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At least 1,135 records · Page 63Linked to original sources
PubMed2003

Endothelial nitric oxide synthase T-786C single nucleotide polymorphism: a putative genetic marker differentiating small versus large ruptured intracranial aneurysms.

BACKGROUND AND PURPOSE: Anecdotal evidence exists for at least 2 subpopulations of intracranial saccular aneurysms, namely, those that may form rapidly and rupture when small versus those that enlarge slowly and may rupture particularly when > or =10 mm in diameter. We sought to determine whether the endothelial nitric oxide synthase (eNOS) T-786C single nucleotide polymorphism (SNP), implicated in cardiovascular disease susceptibility, could facilitate differentiation between small (< or =5 mm) versus large (> or =10 mm) ruptured aneurysms. METHODS: In accordance with institutional guidelines, clinical data were recorded prospectively and genomic DNA was isolated from blood samples obtained from 52 aneurysmal subarachnoid hemorrhage (SAH) patients (cases) and 90 randomly selected controls. Samples were assayed for eNOS gene promoter T-786C SNP with the use of gene microarray technology. Statistical analyses included multiple logistic regression. RESULTS: Although there was no difference in genotype distributions between cases and controls, all 13 patients with large aneurysms were (T/C) heterozygous for the polymorphism, while 9 of 22 patients (41%) with small aneurysms were (T/T or C/C) homozygous (P=0.01). The mean (+/-SD) ruptured aneurysm diameter among all heterozygotes (8.5+/-5.2 mm) was significantly greater than that for C/C (6.0+/-2.3 mm) or T/T (4.7+/-1.8 mm) homozygotes (P=0.04). With the use of multivariate analysis, heterozygosity remained significantly associated with aneurysm size > or =10 mm (P=0.03). CONCLUSIONS: The eNOS T-786C SNP distinguishes genetically between small and large ruptured aneurysms. Although not predictive of SAH in the population at large, our data suggest that among persons with known intracranial aneurysms, eNOS T-786C genotype may be a factor influencing the size at which an aneurysm ruptures, a finding that should be taken into consideration along with other anatomic features of the aneurysm.

Age Distribution↗
PubMed2005

A common haplotype at the 5' end of the RET proto-oncogene, overrepresented in Hirschsprung patients, is associated with reduced gene expression.

Hirschsprung disease (HSCR) is a complex genetic defect of intestinal innervation mainly ascribed to loss of function mutations of the RET gene. Although RETcoding mutations account for only 15% of HSCR sporadic cases, several linkage and association studies still indicate RET as a major HSCR gene, suggesting the existence of noncoding RET variants or common polymorphisms which can act in HSCR pathogenesis. We previously described a predisposing RET haplotype (A-C-A) composed of alleles at three SNPs (-1 bp and -5 bp from the RET transcription start site, NT_033985.6:g.975824G>A and NT_033985.6:g.975820C>A, respectively, and silent polymorphism c.135G>A), which was present in 62% of chromosomes from HSCR patients but only in 22% of control chromosomes. Here we address the question of how this 5' ACA haplotype may functionally act as a predisposing factor in HSCR pathogenesis by performing functional analysis of the same three SNPs. We demonstrate that neither the two promoter variants nor the exon 2 SNP interfere with reporter gene transcription or RET mRNA splicing, respectively. However, real-time RT-PCR, performed in RNA obtained from lymphoblasts of selected individuals, has shown that homozygosity for the whole ACA haplotype is associated with reduced RET gene expression. We propose that a yet unidentified variant in linkage disequilibrium with the ACA haplotype, rather than the single characterizing SNPs, acts as a HSCR susceptibility allele by affecting the normal amount of RET receptor on the cell surface.

5' Flanking Region↗
PubMed2006

SNPs and interaction analyses of noelin 2, myocilin, and optineurin genes in Japanese patients with open-angle glaucoma.

PURPOSE: To evaluate the noelin 2 gene as a disease-causing factor for open-angle glaucoma (OAG) and the interactions between the noelin 2 (OLFM2), optineurin (OPTN), and myocilin (MYOC) genes. METHODS: OLFM2 was analyzed in 770 Japanese subjects including 215 patients with elevated intraocular pressure (IOP), 277 with normal IOP, 38 with juvenile open-angle glaucoma, and 240 control subjects. Two single-nucleotide polymorphisms (SNPs) in OPTN (c.412G-->A and c.603T-->A) and one SNP in MYOC (c.227G-->A) were examined. Single genes were investigated by univariate analysis and the gene-gene interactions by logistic regression analysis. Associations between genotypes and clinical characteristics at the time of diagnosis were examined. RESULTS: In OLFM2, 12 sequence variants were identified in 770 Japanese subjects. Arg144Gln (exon 4) was identified in two (0.3%) of the patients and in none of the control subjects. Combinations of OLFM2/317A and OPTN/412A or OLFM2/1281T and OPTN/412A were associated with patients with elevated IOP (P = 0.018 or P = 0.012, respectively). The combination of OLFM2/317G and OPTN/603A was significantly associated with elevated IOP (P = 0.018). No significant association was detected between SNPs in OLFM2 and in MYOC. Patients with normal IOP and with OLFM2/678A+OPTN/412G or OLFM2/1281C+OPTN/412G had significantly worse visual field scores (P = 0.022 or 0.030, respectively). CONCLUSIONS: The Arg144Gln mutation in OLFM2 is a possible disease-causing mutation in Japanese patients with OAG. Common polymorphisms in OLFM2 and OPTN may interactively contribute to the development of OAG, indicating a polygenic etiology.

Adult↗
PubMed2000

Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse.

Single-nucleotide polymorphisms (SNPs) have been the focus of much attention in human genetics because they are extremely abundant and well-suited for automated large-scale genotyping. Human SNPs, however, are less informative than other types of genetic markers (such as simple-sequence length polymorphisms or microsatellites) and thus more loci are required for mapping traits. SNPs offer similar advantages for experimental genetic organisms such as the mouse, but they entail no loss of informativeness because bi-allelic markers are fully informative in analysing crosses between inbred strains. Here we report a large-scale analysis of SNPs in the mouse genome. We characterized the rate of nucleotide polymorphism in eight mouse strains and identified a collection of 2,848 SNPs located in 1,755 sequence-tagged sites (STSs) using high-density oligonucleotide arrays. Three-quarters of these SNPs have been mapped on the mouse genome, providing a first-generation SNP map of the mouse. We have also developed a multiplex genotyping procedure by which a genome scan can be performed with only six genotyping reactions per animal.

Animals↗
PubMed2006

Identification of a novel polymorphism in the X-chromosome region homologous to the DYS456 locus.

During an extensive multipopulation study with Y-short tandem repeat (STR) loci, amplified using the AmpFlSTR Yfiler PCR amplification kit, amplification of a 71 bp fragment was observed in 2.32% of the male samples analyzed (N = 3141). By direct sequencing of this fragment, it was determined that the primer binding sequences were identical to those of the DYS456 locus. A T to G single-nucleotide polymorphism (SNP) enabled amplification of the 71 bp fragment. The SNP is located within an X-Y homologous region at Xq21.31 and was observed with the highest frequency within the African American and Sub-Saharan African populations in our study. Presence of SNP on the X chromosome did not interfere with the reliability of typing the DYS456 locus and the other Y-STR loci typeable using the AmpFlSTR Yfiler PCR amplification kit. Full profiles in a mixture of male:female at 1:4000 were obtained using the current configuration of the AmpFlSTR Yfiler kit even in the presence of female DNA containing the G variant.

Chromosomes, Human, X↗
PubMed2006

A role for XRCC4 in age at diagnosis and breast cancer risk.

Genetic variants in DNA repair genes influence the ability to repair damaged DNA. Unrepaired or improperly repaired DNA may lead to genetic instability and carcinogenesis. We evaluated the role of four tagging single nucleotide polymorphisms (tSNP) in the DNA repair gene, XRCC4, and its association with breast cancer risk and age at diagnosis of breast cancer in 464 cases and 576 controls selected to be BRCA1/2 mutation negative from high-risk Utah pedigrees. We observed a significant association for two 4-locus tSNP haplotypes and age at diagnosis. Carriage of one haplotype was associated with later diagnosis (haplotype frequency, 0.039; mean age at diagnosis, 67.17 years; P = 0.001), and carriage of the other was associated with earlier diagnosis (haplotype frequency, 0.214; mean age at diagnosis, 54.04 years; P = 0.0085). For breast cancer risk, two 2-locus tSNP haplotypes explained the observed association as well as extended four-locus haplotypes. The two 2-locus haplotypes were nominally associated with breast cancer risk, one for reduced risk (odds ratio, 0.57; 95% confidence interval, 0.36-0.90; P = 0.014) and one for increased risk (odds ratio, 1.30; 95% confidence interval, 1.02-1.67; P = 0.033). Moreover, one of the tSNPs is in strong linkage disequilibrium (D' = 1.00) with an XRCC4 SNP found to be significantly associated with breast cancer risk in Taiwan, hence, confirming their findings. Our results suggest that XRCC4 may play a role in the age at diagnosis and risk of breast cancer in non-BRCA1/2, heritable breast cancer cases.

Age of Onset↗
PubMed2005

Polymorphisms in the promoter region of the alpha1A-adrenoceptor gene are associated with schizophrenia/schizoaffective disorder in a Spanish isolate population.

BACKGROUND: Animal models have implicated the alpha(1)-adrenergic subtypes in cognitive functions relevant to schizophrenia, but no consensus exists with regard to the status of noradrenergic receptor populations in psychiatric patients. We focused on one alpha(1)-adrenergic subtype, the alpha(1A)-adrenergic receptor, and proposed that genetic variants within the regulatory region of this gene (ADRA1A) alter the expression of this receptor, influencing susceptibility toward schizophrenia. METHODS: This study examined this proposal by testing the hypothesis that single nucleotide polymorphisms (SNPs) in the promoter region of the alpha(1A)-adrenergic gene were associated with schizophrenia by performing case-control association analysis on SNPs found in a 5' upstream region, which included the putative promoter region and 5' untranslated region. Our sample consisted of 103 schizophrenia and 14 schizoaffective disorder patients and 176 control subjects. All recruits were from a Spanish population isolate of Basque origin that is characterized by low heterogeneity, which was selected with the intent that it might facilitate the identification of disease-related polymorphisms. RESULTS: A total of eight SNPs (-9625 G/A, -7255 A/G, -6274 C/T, -4884 A/G, -4155 C/G, -2760 A/C, -1873 G/A, and -563 C/T) were confirmed at a rare allele frequency of >5%. Association with schizophrenia and schizoaffective disorder was found for the -563 C/T SNP (p = .0005 for allele and p = .007 for genotype, Bonferroni corrected) and -9625 G/A SNP (p = .02 for allele and p = .03 for genotype, Bonferroni corrected). Significant differences in the 54 haplotypes formed by these eight SNPs were also found between patients and control subjects (p = .008, Bonferroni corrected). CONCLUSIONS: Because of the strength of these results and the location of these SNPs in the regulatory region of this gene, functional studies investigating the possible influence of these SNPs on receptor expression levels in schizophrenia are warranted.

Confidence Intervals↗
PubMed2005

Case-control association study of the close homologue of L1 (CHL1) gene and schizophrenia in the Chinese population.

The close homolog of L1 (CHL1), located on human chromosome 3p26.1, is a newly identified member of the L1 family of cell adhesion molecules which play important roles in cell migration, axonal growth, and synaptic remodeling. A positive association has been reported between a missense polymorphism in CHL1 gene and schizophrenia in the Japanese population [Sakurai, K., Migita, O., Toru, M., Arinami, T., 2002. An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. Mol. Psychiatry 7, 412-415]. An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. In order to test this finding, we genotyped four SNPs in the gene in the Han Chinese population using a sample of 560 cases and 576 controls. Analysis of allele frequencies in both samples also showed strong association between SNP rs2272522 (the same marker studied by K. Sakurai) and the disease (X2=31.591, P<0.000001, OR=1.745, 95% CI=1.435-2.121). Our results confirm the positive association between CHL1 gene and schizophrenia and indicate that CHL1 may be involved in the etiology of schizophrenia.

Adult↗
PubMed2006

GeneRecon--a coalescent based tool for fine-scale association mapping.

UNLABELLED: GeneRecon is a tool for fine-scale association mapping using a coalescence model. GeneRecon takes as input case-control data from phased or unphased SNP and microsatellite genotypes. The posterior distribution of disease locus position is obtained by Metropolis-Hastings sampling in the state space of genealogies. Input format, search strategy and the sampled statistics can be configured through the Guile Scheme programming language embedded in GeneRecon, making GeneRecon highly configurable. AVAILABILITY: The source code for GeneRecon, written in C++ and Scheme, is available under the GNU General Public License (GPL) at http://www.birc.au.dk/~mailund/GeneRecon CONTACT: mailund@birc.au.dk.

Algorithms↗
PubMed1999

Evaluation of cGMP-phosphodiesterase (PDE) subunits for causal association with rod-cone dysplasia 2 (rcd2), a canine model of abnormal retinal cGMP metabolism.

Rod-cone dysplasia types 1 (rcd1; Irish setter) and 2 (rcd2; collie) in dogs are early onset forms of progressive retinal atrophy (PRA) which serve as models of retinitis pigmentosa (RP) in humans. As both rcd1 and rcd2 result from abnormal retinal cGMP metabolism associated with a deficiency in cGMP-phosphodiesterase (PDE) activity, and a nonsense mutation in the PDE6B subunit gene has been shown to cause rcd1, the genes encoding the four subunits of the PDE complex (PDE6A, PDE6B, PDE6G and PDE6D) make compelling candidates for the rcd2 locus. We adopted diverse strategies to evaluate causal association of the four PDE subunit genes with the rcd2 phenotype. Identification in an informative pedigree of obligate recombinations between intragenic polymorphisms within PDE6A and PDE6D and the rcd2 locus unequivocally excludes these two genes. PDE6B was excluded by a breeding strategy demonstrating nonallelism of rcd1 and rcd2. Direct sequencing of PDE6G from an rcd2 -homozygous collie dog revealed no abnormality in the entire genomic sequence. To evaluate cosegregation between PDE6G and rcd2, advantage was taken of prior knowledge that PDE6G and Galactokinase 1 (GALK1) localize to the same canine-rodent somatic hybrid cell line. Linkage analysis using a single nucleotide polymorphism (SNP) in the PDE6G gene, and a (CA)n repeat polymorphism in the GALK1 gene, which were both segregating in an unrelated pedigree, established close linkage of these two genes (theta = 0; Z = 4.21). Identification of obligate recombinations between GALK1 and the rcd2 locus in an informative rcd2 pedigree thus excluded PDE6G as a candidate gene for rcd2; the exclusion distance between GALK1 and rcd2 is at least 0.35 cM. These results therefore exclude the entire set of genes coding for the rod PDE complex as candidates for rcd2.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.

Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis caused by a partial deficiency of ferrochelatase (FECH, EC 4.99.1.1). EPP is transmitted as an autosomal dominant disorder with an incomplete penetrance. Using haplotype segregation analysis, we have identified an intronic single nucleotide polymorphism (SNP), IVS3-48T/C, that modulates the use of a constitutive aberrant acceptor splice site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism (NMD), producing a decreased steady-state level of mRNA and the additional FECH enzyme deficiency necessary for EPP phenotypic expression.

Base Sequence↗
PubMed2005

Choosing SNPs using feature selection.

A major challenge for genomewide disease association studies is the high cost of genotyping large number of single nucleotide polymorphisms (SNP). The correlations between SNPs, however, make it possible to select a parsimonious set of informative SNPs, known as "tagging" SNPs, able to capture most variation in a population. Considerable research interest has recently focused on the development of methods for finding such SNPs. In this paper, we present an efficient method for finding tagging SNPs. The method does not involve computation-intensive search for SNP subsets but discards redundant SNPs using a feature selection algorithm. In contrast to most existing methods, the method presented here does not limit itself to using only correlations between SNPs in local groups. By using correlations that occur across different chromosomal regions, the method can reduce the number of globally redundant SNPs. Experimental results show that the number of tagging SNPs selected by our method is smaller than by using block-based methods.

Artificial Intelligence↗
PubMed2006

Characterization of HPSE gene single nucleotide polymorphisms in Jewish populations of Israel.

Heparanase is a mammalian endoglucuronidase responsible for heparan sulfate (HS) degradation. HS is a major constituent of the extracellular matrix (ECM) and HS-degrading activity plays a decisive role in fundamental biological processes associated with remodeling of the ECM, such as cancer metastasis, angiogenesis and inflammation. There is great interest in the prospect of genome-wide association studies to identify genetic factors underlying complex diseases. It is important to establish a detailed description of the heparanase (HPSE) gene single nucleotide polymorphisms (SNPs). In this study, four Israeli Jewish populations (Ashkenazi, North African, Mediterranean and Near Eastern) were examined for 7 HPSE gene SNPs. Four out of 7 SNPs (rs4693608, db11099592, rs4364254, db6856901) were found to be polymorphic. Population comparisons revealed significant differences in SNPs allele frequency between Near Eastern and each of the other three populations. Genotype and allele frequencies in Jewish populations were different from non-Jewish populations, except for a certain similarity to Caucasians. Although the distance between SNPs is relatively small, the db11099592 SNP was in linkage disequilibrium (LD) only with the proximal SNP rs4693608. LD between distal SNPs rs4364254 and db6856901 was found only in Mediterraneans and North Africans. The current study provides a characterization of the normally occurring HPSE gene SNPs in different populations. This information is obligatory for further studies on the linkage between these SNPs and heparanase expression and function in various pathological processes, primarily cancer progression.

Africa, Northern↗
PubMed2005

Reduced insulin/IGF-1 signalling and human longevity.

Evidence is accumulating that aging is hormonally regulated by an evolutionarily conserved insulin/IGF-1 signalling (IIS) pathway. Mutations in IIS components affect lifespan in Caenorhabditis elegans, Drosophila melanogaster and mice. Most long-lived IIS mutants also show increased resistance to oxidative stress. In D. melanogaster and mice, the long-lived phenotype of several IIS mutants is restricted to females. Here, we analysed the relationship between IIS signalling, body height and longevity in humans in a prospective follow-up study. Based on the expected effects (increased or decreased signalling) of the selected variants in IIS pathway components (GHRHR, GH1, IGF1, INS, IRS1), we calculated composite IIS scores to estimate IIS pathway activity. In addition, we analysed the relative impact on lifespan and body size of the separate variants in multivariate models. In women, lower IIS scores are significantly associated with lower body height and improved old age survival. Multivariate analyses showed that these results were most pronounced for the GH1 SNP, IGF1 CA repeat and IRS1 SNP. In females, for variant allele carriers of the GH1 SNP, body height was 2 cm lower (P = 0.007) and mortality 0.80-fold reduced (P = 0.019) when compared with wild-type allele carriers. Thus, in females, genetic variation causing reduced IIS activation is beneficial for old age survival. This effect was stronger for the GH1 SNP than for variation in the conserved IIS genes that were found to affect longevity in model organisms.

Aged↗
PubMed2004

A single nucleotide polymorphism in glycogen synthase kinase 3-beta promoter gene influences onset of illness in patients affected by bipolar disorder.

Genetic studies in medicine exploited age of onset as a criterion to delineate subgroups of illness. Bipolar patients stratified with this criterion were shown to share clinical characteristics and patterns of inheritance of illness. The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50 T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been identified. GSK3-beta codes for an enzyme which is a target for the action of lithium and which is also known to regulate circadian rhythms in Drosophila. We studied the effect of this polymorphism on the age at onset of bipolar disorder type I. A homogeneous sample of 185 Italian patients affected by bipolar disorder was genotyped. Age at onset was retrospectively ascertained with best estimation procedures. No association was detected between GSK3-beta -50 T/C SNP and the presence of bipolar illness. Homozygotes for the wild variant (T/T) showed an earlier age at onset than carriers of the mutant allele (F=5.53, d.f.=2,182, P=0.0047). Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited.

Adolescent↗
PubMed2005

A Bayesian framework for SNP identification.

As evolutionary models for single-nucleotide polymorphisms (SNPs) become available, methods for using them in the context of evolutionary information and expert prior information is a necessity. We formulate a probability model for SNPs as a Bayesian inference problem. Using this framework we compare the individual and combined predictive ability of four evolutionary models of varying levels of specificity on three SNP databases (two specifically targeted at functional SNPs) by calculating posterior probabilities and generating Receiver Operating Characteristic (ROC) curves. We discover that none of the models do exceptionally well, in some cases no better than a random-guess model. However, we demonstrate that several properties of the Bayesian formulation improve the predictability of SNPs in the three databases, specifically the ability to utilize mixtures of evolutionary models and a prior based on the genetic code.

Bayes Theorem↗
PubMed2004

A genotoxic screen: rapid analysis of cellular dose-response to a wide range of agents that either damage DNA or alter genome maintenance pathways.

SNP analysis has come to the forefront of genomics since the mouse and human genomes have been sequenced. High throughput functional screens are necessary to evaluate these sequence databases. Described here is a genotoxic screen: a rapid method that determines the cellular dose-response to a wide range of agents that either damage DNA or alter basic cellular pathways important for maintaining genomic integrity. Importantly, a single person utilizing standard tissue culture equipment may perform these assays composed of 20 agents that attack genomic integrity or maintenance at many different levels. Thus, a small lab may perform this screen to determine the integrity of a wide range of DNA repair, chromatin metabolism, and response pathways without the limitations of investigator bias. A genotoxic screen will be useful when analyzing cells with either known genetic alterations (generated directly by the investigator or derived from individuals with known mutations) or unknown genetic alterations (cells with spontaneous mutations such as cancer-derived cells). Screening many genotoxins at one time will aid in determining the biological importance of these altered genes. Here we show the dose-response curves of mouse embryonic stem (ES) cells and HeLa cells exposed to 20 genotoxic agents. ES cells were chosen since they are amenable to genetic alteration by the investigator. HeLa cells were chosen since they were derived from cancer and are commonly used. Comparing the dose-response curves of these two cell lines show their relative sensitivity to these agents and helps define their genotoxic profile. As a part of phenomics, a large genotoxic profile database for cancer-derived cells, when integrated with other databases such as expression profiles and comparative genomic hybridization, may aid in maximizing the effectiveness of developing anti-cancer protocols.

Alkylating Agents↗
PubMed2006

U1-like snRNAs lacking complementarity to canonical 5' splice sites.

We have detected a surprising heterogeneity among human spliceosomal U1 small nuclear RNA (snRNA). Most interestingly, we have identified three U1 snRNA variants that lack complementarity to the canonical 5' splice site (5'SS) GU dinucleotide. Furthermore, we have observed heterogeneity among the identified variant U1 snRNA genes caused by single nucleotide polymorphism (SNP). The identified snRNAs were ubiquitously expressed in a variety of human tissues representing different stages of development and displayed features of functional spliceosomal snRNAs, i.e., trimethylated cap structures, association with Sm proteins and presence in nuclear RNA-protein complexes. The unanticipated heterogeneity among spliceosomal snRNAs could contribute to the complexity of vertebrates by expanding the coding capacity of their genomes.

Base Pairing↗