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At least 1,297 records · Page 72Linked to original sources
PubMed2005

Clinical and biological relevance of single-nucleotide polymorphisms and acquired somatic mutations of the BCL6 first intron in follicular lymphoma.

Genetic modifications of the BCL6 gene in lymphoma include translocations, deletions, and somatic mutations (SM) of the 5' noncoding region. Three single-nucleotide polymorphisms (SNPs) of the major mutation cluster region (MMC) have been reported, including two substitutions (397G/C, 502G/A) and one deletion (520DeltaT). Clinical and biological relevance of these SNPs are unknown. Based on a case-control study, BCL6 SNPs frequencies were assessed in 97 t(14;18) follicular lymphomas (FL) and in 54 lymphomas with 3q27 rearrangement. Allele frequencies were similar in the FL and controls groups. The 397 G/C genotype was correlated to a higher-grade transformation risk (P=0.02). SM were observed in 39.1% of FL and were characterized by a clustering distribution (hot spots spanning position 420-435, 106-127, and 590-600). No correlation between genotypes or acquired mutational status and BCL6 expression was demonstrated. However, gel mobility-shift assays, using SNPs containing probes show results representative for protein/DNA complexes. This study demonstrates that the first BCL6 intron is a highly variable region as a consequence of both SNP and SM, which may contribute to biology and outcome of FL.

Adult↗
PubMed2004

Single nucleotide polymorphism screening and association analysis--exclusion of integrin beta 7 and vitamin D receptor (chromosome 12q) as candidate genes for asthma.

BACKGROUND: The human genes coding for integrin beta 7 (ITGB7) and vitamin D receptor (VDR) are two of the several candidate genes for asthma and related phenotypes found in a promising candidate region on chromosome 12q that has been identified in multiple genomewide screens and candidate gene approaches. METHODS: All exons, including parts of the neighbouring introns, and the predicted promoter region of the ITGB7 gene were screened for common polymorphisms in 32 independent asthmatic and healthy probands, resulting in the detection of two single nucleotide polymorphisms (SNPs) unknown so far. In addition to these SNPs, five already described SNPs of the ITGB7 and one in the human VDR gene were analysed in a Caucasian sib pair study of 176 families with at least two affected children, using matrix assisted laser desorption/ionization time of flight mass spectrometry. All confirmed SNPs were tested for linkage/association with asthma and related traits (total serum IgE level, eosinophil cell count and slope of the dose-response curve after bronchial challenge). RESULTS: Two new variations in the ITGB7 gene were identified. The coding SNP in exon 4 causes a substitution of the amino acid GLU by VAL, whereas the other variation is non-coding (intron 3). None of the eight analysed SNPs, of either the ITGB7 or the VDR genes, showed significant linkage/association with asthma or related phenotypes in the family study. CONCLUSIONS: These findings indicate that neither the human ITGB7 nor the VDR gene seem to be associated with the pathogenesis of asthma or the expression of related allergic phenotypes such as eosinophilia and changes in total IgE level.

Adolescent↗
PubMed2006

Single-nucleotide polymorphism identification in the caprine myostatin gene.

Polymerase chain reaction (PCR) products of MSTN gene amplified from 35 goats representing 17 Chinese indigenous goat breeds and five imported goat breeds were sequenced to identify the single-nucleotide polymorphisms (SNPs) of a 379-bp fragment including part of intron 2 and exon 3 of MSTN gene. A total of eight SNPs (A1980G, G1981C, A1982G, G1984T, A2121G, T2124C, G2174A and A2246G) were identified among the sequenced goats. The SNPs found are all located in intron 2 except for A2246G, which was a synonymous mutation in exon 3. Four haplotypes were sorted from these eight SNPs, of which, haplotype I (AGAGATGA) and haplotype II (GCGTGTAA) are the two main haplotypes with the frequency of 77.8% and 14.8% respectively. The SNPs found at positions 1980, 1981, 1982, 1984 and 2121 might be linked to inheritance completely.

Animals↗
PubMed2006

The promoter region of the MDR1 gene is largely invariant, but different single nucleotide polymorphism haplotypes affect MDR1 promoter activity differently in different cell lines.

The MDR1 multidrug transporter represents one of the better characterized drug transporters that play an important role in protecting the body against xenobiotic insults. Single nucleotide polymorphisms (SNPs) and SNP haplotypes within this gene have been variously associated with differences in MDR1 expression/function, drug response as well as disease susceptibility. Nonetheless, the effect of polymorphisms at the MDR1 promoter region on its promoter activity remains less characterized. Through the examination of approximately 1.5 kilobases of MDR1 promoter region from five populations, including the Chinese, Malays, Indians, European Americans, and African Americans, we identified eight low-frequency SNPs, of which only two were polymorphic in at least four of the five populations examined. The other SNPs are mainly population-specific, the majority of which occur only in the African-American population. Recapitulation of the various combinations of SNP haplotypes in vitro in promoter-reporter assays revealed a few notable trends. The African and European American-specific haplotypes tended to result in enhanced MDR1 promoter activity only in the human embryonic kidney (HEK) 293 cell line. Haplotype GCTAACC, which occurs at variable frequencies in all the populations examined, with Asians having much lower frequencies (<2%) compared with the European Americans/African Americans (>4%), affected MDR1 promoter activity differently in different cell lines. Compared with the commonest haplotype, GCTA-ACC haplotype resulted in a significant decrease in MDR1 promoter activity in HeLa cells (P < 0.05) but a significant increase in the same promoter activity in HEK293 cells (P < 0.05). These results suggest that the MDR1 promoter region is largely invariant but that different haplotypes have differential effects on the MDR1 promoter activity in different cell lines.

Black or African American↗
PubMed2005

Detection of CX3CR1 single nucleotide polymorphism and expression on archived eyes with age-related macular degeneration.

There is a significant genetic component in age-related macular degeneration (AMD). CX3CR1, which encodes the fractalkine (chemokine, CX3CL1) receptor, has two single nucleotide polymorphisms (SNPs): V249I and T280M. These SNPs are correlated with other aged-related diseases such as atherosclerosis. We have reported an association of CX3CR1 SNP and AMD. In this study we examined CX3CR1 SNP frequencies and protein expression on archived sections of AMD and normal eyes. We microdissected non-retinal, peripheral retinal and macular cells from archived slides of eyes of AMD patients and normal subjects. CX3CR1 SNP typing was conducted by PCR and restriction fragment length polymorphism analysis. CX3CR1 transcripts from retinal cells were also measured using RT-PCR. CX3CR1 protein expression was evaluated using avidin-biotin complex immunohistochemistry. We successfully extracted DNA from 32/40 AMD cases and 2/2 normal eyes. Among the 32 AMD cases, 18 had neovascular AMD and 14 had non-neovascular AMD. The M280 allele was detected in 19/64 (32 cases x2) with a frequency of 29.7%, which was significantly higher as compared to the frequency in the normal population (11.2%). We detected CX3CR1 expression in the various retinal cells. CX3CR1 transcript and protein levels were diminished in the macular lesions. This study successfully analyzed CX3CR1 SNP and transcript expression in microdissected cells from archived paraffin fixed slides. Our data suggest that the M280 allele, a SNP resulting in aberrant CX3CR1 and CX3CL1 interaction, as well as lowered expression of macular CX3CR1, may contribute to the development of AMD.

Age Factors↗
PubMed2002

Identification of single-nucleotide polymorphisms in the human LPIN1 gene.

Because mutations in the murine analog of human LPIN1 cause lipodystrophy in mice, LPIN1 is a candidate gene for human lipodystrophy syndromes. To identify possible disease mutations and/or common single-nucleotide polymorphisms (SNPs), we developed primer pairs to amplify the 21 exons of LPIN1. We used these primer pairs to sequence LPIN1 in lipodystrophy patients who had no mutations in known lipodystrophy genes, and also in normal control subjects. We found no rare LPIN1 coding sequence variants that were exclusive to patients with lipodystrophy. However, we found four silent SNPs, namely, +17C>T in exon 3, 935C>T in exon 5, and 1040G>A and 1079G>C in exon 6, and one nonsynonymous SNP, namely, 2211C>T (P616S) in exon 15. The findings suggest that LPIN1mutations are not commonly seen in patients with lipodystrophy who had no mutations in known disease genes. However, the identification of amplification primers and SNPs provides tools to further investigate LPIN1for association with other phenotypes.

Animals↗
PubMed2005

Associations between two single nucleotide polymorphisms in the adiponectin gene and polycystic ovary syndrome.

In the present study we determined whether genetic variability in the gene encoding adiponectin is associated with polycystic ovary syndrome (PCOS). Altogether 143 Caucasian women with PCOS and 245 healthy controls were genotyped for two single nucleotide polymorphisms (SNPs) in exon 2 and intron 2 in the adiponectin gene. Single-point analysis was expanded to pair-of-loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, in the PCOS and control groups. Estimated haplotype frequencies were assessed using the maximum-likelihood method, employing an expectation-maximization algorithm. A significantly different allele distribution in intron 2 SNP was observed between the groups, with the T allele being significantly reduced in the PCOS group (25.9%) compared with the control group (32.7%) ( p = 0.047), at an odds ratio of 0.72 (95% confidence interval 0.52-0.99). Otherwise, the allele and genotype distributions in either SNP were not statistically different between the groups. In haplotype estimation analysis, there was a lower frequency of the haplotype T-T in the PCOS group (25.9%) than in the control group (32.7%) ( p = 0.058). We conclude that polymorphisms of the adiponectin gene may be implicated in individual susceptibility to PCOS.

Adiponectin↗
PubMed2005

DNA-based diagnosis of xeroderma pigmentosum group C by Whole-genome scan using single-nucleotide polymorphism microarray.

In this study, we have established the molecular basis of xeroderma pigmentosum (XP) in two unrelated Chinese families. In the first patient with consanguineous parents, we mapped the disease-causing locus XPC using single-nucleotide polymorphism microarray. Mutational analysis of the XPC gene showed that the patient is homozygous for a nonsense mutation, E149X. After developing DNA-based diagnosis of XPC, we screened another XP patient for XPC mutations. We found that the second patient is a compound heterozygote of 1209delG and Q554X in this gene. These are the first XPC-causing mutations identified in Chinese patients.

Adult↗
PubMed2005

Functional analysis of a single nucleotide polymorphism in a potential binding site for GATA transcription factors in the ovine interleukin 2 gene.

The transcription factor GATA-3 is one regulator of Th1/Th2 differentiation. In sheep, we recently discovered a putative GATA-binding site (WGATAR) in the second intron of the Th1-cytokine gene interleukin 2 (IL2), showing a single nucleotide polymorphism (G/C). As genetic variations in cytokine genes are thought to regulate cytokine production, we studied the significance of this polymorphism for IL2 transcription. Sheep with different IL2 genotypes were identified by single-strand conformation polymorphism (SSCP)-analysis and IL2 transcription levels in peripheral blood mononuclear cells (PBMC) isolated from these animals were compared. For this purpose, transcription of IL2 mRNA was quantified by real-time polymerase chain reaction in unstimulated PBMC and in PBMC incubated for 4h in the presence of concanavalin A (ConA) or phorbol 12-myristate 13-acetate plus ionomycin (PMA/I). Compared to unstimulated cells, stimulation with ConA and PMA/I increased the IL2 mRNA transcription in average by 300- and 20-fold, respectively. Nevertheless, no significant differences in IL2 transcription between the genotypes could be detected. These findings were confirmed by band shift studies using different oligonucleotides containing variations of the potential binding motif, which showed no differences in the gel mobility after incubation with nuclear extract containing GATA-3. The obtained results argue against an impact of this polymorphism on the IL2 transcription and the genetic disease resistance in sheep.

Animals↗
PubMed2004

Single nucleotide polymorphism, haplotype diversity and recombination in the Isa gene of barley.

The Isa gene from barley--an intronless gene expressed in maternal tissues of the seed--has a likely role in defence against pathogens. The protein product--bi-functional alpha-amylase/subtilisin inhibitor--inhibits the seed's own amylase in addition to the bacterial protease subtilisin and fungal xylanase. Sixteen barley genotypes were targeted to amplify and sequence the Isa gene region to detect sequence polymorphisms, since little is known about genetic diversity at this locus. A total of 80 single nucleotide polymorphisms (SNPs) and 23 indels were detected in 2,164 bp of sequence containing the Isa transcript, promoter and 3' non-transcribed region (overall one SNP per 27 bp and one indel per 94 bp), with eight sequence-based haplotypes distinguishable amongst the 16 varieties. Sequencing a polymorphic region in the promoter in an additional 27 barley genotypes increased the number of sequence-based haplotypes discovered to 11. However there is low haplotype diversity amongst the cultivated barley varieties sampled, with most varieties represented by a single haplotype. There was minor amino acid diversity in the protein, with five out of ten SNP sites in the coding region predicted to produce amino acid substitutions. SNP analysis indicated a history of recombination events--a minimum of seven based on the initial eight haplotypes from the whole sequenced region. Most of the recombination events occurred in the highly polymorphic regions, the 3' non-transcribed region and sequences flanking a microsatellite in the Isa promoter.

Base Sequence↗
PubMed2006

Single-nucleotide polymorphisms in the epsilon-globin gene for differentiating primate infraorders.

Molecular methods are being used to enforce wildlife conservation laws by identifying the species or the geographic origin of an unknown sample. However, the promising use of single-nucleotide polymorphisms (SNPs) in this field is still widely unexplored. In the present work, we have developed a reliable and easy method based on single-base extension technology for the scoring of 3 SNPs in the epsilon-globin gene that successfully identifies the primate infraorder a sample belongs to. Since primates are of high conservation concern and different infraorders are distributed in specific parts of the world, this method will serve for an initial potentially automated screening of the taxonomy and geographic origin of an unknown primate sample arriving at customs.

Animals↗
PubMed2002

Functional genomics of C190T single nucleotide polymorphism in human N-acetyltransferase 2.

N-acetyltransferase 2 (NAT2) catalyzes N-acetylation and O-acetylation of many drugs and environmental carcinogens. Genetic polymorphisms in the NAT2 gene have been associated with differential susceptibility to cancers and drug toxicity from these compounds. Single nucleotide polymorphisms (SNPs) have been identified in the human NAT2 coding region. A new allele, NAT2*19, possessing the C190T (R64W) exchange, was recently identified. In order to understand the effect of this new SNP, recombinant NAT2*4 (reference) and NAT2*19 were expressed in yeast (Schizosaccharomyces pombe). The C190T (R64W) SNP in NAT2*19 caused substantial reduction in the NAT2 protein level and stability, but did not cause significant reduction in transformation efficiency or mRNA level. The enzymatic activities for N-acetylation of two arylamine carcinogens (2-aminofluorene, 4-aminobiphenyl), and a sulfonamide drug (sulfamethazine) were over 100-fold lower for NAT2 19 compared to reference NAT2 4. Kinetic studies showed a reduction in Vmax but no significant change in substrate Km. In addition, the SNP caused significant reduction in the O-acetylation of the N-hydroxy-2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine. These results show that NAT2*19 possessing the C190T (R64W) SNP encodes a slow acetylator phenotype for both N- and O-acetylation, due to a reduction in the amount and stability of the NAT2 19 allozyme.

Arylamine N-Acetyltransferase↗
PubMed2005

Single nucleotide polymorphisms of DNA repair genes XRCC1 and XPD and its molecular mapping in Indian oral cancer.

Tobacco users with diminished ability to repair somatic mutations may be more susceptible to tobacco attributable cancers. The distribution of single nucleotide polymorphisms (SNPs) in DNA repair genes XRCC1 and XPD in 110 oral carcinoma cases, 84 leukoplakia and 110 controls belonging to the Travancore South Indian population were examined. SNPs investigated included Arg194Trp, Arg280His, and Arg399Gln of the XRCC1 gene and Lys751Gln of the XPD gene. In addition, one of the variants positions, A399G, was mapped onto the BRCT I domain model built by comparative modeling (threading). Presence of the polymorphic variant of XRCC1 codon 194 and 399 and XPD was associated with increased risk of oral cancer compared to the wild genotype. Smokers and betel quid chewers with the variant allele of XRCC1 399 codon and XPD also exhibited increased risk of oral cancer. The A399G variant position mapped onto the surface of the BRCT I domain provides a possible rationale for altered XRCC1 function. These results suggest that polymorphisms in functionally important repair genes, specifically, those that map onto the protein surface may alter protein function without significantly affecting its structure.

Case-Control Studies↗
PubMed2002

Genotyping single-nucleotide polymorphisms by matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry.

In recent years matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI) has emerged as a very powerful method for genotyping single nucleotide polymorphisms. The accuracy, speed of data accumulation, and data structure are the major features of MALDI. Several SNP genotyping methods have been implemented with a high degree of automation and are being applied for large-scale association studies. Most methods for SNP genotyping using MALDI mass spectrometric detection and their potential application for high-throughput are reviewed here.

Automation↗
PubMed2006

Novel single nucleotide polymorphism of UGT1A9 gene in Japanese.

We sequenced from 5'-franking region to intron 1 (to 337 bp downstream from exon 1) of the UDP-glucuronosyltransferase (UGT) 1A9 gene prepared from 55 Japanese cancer patients. Seven single nucleotide polymorphisms (SNPs) were found. Two of them were UGT1A9 -118(T)n (n=10) and UGT1A9*5, and four were reported SNPs in intron 1 of UGT1A9 gene (89540C>T, 89549G>A, 89616T>A and 89710A>C). A novel SNP (89587T>C) was found. The sequence is as follows: SNP, 050824FujitaK001; Gene Name, UGT1A9; Accession Number, AF297093; Length, 25 bases; 5'-CCTTCTTGAAGAT/CATGTATTTATAA-3'. Two patients were heterozygous for the mutant allele, resulting in the allele frequency of 1.82%.

Alleles↗
PubMed2005

Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis.

Genome-wide copy number changes were analyzed in 70 primary human lung carcinoma specimens and 31 cell lines derived from human lung carcinomas, with high-density arrays representing approximately 115,000 single nucleotide polymorphism loci. In addition to previously characterized loci, two regions of homozygous deletion were found, one near the PTPRD locus on chromosome segment 9p23 in four samples representing both small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) and the second on chromosome segment 3q25 in one sample each of NSCLC and SCLC. High-level amplifications were identified within chromosome segment 8q12-13 in two SCLC specimens, 12p11 in two NSCLC specimens and 22q11 in four NSCLC specimens. Systematic copy number analysis of tyrosine kinase genes identified high-level amplification of EGFR in three NSCLC specimens, FGFR1 in two specimens and ERBB2 and MET in one specimen each. EGFR amplification was shown to be independent of kinase domain mutational status.

Carcinoma, Non-Small-Cell Lung↗
PubMed2006

Novel functional single nucleotide polymorphisms in the latent transforming growth factor-beta binding protein-1L promoter: effect on latent transforming growth factor-beta binding protein-1L expression level and possible prognostic significance in ovarian cancer.

Latent transforming growth factor (TGF)-beta binding proteins (LTBPs) play important roles in the secretion and activation of TGF-beta. We previously reported that LTBP-1L is overexpressed in some patients with ovarian cancer. To clarify the molecular mechanism of LTBP-1L regulation, we analyzed DNA sequences in the promoter region of LTBP-1L and identified two novel single nucleotide polymorphisms, -202G/C and +20A/C. While the alleles with -202C and +20C were initially reported, our data demonstrated that -202G and +20A are common in both ovarian cancer patients and healthy patients in the Japanese population. Luciferase reporter assays revealed that the G-A haplotype induced transcriptional activation in a Sp1-dependent manner. Electrophoretic mobility shift assays showed that increased binding affinity of Sp1 to the promoter with -202G and +20A. Interestingly, ovarian cancer patients (n = 42) with G-A/G-A homozygous genotype had increased expression of LTBP-1 and apparently poorer survival than those with other genotypes (P = 0.02). These findings suggest that the single nucleotide polymorphisms -202G/C and +20A/C on the LTBP-1L promoter may affect the clinical outcome of ovarian cancer patients, probably via up-regulating protein expression. Further studies using a larger number of samples will definitively determine the correlation between LTBP-1 haplotype and clinical behavior of ovarian cancer.

Adult↗
PubMed2005

Prediction of the phenotypic effects of non-synonymous single nucleotide polymorphisms using structural and evolutionary information.

MOTIVATION: There has been great expectation that the knowledge of an individual's genotype will provide a basis for assessing susceptibility to diseases and designing individualized therapy. Non-synonymous single nucleotide polymorphisms (nsSNPs) that lead to an amino acid change in the protein product are of particular interest because they account for nearly half of the known genetic variations related to human inherited diseases. To facilitate the identification of disease-associated nsSNPs from a large number of neutral nsSNPs, it is important to develop computational tools to predict the phenotypic effects of nsSNPs. RESULTS: We prepared a training set based on the variant phenotypic annotation of the Swiss-Prot database and focused our analysis on nsSNPs having homologous 3D structures. Structural environment parameters derived from the 3D homologous structure as well as evolutionary information derived from the multiple sequence alignment were used as predictors. Two machine learning methods, support vector machine and random forest, were trained and evaluated. We compared the performance of our method with that of the SIFT algorithm, which is one of the best predictive methods to date. An unbiased evaluation study shows that for nsSNPs with sufficient evolutionary information (with not <10 homologous sequences), the performance of our method is comparable with the SIFT algorithm, while for nsSNPs with insufficient evolutionary information (<10 homologous sequences), our method outperforms the SIFT algorithm significantly. These findings indicate that incorporating structural information is critical to achieving good prediction accuracy when sufficient evolutionary information is not available. AVAILABILITY: The codes and curated dataset are available at http://compbio.utmem.edu/snp/dataset/

Algorithms↗