986

[Genetic analysis of precancer-cancer of the stomach system. II. Lactate dehydrogenase in families of the patients: is it a marker of hereditary predisposition?].

The possibility of using the LDH as a marker of hereditary predisposition to the stomach cancer was analysed by using the genetical correlational analysis. The LDH isoenzymes in the gastric body were studied in 56 pedigrees. Similar LDH alterations were detected in relatives with cancer and precancer (ulcer disease, atrophic gastritis). Relatives with no such pathology had LDH isoenzymes, similar to the control individuals. High and significant coefficients of phenotypic and environmental correlation of LDH and predisposition to the stomach cancer were obtained. The coefficient of genetic correlation was not significant. The problem of the origin of these LDH variances is discussed. The preliminary conclusion is that the LDH isoenzyme changes revealed in patients with stomach cancer appear as a consequence of the disease, and cannot be used as the marker of hereditary predisposition.

Disease Susceptibility↗
PubMed1993

A genetic analysis of the Werner syndrome region on human chromosome 8p.

Werner syndrome (WRN) is an inherited disorder that produces symptoms of premature aging. This disease is caused by a recessive mutation that has previously been mapped to chromosome 8p. We have now used genetic linkage analysis to map the WRN gene relative to chromosome 8 reference loci, to screen candidate genes, and to identify a novel dinucleotide repeat polymorphic marker closely linked to WRN. The WRN locus was mapped relative to the marker loci, PLAT, ANK1, D8S135, and D8S87 of the comprehensive chromosome 8 linkage map. The heregulin (HRG) and the fibroblast growth factor receptor 1 genes (FGFR1) have been mapped to chromosome 8p and are involved in cellular growth. Recombination events were detected between WRN and the HRG and FGFR1 genes, excluding them as candidates for the WRN gene. A polymorphic marker generated in this study, WT251, is linked to WRN at a recombination fraction of 0.006, with a lod score of 16.5.

Base Sequence↗
PubMed2004

Genetic analysis of the diversity in Toxoplasma gondii.

More than 50 different genetic markers are now available for Toxoplasma gondii isolate typing. For most of them, allelic polymorphism is low (2 to 4 alleles). A few markers, more polymorphic, can be used to fingerprint isolates for epidemiological studies. Phylogenetic analysis detects 2 main groups in Toxoplasma population. Group 2 is genetically heterogeneous. From a practical point of view, 3 main types (types I, II and III) are usually considered. Multilocus genotyping is necessary to reveal atypical or recombinant genotypes, more frequent among isolates collected in remote areas or in wild game. Toxoplasma isolates from human toxoplasmosis are mainly from type II (whatever the severity of clinical disease), but type I and atypical genotypes are found only in severe cases of human toxoplasmosis.

Animals↗