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Results for “Single nucleotide polymorphisms”

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PubMed2001

A single nucleotide polymorphism of CYP2b6 found in Japanese enhances catalytic activity by autoactivation.

A single nucleotide polymorphism (SNP) resulting in a substitution from Gln to His was found in exon 4 of the CYP2B6 gene in Japanese. The frequency of the variant allele was found to be 19.9%. The mutant- and the wild-type enzymes were expressed in Escherichia coli, and the effects of the single amino acid substitution on the catalytic activity were examined by investigating the kinetic profiles of 7-ethoxycoumarin O-deethylase activity. The wild-type enzyme showed typical Michaelis-Menten kinetics, while the mutant-type enzyme represented the sigmoidal kinetics with a higher V(max) value compared to that of the wild-type enzyme. Eadie-Hofstee plots further revealed an existence of allosteric effects for the reaction catalyzed by the variant. This is the first evidence demonstrating that only one amino acid substitution, Gln172His, caused by natural SNP enhances the catalytic activity of CYP by obtaining the character of homotropic cooperativity.

Allosteric Regulation↗

PubMed2005

TaqMan assays for genotyping of single nucleotide polymorphisms present at a disease susceptibility locus on chromosome 6.

Multiple single-nucleotide polymorphisms in the BAT1-NFKBIL1-LTA region on the short arm of chromosome 6 have been found to be associated with susceptibility to myocardial infarction in a recent case-control study including individuals from Japan. Specifically, the association relates to homozygosity for the minor alleles of five individual polymorphisms (one each in BAT1 and NFKBIL1 and three in LTA) and a haplotype defined by a particular allele combination of 10 polymorphisms (three each in BAT1 and NFKBIL1 and four in LTA). In the Japanese study, genotype determinations were carried out using a multiplex PCR-Invader assay or DNA sequencing. As an alternative to these methods, we have established TaqMan assays for genotyping of nine of the 10 polymorphisms. Accuracy of the genotyping results obtained with the TaqMan reactions was demonstrated in experiments involving restriction enzyme analysis or DNA sequencing. Using the new TaqMan assays, we have genotyped the polymorphisms in a group of 1211 Caucasians who presented without symptoms or signs of acute or previous myocardial infarction. Genotype distributions of each of the five myocardial infarction-associated polymorphisms were significantly different between the present study group and two Japanese control groups (p < or = 0.01). High linkage disequilibrium measures between polymorphisms suggested that the nine polymorphisms reside in a single haplotype block. Based on the nine polymorphisms, eight different haplotypes with allele frequencies above 1% were identified, which together represented 98.4% of the total number of chromosome 6 in the 1211 individuals. This Caucasian study group and the Japanese sample showed strong linkage disequilibrium in the myocardial infarction-associated BAT1-NFKBIL1-LTA genomic region and related haplotype content, but significantly different genotype frequencies. The new TaqMan systems provide relatively simple and fast assays to test the clinical relevance of these polymorphisms.

Alleles↗

PubMed2007

No association between the +874T/A single nucleotide polymorphism in the IFN-gamma gene and susceptibility to TB.

A single nucleotide polymorphism (SNP), +874T/A, in the first intron of the interferon-gamma (IFN-gamma) gene, has presented associations with human susceptibility to tuberculosis (TB) in some ethnic populations, but not in others. In this population-based case-control study with adult TB patients from Houston, Texas, we found no significant differences of + 874T/A genotypic frequencies between cases and ethnically-matched controls or between advanced forms of TB disease (extra-pulmonary involvement or presence of cavitary disease) and pulmonary TB. Given possible sample size limitations, our results suggest that the IFN-gamma +874T/A mutation has no association with TB susceptibility or TB disease severity.

Adult↗

PubMed2003

Approach to analysis of single nucleotide polymorphisms by automated constant denaturant capillary electrophoresis.

Melting gel techniques have proven to be amenable and powerful tools in point mutation and single nucleotide polymorphism (SNP) analysis. With the introduction of commercially available capillary electrophoresis instruments, a partly automated platform for denaturant capillary electrophoresis with potential for routine screening of selected target sequences has been established. The aim of this article is to demonstrate the use of automated constant denaturant capillary electrophoresis (ACDCE) in single nucleotide polymorphism analysis of various target sequences. Optimal analysis conditions for different single nucleotide polymorphisms on ACDCE are evaluated with the Poland algorithm. Laboratory procedures include only PCR and electrophoresis. For direct genotyping of individual SNPs, the samples are analyzed with an internal standard and the alleles are identified by co-migration of sample and standard peaks. In conclusion, SNPs suitable for melting gel analysis based on theoretical thermodynamics were separated by ACDCE under appropriate conditions. With this instrumentation (ABI 310 Genetic Analyzer), 48 samples could be analyzed without any intervention. Several institutions have capillary instrumentation in-house, thus making this SNP analysis method accessible to large groups of researchers without any need for instrument modification.

Algorithms↗

PubMed2005

Whole-genome linkage analysis in mapping alcoholism genes using single-nucleotide polymorphisms and microsatellites.

There is currently a great interest in using single-nucleotide polymorphisms (SNPs) in genetic linkage and association studies because of the abundance of SNPs as well as the availability of high-throughput genotyping technologies. In this study, we compared the performance of whole-genome scans using SNPs with microsatellites on 143 pedigrees from the Collaborative Studies on Genetics of Alcoholism provided by Genetic Analysis Workshop 14. A total of 315 microsatellites and 10,081 SNPs from Affymetrix on 22 autosomal chromosomes were used in our analyses. We found that the results from the two scans had good overall concordance. One region on chromosome 2 and two regions on chromosome 7 showed significant linkage signals (i.e., NPL >or= 2) for alcoholism from both the SNP and microsatellite scans. The different results observed between the two scans may be explained by the difference observed in information content between the SNPs and the microsatellites.

Alcoholism↗

PubMed2002

[Functional analysis of the single nucleotide polymorphisms in the PRKCZ gene].

OBJECTIVE: To study the function of 5 single nucleotide polymorphisms (SNPs) of the PRKCZ gene, a susceptibility gene for type 2 diabetes in Han population of North China, in the pathogenesis of the disease. METHODS: Bioinformatic methods and reporter gene activity determination were used to analyze the function of the 5 SNPs. RESULTS: The reporter gene activities of different alleles of 2 SNPs, rs427811 and rs809912, were obviously different, which implies that these 2 SNPs might be susceptibility loci of the disease. CONCLUSION: The PRKCZ gene is further confirmed to be a susceptibility gene for type 2 diabetes in Han population of North China. Two SNPs in the gene play a role in the pathogenesis of the disease by affecting the expression level of PRKCZ gene.

Alleles↗

PubMed2004

Genotyping of single nucleotide polymorphisms in cytokine genes using real-time PCR allelic discrimination technology.

Single nucleotide polymorphisms (SNPs), particularly those within regulatory regions of genes that code for cytokines often impact expression levels and can be disease modifiers. Investigating associations between cytokine genotype and disease outcome provides valuable insight into disease etiology and potential therapeutic intervention. Traditionally, genotyping for cytokine SNPs has been conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), a low throughput technique not amenable for use in large-scale cytokine SNP association studies. Recently, Taqman real-time PCR chemistry has been adapted for use in allelic discrimination assays. The present study validated the accuracy and utility of real-time PCR technology for a number of commonly studied cytokine polymorphisms known to influence chronic inflammatory diseases. We show that this technique is amenable to high-throughput genotyping and overcomes many of the problematic features associated with PCR-RFLP including post-PCR manipulation, non-standardized assay conditions, manual allelic identification and false allelic identification due to incomplete enzyme digestion. The real-time PCR assays are highly accurate with an error rate in the present study of <1% and concordance rate with PCR-RFLP genotyping of 99.4%. The public databases of cytokine polymorphisms and validated genotyping assays highlighted in the present study will greatly benefit this important field of research.

Base Sequence↗

PubMed2006

Analyses of single nucleotide polymorphisms and haplotype linkage of the human ABCB1 (MDR1) gene in Korean.

Single nucleotide polymorphisms (SNPs) in the MDR1 gene that are responsible for drug efflux can cause toxicity. Therefore, this study determined the SNPs of the Korean MDR1 gene, and analyzed the haplotypes and a linkage disequilibrium (LD) of the SNPs determined. The frequency of 9 SNPs from the MDR1 gene was determined by PCR-RFLP analyses of 100 to 500 healthy individuals. The frequcies of the SNPs were C3435T (47.7%), G2677T (37.6%), G2677A (4.4%), T1236C (21.7%), T129C (8%), A2956G (2.5%), T307C (1.5%), A41aG (9.2%), C145G (0%), and G4030C (0 %). Analyses of the haplotype structure and an estimation of the LD of the combined polymorphisms demonstrated that the frequency of the 1236T-2677G-3435T haplotype is much higher in Koreans (14.1%) than in Chinese and western black Africans and the C3435T SNP in Koreans appears to have LD with T129C in Koreans for the first time. These results provide insight into the genetic variation of MDR1 in Koreans, and demonstrated the possibility of a new LD in this gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Single nucleotide polymorphisms in the human complement C6 and C7 genes.

We analyzed the single nucleotide polymorphisms (SNPs) in the sixth (C6) and the seventh (C7) component genes of the complement system in a sample of the Japanese population, using polymerase chain reaction (PCR)-based methods and PCR direct sequencing. SNPs in the C6 gene studied here are as follows: A413C in exon 3, T1674C in exon 10, T7145A in exon 13, G[357+32]A in intron 2, and G[503-78]A in intron 3. We confirmed that nt413A and nt413C were associated with C6A and C6B, respectively. The result of the nt2145 typing showed that two subtypes exist in the C6B allotype. The SNP of G[357+32]A in intron 2 could be analyzed by using the PCR-RFLP method with HinfI. Allele frequencies in the Japanese population were found to be *G=0.920 and *A=0.080. SNPs in the C7 gene are as follows: T382C in exon 4, G1166C and A1258C in exon 9, and G[+10]A in intron 13. Nt382C and nt1258C would be responsible for C7-5 (=C7-3) and C7-4 allotypes, respectively.

Complement C6↗

PubMed2001

PicSNP: a browsable catalog of nonsynonymous single nucleotide polymorphisms in the human genome.

Recent progress in identification and mapping of single nucleotide polymorphisms (SNPs) in the human genome generates an unprecedented opportunity to explore cause-effect relationships between genetic variations and susceptibility to common diseases. For this purpose, one promising strategy would be to select a set of SNPs that potentially alter the function of proteins involved in the pathogenesis of the diseases and compare their frequencies in the affected individuals and the healthy population. In this respect, SNPs that change amino acid sequences (nonsynonymous SNPs; nsSNPs) are of particular interest, since they are more likely to affect protein functions. In this study, we have constructed a catalog of nsSNPs (PicSNP), whose unique features are (i) nsSNPs are classified according to the functions of the affected genes and are searchable under the guidance of hierarchical lists of protein functions and (ii) nsSNPs that lead to amino acid changes in the known functional sites and domains of proteins are highlighted. Out of 1,190,295 SNPs extracted from public database, we identified 3793 nsSNPs and classified them in 1247 categories of protein functions. 495 sites and domains annotated in the Swiss-Prot database were found to include nsSNPs, including 2 nsSNPs in disulfide-binding sites and 38 nsSNPs in transmembrane regions. PicSNP is available via the World Wide Web (http://picsnp.org) and would support research questing for SNPs involved in common diseases.

Databases, Factual↗

PubMed2006

Association of the IL4R single-nucleotide polymorphism I50V with rapidly erosive rheumatoid arthritis.

OBJECTIVE: To examine whether single-nucleotide polymorphisms (SNPs) of the interleukin-4 receptor gene IL4R influence susceptibility to, or radiographic progression in, rheumatoid arthritis (RA). METHODS: The contribution of 2 SNPs (I50V and Q551R) in the coding region of IL4R to RA susceptibility was analyzed by allele-specific polymerase chain reaction in a case-control study of 471 RA patients and 371 healthy controls. Patients with available radiographs of the hands and feet obtained 2 years after disease onset (n = 302) were stratified retrospectively according to radiologic outcome into an erosive and a nonerosive group to evaluate the association between IL4R SNPs and disease progression. RESULTS: No differences in the genotype and allele frequencies of the I50V or Q551R SNPs were identified between the RA patients and healthy controls. In contrast, significant differences in the distribution of I50V IL4R SNP genotypes between patients with erosive and nonerosive disease were observed (chi2 = 15.68, P = 0.0004). Bone erosions at 2 years after disease onset were present in 68.1% of patients homozygous for the V50 allele compared with 37.0% of patients homozygous for the I50 allele (odds ratio 3.86, P < 0.0001). This association was independent of individual factors previously associated with severe disease, such as rheumatoid factor or the HLA-DR shared epitope. On a cellular level, the V50 allele conferred significantly reduced responsiveness to interleukin-4, providing a possible mechanism for the association of the I50V IL4R polymorphism with early erosions in RA. CONCLUSION: Our data identify the I50V IL4R SNP as a novel genetic marker in RA, showing high predictive value for early joint destruction.

Arthritis, Rheumatoid↗

PubMed2006

[Association of single nucleotide polymorphism of megsin gene with IgA nephropathy].

OBJECTIVE: To investigate whether the single nucleotide polymorphisms (SNPs) in the gene of megsin, a novel serine protease inhibitor, account for the pathogenicity of IgA nephropathy (IgAN). METHODS: A comprehensive megsin gene survey, including the entire coding region, part of the regulatory region, and exon-intron connection region, was performed by PCR-direct sequencing on the DNA samples of peripheral blood from 12 randomly selected IgAN patients and 12 randomly selected healthy persons. Eight SNPs with moderate or high frequencies (with the frequency > 5%) selected from the 11 SNPs found were used as candidate SNPs. Then 210 IgAN patients proven by renal-biopsy, all of Chinese Han nationality, and 103 normal volunteers were recruited. The 8 candidate SNPs were genotyped by direct sequencing or PCR-RFLP and a case-control association study was carried out. RESULTS: The SNP of 267G/A in 5'untranslated region within exon1 was significantly associated with IgAN. The frequency of AG/AA genotype of the IgA patients was 29.0%, significantly higher than that of the controls (16.5%, P < 0.05). The frequency of A allele of the IgA patients was 14.8%, significantly higher than that of the controls (8.7%, P < 0.05). The odds ratio of AG/AA genotype versus GG genotype was 2.07 with the 95% confidence interval of 1.15 - 3.74. The linkage disequilibrium between two SNPs existed commonly within one gene. CONCLUSION: 267G/A in megsin gene is associated with IgAN susceptibility. AG and AA genotypes are the risk factors of pathogenesis of IgAN.

Adolescent↗

PubMed2006

[Expression and single nucleotide polymorphisms of kallikrein 10 in colorectal cancer].

OBJECTIVE: To demonstrate expression and single nucleotide polymorphisms (SNP) of human kallikrein 10 (KLK 10) in colorectal cancer (CRC) and to correlate the KLK 10 expression level with clinicopathological factors of CRC. METHODS: KLK 10 expression in 63 cases of tumoral and nontumoral colorectal tissues at the mRNA and protein levels were evaluated by quantitative real-time RT-PCR (qRT) and Western blot methods. KLK 10 protein was localized by immunohistochemistry. The KLK 10 genomic DNA from 16 cases of paired normal and cancerous colorectal tissues was PCR-amplified and examined for SNP by direct sequencing. RESULTS: The KLK 10 mRNA expression was detected by qRT in 61 of 63 (97%) CRC specimens. The KLK 10 expression was much higher in tumor tissue than in the corresponding normal mucosal tissue at the mRNA and protein levels. The KLK 10 mRNA expression level significantly correlated with the lymphatic invasion (P < 0.05) and clinical stage of CRC (P < 0.05). No mutations or polymorphisms were detected in exon 1, 2 and 5 of KLK 10 gene in CRC. A SNP in codon 50 of exon 3, GCC (alanine) to TCC (serine) was identified. The genetic changes of exon 4 were located at codon 106 [GGC (glycine) to GGA (glycine)], codon 112 [ACG (threonine) to ACC (threonine)], codon 141 [CTA (leucine) to CTG (leucine)], and codon 149 [CCG (proline) to CTG (leucine)]. All these SNP were identical in tumor as well as the corresponding normal tissue DNA from the same individuals. CONCLUSIONS: The KLK 10 expression is up-regulated in CRC and higher expression of KLK 10 closely correlate with advanced disease stage, which predicts a poorer prognosis, however, further follow-up study is needed.

Adult↗

PubMed2003

Cytokine single nucleotide polymorphisms and intrarenal gene expression in chronic allograft nephropathy in children.

BACKGROUND: Single nucleotide polymorphisms (SNPs) have been reported to influence cytokine production. Certain cytokine high producer genotypes have been associated with an increased risk for acute rejection and chronic allograft dysfunction (CAD) after transplantation. Our study evaluates SNP distribution for transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha) in pediatric renal transplant recipients and control individuals and correlates them to corresponding intrarenal gene expression. METHODS: SNPs for TGF-beta1 (codon 10 and 25), IL-10 (positions -1082, -819, -592) and TNF-alpha (position -308) were determined in 30 patients with stable graft function, in 75 patients with CAD, and in 173 control individuals by allele-specific polymerase chain reaction (PCR). Intrarenal cytokine gene expression was studied in 25 biopsies with chronic allograft nephropathy (CAN) and 27 normal kidney specimens by real-time reverse transcription (RT)-PCR. RESULTS: No difference in allele and genotype frequency was detected in any of the investigated groups. No correlation between genotype and intragraft cytokine gene expression was recognized in CAN patients. However, in normal kidney specimens, the low producer TGF-beta1 genotype at codon 10 was associated with significant lower TGF-beta1 mRNA expression. This association was not found for IL-10 or TNF-alpha. CONCLUSION: Our results do not support the proposition that certain specific cytokine genotypes for TGF-beta1, IL-10, and TNF-alpha are associated with CAD. Intrarenal cytokine gene expression only correlated to one TGF-beta1 SNP in normal kidney specimens. Since overall TGF-beta1 expression was higher in transplanted patients compared to controls, this suggests that SNPs may not play a significant role once the immune system is activated.

Adolescent↗

PubMed2006

QualitySNP: a pipeline for detecting single nucleotide polymorphisms and insertions/deletions in EST data from diploid and polyploid species.

BACKGROUND: Single nucleotide polymorphisms (SNPs) are important tools in studying complex genetic traits and genome evolution. Computational strategies for SNP discovery make use of the large number of sequences present in public databases (in most cases as expressed sequence tags (ESTs)) and are considered to be faster and more cost-effective than experimental procedures. A major challenge in computational SNP discovery is distinguishing allelic variation from sequence variation between paralogous sequences, in addition to recognizing sequencing errors. For the majority of the public EST sequences, trace or quality files are lacking which makes detection of reliable SNPs even more difficult because it has to rely on sequence comparisons only. RESULTS: We have developed a new algorithm to detect reliable SNPs and insertions/deletions (indels) in EST data, both with and without quality files. Implemented in a pipeline called QualitySNP, it uses three filters for the identification of reliable SNPs. Filter 1 screens for all potential SNPs and identifies variation between or within genotypes. Filter 2 is the core filter that uses a haplotype-based strategy to detect reliable SNPs. Clusters with potential paralogs as well as false SNPs caused by sequencing errors are identified. Filter 3 screens SNPs by calculating a confidence score, based upon sequence redundancy and quality. Non-synonymous SNPs are subsequently identified by detecting open reading frames of consensus sequences (contigs) with SNPs. The pipeline includes a data storage and retrieval system for haplotypes, SNPs and alignments. QualitySNP's versatility is demonstrated by the identification of SNPs in EST datasets from potato, chicken and humans. CONCLUSION: QualitySNP is an efficient tool for SNP detection, storage and retrieval in diploid as well as polyploid species. It is available for running on Linux or UNIX systems. The program, test data, and user manual are available at http://www.bioinformatics.nl/tools/snpweb/ and as Additional files.

Base Sequence↗

PubMed2005

Affinity capillary electrophoresis of DNA for detection of single-nucleotide polymorphisms and point mutations. Comprehensive study for optimization of the weak affinity.

A single-stranded DNA and its point mutant can be separated with affinity capillary electrophoresis (ACE) in which an appropriate ligand DNA is used as a pseudo-stationary affinity phase. In this paper, we systematically examine the effects of ligand sequence, capillary temperature, and cation concentration on the ACE separation quality, which is quantitatively evaluated in terms of resolution and peak height. For fine tuning of the affinity, control of MgCl(2) concentration and insertion of a spacer sequence into the ligand DNA are more effective than control of the capillary temperature. For design of the ligand DNA, a simple strategy is proposed, based on the prediction of melting temperature. This strategy was tested with eleven different sample sequences. All of them were separated under the same conditions (250 microM MgCl(2) and 25 degrees C), and nine cases of them had satisfactory separation qualities.

Cations↗

PubMed2005

A genotyping system capable of simultaneously analyzing >1000 single nucleotide polymorphisms in a haploid genome.

A high-throughput genotyping system for scoring single nucleotide polymorphisms (SNPs) has been developed. With this system, >1000 SNPs can be analyzed in a single assay, with a sensitivity that allows the use of single haploid cells as starting material. In the multiplex polymorphic sequence amplification step, instead of attaching universal sequences to the amplicons, primers that are unlikely to have nonspecific and productive interactions are used. Genotypes of SNPs are then determined by using the widely accessible microarray technology and the simple single-base extension assay. Three SNP panels, each consisting of >1000 SNPs, were incorporated into this system. The system was used to analyze 24 human genomic DNA samples. With 5 ng of human genomic DNA, the average detection rate was 98.22% when single probes were used, and 96.71% could be detected by dual probes in different directions. When single sperm cells were used, 91.88% of the SNPs were detectable, which is comparable to the level that was reached when very few genetic markers were used. By using a dual-probe assay, the average genotyping accuracy was 99.96% for 5 ng of human genomic DNA and 99.95% for single sperm. This system may be used to significantly facilitate large-scale genetic analysis even if the amount of DNA template is very limited or even highly degraded as that obtained from paraffin-embedded cancer specimens, and to make many unpractical research projects highly realistic and affordable.

Chromosome Mapping↗

PubMed1999

Two single nucleotide polymorphisms of the hSNF5/INI1 gene.

We found two single nucleotide polymorphisms at the hSNF5/INI1 gene located on 22q11.2, encoding a member of the chromatin-remodelling SWI/SNF multiprotein complexes. A guanine/adenine polymorphism at codon 299 in exon 7, and another guanine/adenine polymorphism at 39 bp upstream of exon 9 were identified. As the gene was recently identified as a tumor suppressor gene for malignant rhabdoid tumor, this polymorphism may be useful for the genetic study of susceptibility for human malignancies of various tissue origins.

Adenine↗