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PubMed2004

Identification and interrogation of highly informative single nucleotide polymorphism sets defined by bacterial multilocus sequence typing databases.

A unified, bioinformatics-driven, single nucleotide polymorphism (SNP)-based approach to microbial genotyping has been developed. Multilocus sequence typing (MLST) databases consist of known variants of standardized housekeeping genes. Normally, seven fragments are defined; a sequence type (ST) consists of the variants of these fragments that are found in a particular isolate. A computer program that can identify highly informative sets of SNPs in entire MLST databases has been constructed. The SNPs either define a particular user-specified ST or provide a high value for Simpson's index of diversity (D), and may thus be generally applicable to that species. SNP sets that are diagnostic for Neisseria meningitidis ST-11 and ST-42, and high-D SNP sets for N. meningitidis and Staphylococcus aureus, were identified and real-time PCR methods to interrogate these SNPs were demonstrated. High-D SNP sets were also identified in other MLST databases. This widely applicable approach allows rapid genetic fingerprinting of infectious agents.

Algorithms↗
PubMed2005

DigiTag assay for multiplex single nucleotide polymorphism typing with high success rate.

As a consequence of Human Genome Project and single nucleotide polymorphism (SNP) discovery projects, several millions of SNPs, which include possible susceptibility SNPs for multifactorial diseases, have been revealed. Accordingly, there has been a strong drive to perform the investigation with all candidate SNPs for a certain disease without decreasing the number of analyzed SNPs. We developed DigiTag assay, which uses well-designed oligonucleotides called DNA coded numbers (DCNs) in multiplex SNP genotype analysis. During the analysis, the information of a genotype is converted to one of the DCNs in a one to one manner using oligonucleotide ligation assay (encoding). After the encoding reaction, only the DCNs regions and not the SNP specific regions are amplified using the universal primers and then SNP genotype is read out using DNA capillary arrays. DigiTag assay was found to be successful in SNP genotyping, giving a high success rate (24 of 27 SNPs) for randomly chosen SNPs. Moreover, this assay has the potential to analyze almost all kinds of the target SNPs by applying mismatch-induced probes and redesigned primer pairs at a low-cost.

DNA↗
PubMed2004

[Absence of evidence for the association of single nucleotide polymorphisms in Annexin A1 gene with type 2 diabetes in Chinese].

OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) in the annexin A1(ANXA1) gene and to analyze the association of these SNPs with type 2 diabetes in Shanghai Han population. METHODS: SNPs in the promotor and exon regions (including intron sequence near splicing site) in the ANXA1 gene were screened by direct sequencing in 24 type 2 diabetes patients and were further genotyped by direct sequencing in another 171 type 2 diabetes patients and 189 normal control subjects. RESULTS: The total sequence of ANXA1 gene is 6798 bp. And 7 SNPs were found; among them, 2 SNPs (-7974 C>T and -7040 G>T) were in promotor region, 3 SNPs in intron regions (+9059 A>G, +9204 C>T, +10486 A>G), 1 SNP in 5'-untranslation region (-6614 A>G) and 1 SNP in coding regions (+1784 A>G). These 7 SNPs were genotyped further and the results revealed that the allele frequencies of these SNPs showed no significant difference between the diabetic and the control groups (P>0.05). CONCLUSION: There is no association of these SNPs in ANXA1 gene with type 2 diabetes in Shanghai Han population.

Aged↗
PubMed2003

A novel MALDI-TOF based methodology for genotyping single nucleotide polymorphisms.

A new MALDI-TOF based detection assay was developed for analysis of single nucleotide polymorphisms (SNPs). It is a significant modification on the classic three-step minisequencing method, which includes a polymerase chain reaction (PCR), removal of excess nucleotides and primers, followed by primer extension in the presence of dideoxynucleotides using modified thermostable DNA polymerase. The key feature of this novel assay is reliance upon deoxynucleotide mixes, lacking one of the nucleotides at the polymorphic position. During primer extension in the presence of depleted nucleotide mixes, standard thermostable DNA polymerases dissociate from the template at positions requiring a depleted nucleotide; this principal was harnessed to create a genotyping assay. The assay design requires a primer- extension primer having its 3'-end one nucleotide upstream from the interrogated site. The assay further utilizes the same DNA polymerase in both PCR and the primer extension step. This not only simplifies the assay but also greatly reduces the cost per genotype compared to minisequencing methodology. We demonstrate accurate genotyping using this methodology for two SNPs run in both singleplex and duplex reactions. We term this assay nucleotide depletion genotyping (NUDGE). Nucleotide depletion genotyping could be extended to other genotyping assays based on primer extension such as detection by gel or capillary electrophoresis.

Animals↗
PubMed2003

[Association of single nucleotide polymorphism in human SCN7A gene with essential hypertension in Chinese].

OBJECTIVE: To identify the single nucleotide polymorphisms (SNPs) in the regulatory and coding regions of human SCN7A (sodium channel, voltage-gated, type VII, alpha polypeptide) gene and to investigate the association of some of these SNPs with essential hypertension (EH) in Chinese. METHODS: The promoter region, exons, as well as part of the introns of SCN7A gene were sequenced by a fluorescent labeling automatic sequencing method to identify and characterize the SNPs in Chinese population. SNP genotyping was performed by PCR-RFLP or direct DNA sequencing in unrelated EH patients and normotensive controls from a Chinese Han population residing in Shanghai area. Case-control studies on seven SNPs were first carried out in 96 patients and 96 normotensive controls. The positive finding was further verified in an extended study containing 288 patients and 288 controls. RESULTS: Thirty-two SNPs were identified through a 13,132 bp sequencing of SCN7A gene. Among them, seven were in regulatory region, ten in coding regions, one in 3'UTR and fourteen in introns. Thirty SNPs were novel SNPs, and a cSNP in exon 18 (SNP021) was associated with hypertension. CONCLUSION: The SNP021 in the gene SCN7A is associated with essential hypertension of Chinese Han population in Shanghai and the role of SCN7A gene in hypertension deserves to be further analyzed.

Adult↗
PubMed2003

Single nucleotide polymorphisms and haplotype frequencies of CYP3A5 in a Japanese population.

In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A5 in a Japanese population, we sequenced the proximal promoter region, all exons, and the surrounding intronic regions using genomic DNA from 187 Japanese subjects. Thirteen SNPs, including seven novel ones: 13108T>C, 16025A>G, 16903A>G, 16993C>G, 27448C>A, 29782A>G, and 31551T>C (A of the translational start codon of GenBank Accession # NG_000004.2 is numbered 1 according to the CYP Allele Nomenclature), were identified. The most common SNP was 6986A>G (key SNP for CYP3A5*3), with a 0.759 frequency. Two novel SNPs, 29782A>G (I456V) and 31551T>C (I488T), as well as 12952T>C (*5 marker) were found, but these alterations were always associated with the *3A marker SNPs, 6986A>G and 31611C>T. Using these 13 SNPs, haplotype analysis was performed and five novel *1 haplotypes (subtypes) (*1e to *1i) and six novel *3 haplotypes (subtypes) (*3d to *3i) were identified. Our findings suggest that CYP3A5*3 is the major defective allele and that other functional exonic SNPs are rare in the Japanese.

Adult↗
PubMed2006

Rapid identification of single nucleotide polymorphisms and estimation of allele frequencies using sequence traces from DNA pools.

Millions of single nucleotide polymorphisms (SNP) are now known in the chicken, but the ones that segregate may differ among populations. The current study characterized a simple method to simultaneously identify SNP in populations and to estimate allele frequencies by using relative peak heights of nucleotides in sequencing traces from DNA pools. In the first experiment, known concentration gradients of alleles were produced by measured admixture of DNA from highly inbred individual chickens. In the second experiment, pools of DNA from 100 individuals of each of 3 populations were produced, and the estimated frequencies were compared with those from genotyping of individuals sampled from the same populations. Linear relationships (slope = 0.93 to 1.02) were demonstrated between relative peak heights of nucleotide sequence traces and allelic frequency from both types of experimental samples. The correlation of frequency estimates from pools and individual genotyping was 0.917 to 0.997. Therefore, relative peak heights of nucleotides in sequence traces from DNA isolated from blood pools provide accurate estimates of SNP frequencies of the population from which the pool individuals were sampled and can, therefore, increase efficiency of selecting SNP to genotype in specific populations.

Alleles↗
PubMed2005

[Application of oligonucleotide array in single nucleotide polymorphism typing of cytokines and cytokine receptors].

OBJECTIVE: To develop an oligonucleotide array for single nucleotide polymorphism (SNP) typing of cytokines, such as tumor necrosis factor (TNF)-a, interleukin (IL)-10, tumor growth factor (TGF)-betal, IL-4, and IL-6, and their receptors and evaluate its function by direct sequencing. METHODS: According to relevant literature, SNP database of NCBI and SNP500 Cancer database of NCI, SNP loci and sequences of cytokines of clinical importance, TNF-a, IL-10, TGF-bl, IL-4 and IL-6, and matched cytokine receptors were chosen and 59 synthesized oligonucleotide probes were immobilized on a glass support, then the primer and Cy5-dCTP were used in multi-PCR, thus the products were labeled with Cy5. The labeled PCR products were hybridized with the probes in the array, and the signals were scanned by Scanner and then analyzed by Image software. Peripheral blood samples were collected from 80 healthy donors and 50 patients with uremia to isolate lymphocytes and DNA so as to undergo typing by this array, and the results were validated with direct sequencing. RESULTS: All the samples with PCR products except for 10 from uremia patients had been genotyped by cytokine array successfully. No diversity was found in genotyping for three times. Incorrect locus was not found with direct sequencing. CONCLUSION: With high specificity, sensitivity, repetitiveness, and throughout, and easy to manipulate, oligonucleotide array technique is an ideal molecular method for SNP genotyping of cytokine and cytokine receptor.

Cytokines↗
PubMed2005

Novel human alpha1a-adrenoceptor single nucleotide polymorphisms alter receptor pharmacology and biological function.

We identified nine naturally-occurring human single nucleotide polymorphisms (SNPs) in the alpha(1a)-adrenoceptor (alpha(1a)AR) coding region, seven of which result in amino acid change. Utilizing rat-1 fibroblasts stably expressing wild type alpha(1a)AR or each SNP at both high and low levels, we investigated the effect of these SNPs on receptor function. Compared with wild type, two SNPs (R166K, V311I) cause a decrease in binding affinity for agonists norepinephrine, epinephrine, and phenylephrine, and also shift the dose-response curve for norepinephrine stimulation of inositol phosphate (IP) production to the right (reduced potency) without altering maximal IP activity. In addition, SNP V311I and I200S display altered antagonist binding. Interestingly, a receptor with SNP G247R (located in the third intracellular loop) displays increased maximal receptor IP activity and stimulates cell growth. The increased receptor signaling for alpha(1a)AR G247R is not mediated by altered ligand binding or a deficiency in agonist-mediated desensitization, but appears to be related to enhanced receptor-G protein coupling. In conclusion, four naturally-occurring human alpha(1a)AR SNPs induce altered receptor pharmacology and/or biological activity. This finding has potentially important implications in many areas of medicine and can be used to guide alpha(1a)AR SNP choice for future clinical studies.

Adrenergic alpha-Agonists↗
PubMed2004

Functional analysis of single nucleotide polymorphisms of hepatic organic anion transporter OATP1B1 (OATP-C).

OBJECTIVE: Two kinds of single nucleotide polymorphism (SNP; Asn130Asp and Val174Ala) are frequently observed in the liver specific transporter, organic anion transporting polypeptide 1B1 (OATP1B1/OATP-C) gene. Although these two SNPs occur independently in European-Americans, Val174Ala is mostly associated with Asn130Asp in Japanese. Our previous in-vivo studies in Japanese subjects indicated that the non-renal clearance of pravastatin was decreased to 13% of that in wild-type subjects (Nishizato et al. Clin Pharmacol Ther 2003;73(6):554-564). The purpose of the present study is to characterize the function of SNPs variants of OATP1B1 in cDNA transfected cells. METHODS: The localization and transport activity were analyzed in HEK293 cells stably expressing wild-type OATP1B1 (OATP1B1*1a), OATP1B1*1b (Asn130Asp), OATP1B1*5 (Val174Ala) and OATP1B1*15 (Asn130Asp and Val174Ala). To characterize the intrinsic Vmax, observed Vmax in uptake study were normalized by the expression level estimated from Western blotting. RESULTS: All SNP variants are predominantly located on the cell surface. No significant alteration was observed in Km values for the transport of 17beta-estradiol 17beta-d-glucuronide (E217betaG), a typical substrate of OATP1B1, among these SNP variants. However, the normalized Vmax value for OATP1B1*15 was drastically decreased to less than 30% compared with OATP1B1*1a. In contrast, the transport activity of OATP1B1*1b (Asn130Asp) and OATP1B1*5 (Val 174Ala) was similar to that of OATP1B1*1a. CONCLUSIONS: These results are consistent with the results of our previous clinical studies. It is thus suggested that in-vivo disposition may be predicted from in-vitro results using recombinant transporters.

Cell Line↗
PubMed2005

Haplotypes and haplotype-tagging single-nucleotide polymorphism: presentation Group 8 of Genetic Analysis Workshop 14.

Moderately dense maps of single-nucleotide polymorphism (SNP) markers across the human genome for both the simulated data set and data from the Collaborative Study of the Genetics of Alcoholism were available at Genetic Analysis Workshop 14 for the first time. This allowed examination of various novel and existing methods for haplotype analyses. Three contributors applied Mantel statistics in different ways for both linkage and association analysis by using the shared length between two haplotypes at a marker locus as a measure of genetic similarity. The results indicate that haplotype-sharing based on Mantel statistics can be a powerful approach and needs further methodological evaluation. Four contributors investigated haplotype-tagging SNP (htSNP) selection procedures, two contributors examined the use of multilocus haplotypes compared to single loci in association tests, and two contributors compared the accuracy of various methods for reconstructing haplotypes and estimating haplotype frequencies for both pedigree data and data from unrelated individuals. For all three different tasks, software packages and procedures gave similar results in regions of high linkage disequilibrium (LD). However, they were not as consistent in regions of moderate to low LD. One coalescence-based approach for estimating haplotype frequencies, coupled with a Markov chain Monte Carlo technique, outperformed the other haplotype frequency estimation methods in regions of low LD. In conclusion, regardless of the task, results were similar in chromosomal regions of high LD. However, based on the differing results observed here, methodological improvements are required for chromosomal regions of low to moderate LD.

Alcoholism↗
PubMed2005

Varied prevalence of factor V G1691A (Leiden) and prothrombin G20210A single nucleotide polymorphisms among Arabs.

BACKGROUND: Factor V G1691A (FV-Leiden) and prothrombin (PRT) G20210A single nucleotide polymorphisms (SNPs) are major inherited risk factors of venous thromboembolism. In view of the heterogeneity in their world distribution and lack of sufficient information about their distribution among Arabs, we addressed the prevalence of both SNPs in 4 distinct Arab populations (Lebanon, Tunisia, Bahrain, and Saudi Arabia). METHODS: Study subjects comprised 698 Lebanese, 313 Tunisian, 194 Bahraini, and 149 Saudi Arabian healthy subjects; genotyping was done by PCR-RFLP using Mnl I and Hind III for FV-Leiden and PRT G20210A, respectively. RESULTS: The prevalence of the mutant A alleles of FV-Leiden and PRT G20210A were significantly higher among Lebanese (0.0788 and 0.0136) and Tunisians (0.0351 and 0.0128), as compared to Bahraini (0.0155 and 0.0052) and Saudi (0.0101 and 0.000) subjects. Higher frequency of the FV-Leiden G/A and A/A genotypes were seen in Lebanon (13.8 and 1.0%), followed by Tunisia (5.8 and 0.6%), Bahrain (3.1 and 0.0%) and Saudi Arabia ((2.0 and 0.0%). All PRT G20210A positive cases were in the heterozygote (G/A) state, and these comprised 3.6% for Lebanon, 2.6% for Tunisia, 1.0% for Bahrain. The carrier rate of FV-Leiden was significantly higher among Lebanese compared to the other populations (p < 0.001), while the difference in the prevalence of FV-Leiden between the other populations was not statistically different. With the exception of Lebanese-Saudi (p = 0.038), the prevalence of PRT G20210A was similar among the study communities. Furthermore, the overall average genetic differentiation between populations (estimated with the F(ST)) was 0.0022 for FV-Leiden and 0.005 for PRT G20210A. CONCLUSIONS: These results further confirm the heterogeneity in FV-Leiden and PRT G20210A distribution among Arabs, and recommend potential institution of prophylactic measures for carriers of either or both SNPs.

Alleles↗
PubMed2005

A single nucleotide polymorphism based approach for the identification and characterization of gene expression modulation using MassARRAY.

Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation. Their abundance and the ease with which they can be assayed have lead to their use in applications beyond simple genotyping. One such application is the quantitative determination of transcript levels associated with distinct alleles or haplotypes found in promoters and coding regions of genes. These changes in expression due to allelic variation are often associated with additional genomic or transcript modifications such as DNA methylation or RNA editing. Here, we describe the use of an integrated genetic analysis platform, based on matrix-assisted laser desorption/ionisation-time-of-flight (MALDI-TOF) to first, discover coding SNPs (cSNPs); second, use these cSNPs to identify and analyze allele-specific expression; and third, from this knowledge to further analyze methylation patterns as a putative cause for the allele-specific expression. An established model involving allele-specific expression profiles of the human tumor protein 73 (TP73) gene is presented as an example to outline and validate data obtained from the MassARRAY platform. The availability of a single integrated platform to assay stable and dynamic variation at the genomic and transcript level greatly simplifies complex functional genomic studies.

5' Untranslated Regions↗
PubMed2001

Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine.

We have identified a migraine locus on chromosome 19p13.3/2 using linkage and association analysis. We isolated 48 single-nucleotide polymorphisms within the locus, of which we genotyped 24 in a Caucasian population comprising 827 unrelated cases and 765 controls. Five single-nucleotide polymorphisms within the insulin receptor gene showed significant association with migraine. This association was independently replicated in a case-control population collected separately. We used experiments with insulin receptor RNA and protein to investigate functionality for the migraine-associated single-nucleotide polymorphisms. We suggest possible functions for the insulin receptor in migraine pathogenesis.

Alleles↗
PubMed2005

Interaction of the -308G/A promoter polymorphism of the tumor necrosis factor-alpha gene with single-nucleotide polymorphism 45 of the adiponectin gene: effect on serum adiponectin concentrations in a Spanish population.

BACKGROUND: We investigated whether interactions of the -308G/A polymorphism in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene with single-nucleotide polymorphisms (SNPs) 45 and 276 of the adiponectin gene are associated with circulating adiponectin and soluble TNF-alpha receptor 2 (sTNFR2) concentrations in a Spanish population. METHODS: We performed anthropometric and physiologic measurements in 809 unrelated participants recruited with a simple random sampling approach from respondents to a cross-sectional population-based epidemiologic survey in the province of Segovia in central Spain (Castille). RESULTS: The 2-h postload glucose and serum insulin concentrations were higher in -308A allele carriers than in -308G/G individuals homozygous for the TNF-alpha gene. Plasma concentrations of sTNFR2 were positively correlated with body mass index, waist-to-hip ratio, and sagittal abdominal diameter among individuals with type 2 diabetes. Individuals with type 2 diabetes and the -308A allele had higher sTNFR2 and lower adiponectin concentrations than -308G homozygotes. Moreover, individuals carrying both the TNF-alpha -308A allele and the G allele of SNP 45 in the adiponectin gene had the highest prevalence of impaired glucose tolerance (adjusted odds ratio, 1.26; 95% confidence interval, 1.01-1.56; P = 0.038) and had lower adiponectin concentrations (beta = -0.090; P = 0.005) than individuals without these genotypes. CONCLUSIONS: Our findings are the first to indicate that a higher incidence of impaired glucose tolerance and low circulating adiponectin concentration may be associated with interaction between the -308G/A promoter polymorphism of the TNF-alpha gene and SNP 45 in the adiponectin gene.

Abdomen↗
PubMed2002

Polymorphisms and HNPCC: PMS2-MLH1 protein interactions diminished by single nucleotide polymorphisms.

Hereditary nonpolyposis colorectal cancer (HNPCC) is one of the most common autosomal dominant inherited diseases. Mutations in the human mismatch repair (MMR) proteins MLH1, MSH2, MSH6, PMS1, and PMS2 have been found to co-segregate with HNPCC. The MLH1 and MSH2 proteins have been demonstrated to interact with PMS1, PMS2, and MSH6 proteins. A previous study reported that missense mutations in specific regions of MLH1 can lead to defects in protein-protein interactions with PMS2. Here we report that three missense alterations previously identified as single nucleotide polymorphisms (SNPs) in PMS2 (P511K, T597S, and M622I) cause defective protein-protein interactions with MLH1, even though the alterations are not in the previously reported interaction domain. These results suggest that an additional domain in PMS2 affects MLH1-PMS2 interaction. This study also demonstrates that SNPs can result in gene alterations that indeed have a functional effect on protein phenotype. Thus, these three SNPs may ultimately represent variants with an increased risk factor for tumorgenesis in HNPCC. This study is one of the first to use a functional assay to appraise the role of SNPs and suggests that traditional definitions of polymorphisms and mutations are in need of reconsideration.

Adaptor Proteins, Signal Transducing↗