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At least 667 records · Page 37Linked to original sources
PubMed2006

Analysis of LDLR mutations in familial hypercholesterolemia patients in Greece by use of the NanoChip microelectronic array technology.

BACKGROUND: Three mutations in the low density lipoprotein receptor (LDLR) gene account for 49% of familial hypercholesterolemia (FH) cases in Greece. METHODS: We used the microelectronic array technology of the NanoChip Molecular Biology Workstation to develop a multiplex method to analyze these single-nucleotide polymorphisms (SNPs). Primer pairs amplified the region encompassing each SNP. The biotinylated PCR amplicon was electronically addressed to streptavidin-coated microarray sites. Allele-specific fluorescently labeled oligonucleotide reporters were designed and used for detection of wild-type and SNP sequences. Genotypes were compared to PCR-restriction fragment length polymorphism (PCR-RFLP). RESULTS: We developed three monoplex assays (1 SNP/site) and an optimized multiplex assay (3SNPs/site). We performed 92 Greece II, 100 Genoa, and 98 Afrikaner-2 NanoChip monoplex assays (addressed to duplicate sites and analyzed separately). Of the 580 monoplex genotypings (290 samples), 579 agreed with RFLP. Duplicate sites of one sample were not in agreement with each other. Of the 580 multiplex genotypings, 576 agreed with the monoplex results. Duplicate sites of three samples were not in agreement with each other, indicating requirement for repetition upon which discrepancies were resolved. CONCLUSIONS: The multiplex assay detects common LDLR mutations in Greek FH patients and can be extended to accommodate additional mutations.

Genetic Testing↗
PubMed2006

A new SNP in the promoter region of the porcine MYF5 gene has no effect on its transcript level in m. longissimus dorsi.

Myogenic factor 5 (myf-5) is the product of the MYF5 gene, belonging to the MyoD family. This transcription factor participates in the control of myogenesis. We identified 3 new mutations in the promoter region of the gene: A65C, C580T and C613T. The aim of this study was to evaluate the influence of the A65C transversion on gene expression. The analysis was conducted on 15 Polish Large White gilts. The relative content of MYF5 mRNA in m. longissimus dorsi did not differ significantly across MYF5 genotypes (AA, AC, CC). This result suggests that the A65C transversion may not play an important role in the expression of the MYF5 gene in analysed adult muscle but it abolishes a putative binding site for two transcription factors (CDP and HSF1) and creates such a site for Sp1.

Amino Acid Substitution↗
PubMed2003

Enhanced allele-specific PCR discrimination in SNP genotyping using 3' locked nucleic acid (LNA) primers.

The specificity and reliability of locked nucleic acid (LNA) substitution at the 3' position of allele-specific PCR (AS-PCR) primers for SNP detection was investigated in direct comparison to DNA primers. Both plasmid and human genomic DNA templates were examined in this study. All possible DNA and 3' LNA mismatch combinations were tested in triplicate with the plasmid target. LNA primers yield consistently low amounts of mismatch products with all base combinations, whereas certain mismatches with DNA primers generate strong false positive amplicons. Amplified human SNP alleles within the cystic fibrosis (CFTR) gene were analyzed in AS-PCR by gel analysis and real-time fluorescence generation. A 3' LNA residue in the primer at the SNP site improves allelic discrimination and functions under a wide window of PCR conditions. We demonstrate increased AS-PCR specificity with comparable sensitivity using 3' LNA primers in gel electrophoresis and real-time detection experiments. This increase in AS-PCR discrimination with 3' LNA primers should facilitate the use of this simple, rapid, and inexpensive technique for SNP genotyping applications.

Alleles↗
PubMed2006

Genotyping of different varicella vaccine strains.

BACKGROUND: Little is known about single nucleotide polymorphism (SNP) in different lots of varicella vaccines distributed by the manufacturers. Recently, the genetic analysis of several genomic regions revealed a polymorphism in different vaccine lots of Varilrix manufactured by GlaxoSmithKline. These findings need attention since mutations in the vaccine strain could result in changes of virulence and efficacy of the vaccine. OBJECTIVES: To identify SNPs in three varicella vaccine lots of Varilrix and to compare the results with that of Varivax as well as the published sequences of the Oka vaccine strain (V-Oka) and its parental virus (P-Oka). STUDY DESIGN: The open reading frames (ORF) 1, 6, 10, 21, 50, 54, and 62 were analyzed by sequencing of amplified DNA fragments. RESULTS: Wild-type nucleotides identical to that of P-Oka and/or the European wild-type reference strain Dumas and in contrast to V-Oka could be identified in ORF 1 of a Varilrix vaccine lot distributed in 1991. In the ORF 62 probably responsible for attenuation of V-Oka, this vaccine strain contained 16 SNPs which were nearly all wild-type-like. By contrast, different lots of the Varivax vaccine revealed uniform sequencing results. The vaccine Varilrix 1999 showed a high similarity to the Varivax vaccine currently available. CONCLUSIONS: The obvious genetic diversity of different lots of the varicella vaccine Varilrix cannot be explained with the coexistence of several strain variants in the vaccine, but most likely with different seed lot preparations used for vaccine production.

Amino Acid Substitution↗
PubMed1999

Cyclic GMP-dependent protein kinase activates cloned BKCa channels expressed in mammalian cells by direct phosphorylation at serine 1072.

NO-induced activation of cGMP-dependent protein kinase (PKG) increases the open probability of large conductance Ca2+-activated K+ channels and results in smooth muscle relaxation. However, the molecular mechanism of channel regulation by the NO-PKG pathway has not been determined on cloned channels. The present study was designed to clarify PKG-mediated modulation of channels at the molecular level. The cDNA encoding the alpha-subunit of the large conductance Ca2+-activated K+ channel, cslo-alpha, was expressed in HEK293 cells. Whole cell and single channel characteristics of cslo-alpha exhibited functional features of native large conductance Ca2+-activated K+ channels in smooth muscle cells. The NO-donor sodium nitroprusside increased outward current 2.3-fold in whole cell recordings. In cell-attached patches, sodium nitroprusside increased the channel open probability (NPo) of cslo-alpha channels 3.3-fold without affecting unitary conductance. The stimulatory effect of sodium nitroprusside was inhibited by the PKG-inhibitor KT5823. Direct application of PKG-Ialpha to the cytosolic surface of inside-out patches increased NPo 3.2-fold only in the presence of ATP and cGMP without affecting unitary conductance. A point mutation of cslo-alpha in which Ser-1072 (the only optimal consensus sequence for PKG phosphorylation) was replaced by Ala abolished the PKG effect on NPo in inside-out patches and the effect of SNP in cell attached patches. These results indicate that PKG activates cslo-alpha by direct phosphorylation at serine 1072.

Base Sequence↗
PubMed2003

Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution.

Six measures of evolutionary change in the human genome were studied, three derived from the aligned human and mouse genomes in conjunction with the Mouse Genome Sequencing Consortium, consisting of (1) nucleotide substitution per fourfold degenerate site in coding regions, (2) nucleotide substitution per site in relics of transposable elements active only before the human-mouse speciation, and (3) the nonaligning fraction of human DNA that is nonrepetitive or in ancestral repeats; and three derived from human genome data alone, consisting of (4) SNP density, (5) frequency of insertion of transposable elements, and (6) rate of recombination. Features 1 and 2 are measures of nucleotide substitutions at two classes of "neutral" sites, whereas 4 is a measure of recent mutations. Feature 3 is a measure dominated by deletions in mouse, whereas 5 represents insertions in human. It was found that all six vary significantly in megabase-sized regions genome-wide, and many vary together. This indicates that some regions of a genome change slowly by all processes that alter DNA, and others change faster. Regional variation in all processes is correlated with, but not completely accounted for, by GC content in human and the difference between GC content in human and mouse.

Animals↗
PubMed2004

[Single nucleotide polymorphism analysis in sow mu opioid receptor gene].

Mu opioid receptor (MOR) is a member of G protein-coupled receptor family, distributed in the pain transduction region in the brain and related to emotion and behaviour. This study was designed to investigate the Single Nucleotide Polymorphism (SNP) of Mu opioid receptor gene in various breeds,including duroc, landrace and Yorkshire. 5' UTR (untranslate region), coding region and 3' UTR of Mu opioid receptor gene were amplified by eight pairs of primers, and the Single Nucleotide Polymorphism (SNP) were detected by SSCP. Five polymorphisms were found (Genebank Accession number: AF521309). The results of chi(2) test showed that the frequencies of genotypes in different breeds were significantly different (P<0.01). The frequencies of mutation genotypes in Yorkshire were significantly higher than Duroc and Landrace. According to the above results, we can speculate the difference of the frequencies of genotypes may be the results of long term choice pressure.

3' Untranslated Regions↗
PubMed2004

Study on SNP of melanocyte stimulating hormone receptor gene in several Chinese indigenous sheep breeds using DHPLC.

Single nucleotide polymorphism (SNP) of melanocyte stimulating hormone receptor (MSHR) gene was studied by sequencing and denaturing high performance liquid chromatography (DHPLC) in Mongolian sheep, Kazakstan sheep, Tan sheep and Tibetan sheep. The results showed that there is a mutation at position 317 (T317C) within the length of 415bp and the DHPLC is a high-throughput and simple method for screening this mutation. The heterozygote (TC) with shoulder peak could be detected quickly at the first time of DHPLC, and two homozygotes (TT or CC) could be discriminated easily through two times of DHPLC when each homozygous DNA was mixed with a known homozygous reference sample at the second time of DHPLC. All of the populations for this site are in Hardy-Weinberg equilibrium. The results also indicated that Mongolian sheep and Kazakstan sheep had close relationship, Tibetan sheep and Tan sheep had close relationship. The relationship among breeds was consistent with that of microsatellite DNA.

Animals↗
PubMed2006

Fine mapping of disease genes via haplotype clustering.

We propose an algorithm for analysing SNP-based population association studies, which is a development of that introduced by Molitor et al. [2003: Am J Hum Genet 73:1368-1384]. It uses clustering of haplotypes to overcome the major limitations of many current haplotype-based approaches. We define a between-haplotype score that is simple, yet appears to capture much of the information about evolutionary relatedness of the haplotypes in the vicinity of a (unobserved) putative causal locus. Haplotype clusters can then be defined via a putative ancestral haplotype and a cut-off distance. The number of an individual's two haplotypes that lie within the cluster predicts the individual's genotype at the causal locus. This predicted genotype can then be investigated for association with the phenotype of interest. We implement our approach within a Markov-chain Monte Carlo algorithm that, in effect, searches over locations and ancestral haplotypes to identify large, case-rich clusters. The algorithm successfully fine-maps a causal mutation in a test analysis using real data, and achieves almost 98% accuracy in predicting the genotype at the causal locus. A simulation study indicates that the new algorithm is substantially superior to alternative approaches, and it also allows us to identify situations in which multi-point approaches can substantially improve over single-SNP analyses. Our algorithm runs quickly and there is scope for extension to a wide range of disease models and genomic scales.

Algorithms↗
PubMed2001

High-density single-nucleotide polymorphism (SNP) map of the 150-kb region corresponding to the human ATP-binding cassette transporter A1 (ABCA1) gene.

Highly dense catalogs of human genetic variations, in combination with high-throughput genotyping technologies, are expected to clarify individual genetic differences in pharmacological responsiveness and predispositions to common diseases. Here we report single-nucleotide polymorphisms (SNPs) present among 48 Japanese individuals at the locus for the human ATP-binding cassette transporter A1 (ABCA1) gene. ABCA1 plays a key role in apolipoprotein-mediated cholesterol transport, and mutations in this gene are responsible for Tangier disease and familial high-density lipoprotein deficiency associated with reduced cholesterol efflux. We identified a total of 162 SNPs, 149 of which were novel, within the 150-kb region encompassing the entire ABCA1 gene. Eight of the SNPs lie within coding elements, two in 5' flanking regions, 147 in introns, and five in 3' untranslated regions, but none were found in 5' untranslated or 3' flanking regions. The ratio of transitions to transversions was approximately 2.37 to 1. Our dense SNP map of this region could serve as a powerful resource for studies of complex genetic diseases that may be associated with ABCA1 and of individual responses to drug therapy.

ATP Binding Cassette Transporter 1↗
PubMed2006

Ala228 variant of trail receptor 1 affecting the ligand binding site is associated with chronic lymphocytic leukemia, mantle cell lymphoma, prostate cancer, head and neck squamous cell carcinoma and bladder cancer.

Allelic loss of chromosome 8p21-22 is a frequent event in various human cancers including mantle cell lymphoma (MCL), prostate cancer, head and neck squamous cell carcinoma (HNSCC) and bladder cancer. The tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, including TNFRSF10A and TNFRSF10B, are located within this chromosomal region. Since recent studies demonstrate that chronic lymphocytic leukemia (CLL) and prostate cells are TRAIL induced apoptosis, TRAIL-receptors are strong tumor suppressor candidate genes in human cancers exhibiting loss of chromosomal material in 8p21.3. However, no mutation of the TRAIL receptor genes has been reported in CLL, MCL, prostate cancer, HNSCC so far. In this study we analyzed the complete coding region of TNFRSF10A and TNFRSF10B in a series of 32 MCL and 101 CLL samples and detected a single nucleotide polymorphism (SNP) in TNFRSF10A (A683C) with tumor specific allele distribution. We examined allele distribution in 395 samples of different tumor entities (prostate cancer, n = 43; HNSCC, n = 40; bladder cancer, n = 179) and compared them to 137 samples from healthy probands. We found the rare allele of TNFRSF10A is more frequent in CLL, MCL, prostate cancer, bladder cancer and HNSCC. The A683C polymorphism did not cosegregate with other TNFRSF10A polymorphisms previously described. Thus screening for 683A-->C nucleotide exchanges may become important in diagnosis and/or treatment of these malignancies.

Binding Sites↗
PubMed2004

Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients.

The genotypic consequences of numerous single-nucleotide variants in human mismatch repair genes are mostly undetermined. We examined 27 reported single-nucleotide variants, rarely or ambiguously verified in a population-based study, to identify single-nucleotide polymorphisms (SNPs), haplotypes, and the genotype-phenotype association in Korean populations of 330 healthy individuals, 107 sporadic colorectal cancer patients, and 107 of their first-degree relatives. Real-time PCR 5'-nuclease assays (TaqMan) MGB assay) were used to determine 24 single-nucleotide variants, and restriction fragment length polymorphism (RFLP) assays were used to determine 3 variants. Of these 27 variants, 4 (hMSH2 gIVS12-6, hMLH1 655, hMLH1 1151, and hMSH2 1168, in descending order) were identified as SNPs occurring in 4.5 to 53.1% of healthy individuals, with polymorphism levels of 0.023-0.3 (mean, 0.092). East Asian populations had an ethnic predilection for the hMLH1 1151 SNP. The genotype distribution for all four SNPs showed no association with sporadic colorectal cancer. Twenty-three variants were not identified in the Korean population, suggesting that fifteen of these variants are colorectal cancer-related mutations and eight are SNPs. Two haplotype patterns existed exclusively, but with rare frequency, in sporadic colorectal cancer patients. The hMLH1 655 allele was closely correlated with hMLH1 protein expression (P = 0.02), but none of the four SNPs was associated with clinicopathologic variables. Among the 27 single nucleotide variants of mismatch repair genes, 12 were suggestive of nonfunctional SNPs and 15 may be colorectal cancer-related mutations. Further verification in other ethnic groups may provide the genotypic and phenotypic significance of single nucleotide variants found in mismatch repair genes.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women.

BACKGROUND: Aromatase catalyses the conversion of androgens to estrogens and thus variation in the aromatase gene could contribute to female syndromes of androgen excess, such as precocious pubarche (PP) and polycystic ovarian syndrome (PCOS). METHODS: Two groups, one case-control containing girls from Barcelona, Spain with PP (n = 186) or healthy controls (n = 71), and the other a population study of young women from Oxford, UK, who volunteered for a study of normal women's health (n = 109), were genotyped at four aromatase gene haplotype-tag single nucleotide polymorphisms (SNP). Clinical features and hormone concentrations relevant to hyperandrogenism were compared across haplotypes or genotypes. RESULTS: Distributions of aromatase haplotypes (P < 0.0001) and aromatase SNP_50 genotype (P = 0.001) were significantly different between PP girls and Spanish controls. The AGGG haplotype was associated with an odds ratio (95% confidence interval) of 0.5 (0.3-0.9) (P = 0.005) for the presence of PP compared to GAGG. In 84 post-pubertal PP girls, aromatase haplotype was associated with functional ovarian hyperandrogenism (P < 0.05), independently of insulin sensitivity. In the Oxford population, SNP_50 was associated with variation in PCOS symptom score (P = 0.008) and circulating testosterone concentrations (P = 0.02). CONCLUSIONS: This study suggests that common variation at the aromatase gene (and not just rare loss-of-function mutations) is associated with androgen excess in girls and young women.

Adolescent↗
PubMed2004

[Single nucleotide polymorphism in SCN5A and the distribution in Chinese Han ethnic group].

Mutations in voltage-gated sodium channel type (SCN5A) may evoke severe, life-threatening disturbances in cardiac rhythm, including long QT syndrome, idiopathic ventricular fibrillation (Brugada Syndrome), and isolated cardiac conduction disease. There is increasing awareness of the role of common polymorphisms in altering gene function and in susceptibility to diseases. The aim of the present study was to investigate single nucleotide polymorphism (SNP) in SCN5A gene and the distribution of these identified SNPs in Chinese Han nationality. SCN5A gene was sequenced by fluorescent labeling automatic sequencing method in 120 unrelated samples from Han nationality in South China. Allele frequency distribution was tested by Hardy-Weinberg equilibrium. The results showed that a total of 5 SNPs were identified in SCN5A gene, including three SNPs in code region, one SNP in regulatory region and the other in intron 23 adjacent to donor splicing site. The distribution of the SNPs in SCN5A gene was uneven. These allele frequencies in Han population of South China were as follows: G87A (A29A) 27.5%, A1673G (H588R) 10.4%, 4245+82A>G 32.8%, C5457T (D1819D) 41.3% and G6174A 44.9% respectively. The SNPs G87A (A29A), 4245+82A>G and G6174A were reported for the first time. There was no significant difference in the allele frequency of A1673G (H558R) within different ethical populations (P>0.05). C5457T (D1819D) allele frequency of Han population in South China was similar to that observed in Japanese (P>0.5), but higher than that in American (p<0.005). There was no significant difference in the distribution of the SNPs between male group and female group (all p>0.05). S1102Y and other 10 SNPs identified in other ethnic populations have not been detected in Chinese Han population. The allele distribution of SNPs was in good unity with the Hardy-Weinberg equilibrium. It is suggested that the SNP distribution of SCN5A gene varies within different nationalities. These data will be of use for genetic association studies of acquired arrythmias and investigation of sensitivity to drug therapy.

Arrhythmias, Cardiac↗
PubMed2005

Assessment of tailor-made prevention of atherosclerosis with folic acid supplementation: randomized, double-blind, placebo-controlled trials in each MTHFR C677T genotype.

This study aimed at assessing the effect of folic acid supplementation quantitatively in each MTHFR C677T genotype and considered the efficiency of tailor-made prevention of atherosclerosis. Study design was genotype-stratified, randomized, double-blind, placebo-controlled trials. The setting was a Japanese company in the chemical industry. Subjects were 203 healthy men after exclusion of those who took folic acid or drugs known to effect folic acid metabolism. Intervention was folic acid 1 mg/day p.o. for 3 months. The primary endpoint was plasma total homocysteine level (tHcy). In all three genotypes, there were significant tHcy decreases. The greatest decrease was in the TT homozygote [6.61 (3.47-9.76) micromol/l] compared with other genotypes [CC: 2.59 (1.81-3.36), CT: 2.64 (2.16-3.13)], and there was a significant trend between the mutated allele number and the decrease. The tHcy were significantly lowered in all the genotypes, but the amount of the decrease differed significantly in each genotype, which was observed at both 1 and 3 months. Using these time-series data, the largest benefit obtained by the TT homozygote was appraised as 2.4 times compared with the CC homozygote. Taking into account the high allele frequency of this SNP, this quantitative assessment should be useful when considering tailor-made prevention of atherosclerosis with folic acid.

Alleles↗
PubMed2004

Identification and evaluation of 55 genetic variations in the BRCA1 and the BRCA2 genes of patients from 50 Japanese breast cancer families.

We sequenced approximately 23 kb genomic regions containing all the coding exons and their franking introns of two breast cancer susceptibility genes, BRCA1 and BRCA2, of 55 individuals from 50 unrelated Japanese breast cancer families. We identified 55 single-nucleotide polymorphisms (SNPs) (21 in BRCA1 and 34 in BRCA2) containing nine pathogenic protein-truncating mutations (four in BRCA1 and five in BRCA2 from ten patients). Among the remaining 46 SNPs, allele frequencies of 40 were examined in both the breast cancer patients and 28 healthy volunteers with no breast cancer family history by PCR-RFLP or by direct DNA sequencing. Twenty-eight SNPs were common and were also found in the healthy volunteers and/or a SNP database. The remaining 18 were rare (allele frequency <0.05) and were not found in the healthy volunteers and/or the database. The pathogenic significance of these coding SNPs (cSNPs) remains to be clarified. The SNP information from this study will be useful in the future genetic testing of both BRCA1 and BRCA2 genes in the Japanese population.

Alleles↗
PubMed2002

Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy.

Idiopathic generalised epilepsy (IGE) is a common form of epilepsy, including several defined and overlapping syndromes, and likely to be due to the combined actions of mutations in several genes. In a recent study we investigated the calcium channel gene CACNA1A for involvement in IGE, unselected for syndrome, by means of association studies using several polymorphisms within the gene. We reported a highly significant case/control association with a silent single nucleotide polymorphism (SNP) in exon 8 that we confirmed by within-family analyses. In this present study we screened the gene for novel SNPs within 25 kb of exon 8, which have enabled us to define the critical region of CACNA1A in predisposing to IGE. Several intronic SNPs were identified and three, within 1.5 kb of exon 8 and in strong linkage disequilibrium with each other and with the original SNP, were significantly associated with IGE (P=0.00029, P=0.0015 and P=0.010). The associations were not limited to an IGE syndrome or other subgroup. Another SNP, 25 kb away, in intron 6 was also significantly associated with IGE (P=0.0057) but is not in linkage disequilibrium with the SNPs around exon 8. Haplotype predictions revealed even more significant associations (3-marker haplotype: P<10(-6)). Logistic regression showed that all the data can be explained by two of the SNPs, which is consistent with two functionally significant variants being responsible for all five associations, although a single variant cannot be excluded. The functionally significant variant(s) are unlikely to be exonic and suggests an effect on expression or alternative splicing.

Adolescent↗
PubMed2006

Capture and release of DNA using aminosilane-modified bacterial magnetic particles for automated detection system of single nucleotide polymorphisms.

Bacterial magnetic particles (BMPs) were modified with 3-[2-(2-aminoethylamino)-ethylamino]-propyltrimethoxysilane (AEEA) to produce a dense amine surface. Modification of BMPs in a toluene solution resulted in an increased amine yield, and approximately 11.3 x 10(4) surface amines were detected on a single particle. The modified BMPs were capable of efficient electrostatic capture of DNA. The maximum amount of DNA captured on 10 microg of aminosilane-modified BMPs was 600 ng. A 10 mM phosphate buffer effectively released the captured DNA. This efficiency was dramatically enhanced by incubation at 80 degrees C and DNA recovery from aminosilane-modified BMPs approached 95%. DNA extraction from whole blood using these modified BMPs, followed by PCR, was successfully performed. Furthermore, automated single nucleotide polymorphism (SNP) detection of the aldehyde dehydrogenase 2 (ALDH2) was demonstrated.

Bacterial Proteins↗