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At least 307 records · Page 17Linked to original sources
PubMed2006

Single nucleotide polymorphisms (SNPs) in human lactoferrin gene.

The lactoferrin protein possesses antimicrobial and antiviral activities. It is also involved in the modulation of the immune response. In a normal healthy individual, lactoferrin plays a role in the front-line host defense against infection and in immune and inflammatory responses. Whether genomic variations, such as single nucleotide polymorphisms (SNPs), have an effect on the structure and function of lactoferrin protein and whether these variations contribute to the different susceptibility of individuals in response to environmental insults are interesting health-related issues. In this study, the lactoferrin gene was resequenced as part of the Environmental Genome Project of the National Institute of Environmental Health Sciences, which operates within the National Institutes of Health. Ninety-one healthy donors of different ethnicities were used to establish common SNPs in the exons of the lactoferrin gene in the general population. The data will serve as a basis from which study the association of lactoferrin polymorphism and disease.

Ethnicity↗
PubMed2003

Population frequencies of single nucleotide polymorphisms (SNPs) in immuno-modulatory genes.

Inherited polymorphisms in immuno-modulatory genes may contribute to variations in immune function and genetic susceptibility for complex diseases, including cancer. We report results from a comprehensive study to discover novel single nucleotide polymorphisms (SNPs) and to estimate allelic frequency for both novel and known coding and regulatory region SNPs in genes encoding proteins that have been implicated in the immune response to tumors. We identified 12 novel nucleotide substitution variants and one deletion variant in 17 genes analyzed (TGFBETA;R, BETA;2M, IFNGAMMA;, TNFALPHA;, TNFALPHA;R, LTALPHA;, IL-6, IL-12, IL-2, IL-1ALPHA;, IL-1BETA;, IL-1RN, IL-10, CTLA4, CD40L, FAS and FASL). We determined the frequency of these novel polymorphisms, as well as 17 previously identified polymorphisms, in a control sample of 158 individuals, approximately half of which were Caucasian (n = 74) and half of which were African American (n = 84). Significant differences in allele frequencies were observed between the two racial groups for 13/17 genes tested. These allelic variations maybe associated with alterations in immune function and thus susceptibility to a number of complex disease states such as cancer.

Black or African American↗
PubMed2006

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

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

Adult↗
PubMed2007

TAMGeS: a Three-array Method for Genotyping of SNPs by a dual-colour approach.

BACKGROUND: Many of the most effective high-throughput protocols for SNP genotyping employ microarrays. Genotypes are assessed by comparing the signal intensities that derive from the hybridization of different allele-specific probes labelled either by using four fluorescent dyes, one for each base, or by using only two dyes and investigating the polymorphic alleles two by two on separate arrays. The employment of only two dyes makes it possible to use a dual-laser scanner, which has the advantage of being present in every microarray laboratory. However, this protocol may present some drawbacks. To infer all the six possible genotypes it is necessary to compare signals from two arrays, but this comparison not always is successful. A number of systematic errors in the experimental protocol, in fact, may differently affect signal intensities on separate arrays. Here we present TAMGeS (Three-Array Method for Genotyping of SNPs), an exhaustive method for SNP genotyping through SBE (Single Base Extension) and dual-colour microarrays, which makes the comparison of signals on distinct arrays reliable by using a third array and a data handling method for signal normalization based on bilinear regression theory. RESULTS: We tested the effectiveness of the proposed method by evaluating the results obtained from the direct comparison of the two arrays or by applying TAMGeS, both on experimental and synthetic data. With synthetic data, TAMGeS reduced the frequency of errors by an order of magnitude, when the incidence of systematic errors was not negligible. With the experimental data, produced by genotyping 25 SNPs in 437 subjects, TAMGeS reduced the percentage of missing genotypes from 54% (Two-Array Method) to 14.5%. Allelic and genotypic call rates were 99.3% and 99.5%, respectively. The normalization procedure takes into account also systematic errors, which can be generated by a time-delayed assay, thus making the protocol more flexible. CONCLUSION: TAMGeS represents an innovative method, which proved to be very effective in producing reliable SNP genotyping data by dual-colour microarrays. The requirement of a third array is well balanced by the strong enhancement in data quality and by the greater flexibility of the experimental protocol.

Base Sequence↗
PubMed2005

Characterization of the linkage disequilibrium structure and identification of tagging-SNPs in five DNA repair genes.

BACKGROUND: Characterization of the linkage disequilibrium (LD) structure of candidate genes is the basis for an effective association study of complex diseases such as cancer. In this study, we report the LD and haplotype architecture and tagging-single nucleotide polymorphisms (tSNPs) for five DNA repair genes: ATM, MRE11A, XRCC4, NBS1 and RAD50. METHODS: The genes ATM, MRE11A, and XRCC4 were characterized using a panel of 94 unrelated female subjects (47 breast cancer cases, 47 controls) obtained from high-risk breast cancer families. A similar LD structure and tSNP analysis was performed for NBS1 and RAD50, using publicly available genotyping data. We studied a total of 61 SNPs at an average marker density of 10 kb. Using a matrix decomposition algorithm, based on principal component analysis, we captured >90% of the intragenetic variation for each gene. RESULTS: Our results revealed that three of the five genes did not conform to a haplotype block structure (MRE11A, RAD50 and XRCC4). Instead, the data fit a more flexible LD group paradigm, where SNPs in high LD are not required to be contiguous. Traditional haplotype blocks assume recombination is the only dynamic at work. For ATM, MRE11A and XRCC4 we repeated the analysis in cases and controls separately to determine whether LD structure was consistent across breast cancer cases and controls. No substantial difference in LD structures was found. CONCLUSION: This study suggests that appropriate SNP selection for an association study involving candidate genes should allow for both mutation and recombination, which shape the population-level genomic structure. Furthermore, LD structure characterization in either breast cancer cases or controls appears to be sufficient for future cancer studies utilizing these genes.

Acid Anhydride Hydrolases↗
PubMed2005

Single nucleotide polymorphisms (SNPs) are inherited from parents and they measure heritable events.

Single nucleotide polymorphisms (SNPs) are extensively used in case-control studies of practically all cancer types. They are used for the identification of inherited cancer susceptibility genes and those that may interact with environmental factors. However, being genetic markers, they are applicable only on heritable conditions, which is often a neglected fact. Based on the data in the nationwide Swedish Family-Cancer Database, we review familial risks for all main cancers and discuss the evidence for a heritable component in cancer. The available evidence is not conclusive but it is consistent in pointing to a minor heritable etiology in cancer, which will hamper the success of SNP-based association studies. Empirical familial risks should be used as guidance for the planning of SNP studies. We provide calculations for the assessment of familial risks for assumed allele frequencies and gene effects (odds ratios) for different modes of inheritance. Based on these data, we discuss the gene effects that could account for the unexplained proportion of familial breast and lung cancer. As a conclusion, we are concerned about the indiscriminate use of a genetic tool to cancers, which are mainly environmental in origin. We consider the likelihood of a successful application of SNPs in gene-environment studies small, unless established environmental risk factors are tested on proven candidate genes.

Editorial↗
PubMed2004

The genomic distribution of population substructure in four populations using 8,525 autosomal SNPs.

Understanding the nature of evolutionary relationships among persons and populations is important for the efficient application of genome science to biomedical research. We have analysed 8,525 autosomal single nucleotide polymorphisms (SNPs) in 84 individuals from four populations: African-American, European-American, Chinese and Japanese. Individual relationships were reconstructed using the allele sharing distance and the neighbour-joining tree making method. Trees show clear clustering according to population, with the root branching from the African-American clade. The African-American cluster is much less star-like than European-American and East Asian clusters, primarily because of admixture. Furthermore, on the East Asian branch, all ten Chinese individuals cluster together and all ten Japanese individuals cluster together. Using positional information, we demonstrate strong correlations between inter-marker distance and both locus-specific FST (the proportion of total variation due to differentiation) levels and branch lengths. Chromosomal maps of the distribution of locus-specific branch lengths were constructed by combining these data with other published SNP markers (total of 33,704 SNPs). These maps clearly illustrate a non-uniform distribution of human genetic substructure, an instructional and useful paradigm for education and research.

Genetics, Population↗
PubMed2005

Genotyping SNPs using a UV-photocleavable oligonucleotide in MALDI-TOF MS.

Matrix-assisted laser desorption time-of-flight mass spectrometry coupled with allele-specific primer extension is a proven method for typing single nucleotide polymorphisms (SNPs). A novel modification upon this methodology is the incorporation of a photocleavable linker within the extension primer. After completion of the primer extension reaction, photocleavage of the extension products results in two deoxyribonucleic acid (DNA) fragments of lower mass. Typically, the smaller cleavage product, which contains the genotyping information, is in the range of 1000-3000 Daltons. The decrease in primer mass allows for higher sensitivity in mass spectrometric measurement and increases the potential for higher levels of multiplexing. The disturbing mass spectrometric analysis peaks caused by salt adducts and doubly charged ions are diminished when analyzing lower-mass DNA fragments. Here, we illustrate the methodology for using photocleavable modified extension primers for detection of SNPs located on the Y chromosome. Genomic templates were prepared from anonymous male donors. Five regions of the Y chromosome containing the SNP markers M9, M42, M45, M89, and M96 were amplified by polymerase chain reaction, treated with shrimp alkaline phosphatase, and subjected to primer extension reactions using primers containing a photocleavable building block at specific sites. After elongation, the extension primers were desalted and subjected to ultraviolet irradiation to cleave the products at the photocleavable site. Subsequently, the small fragments derived from the 3' ends of the molecules containing the genotype information were analyzed by matrix-assisted laser desorption ionization time-of-flight using a 3-hydroxypicolinic acid matrix.

Base Sequence↗
PubMed2004

Single nucleotide polymorphisms (SNPs) at -238 and -308 positions in the TNFalpha promoter: clinical and bacteriological evaluation in leprosy.

Tumor necrosis factor alpha (TNFalpha) plays a key role in orchestrating the complex events involved in inflammation and immune response. The presence of single nucleotide polymorphisms (SNPs) within the promoter region of the TNFa gene has been associated with a number of diseases. The aim of this study was to investigate the distribution of polymorphisms at positions -238 (G/A) and -308 (G/A) at the TNFalpha promoter, and its association to the outcome of different clinical forms of leprosy. Furthermore, the bacteriological index (BI) was evaluated among genotyped multibacillary (MB) patients in order to investigate the possible influence of each polymorphism on the bacterial load. This study included a total of 631 leprosy patients being 401 MB and 230 paucibacillary (PB), that was further separated according to its ethnicity (Afro- and Euro-Brazilians). The combination of SNPs in haplotypes generated three different arrangements: TNFG-G, TNFG-A and TNFA-G. In spite of the marked differences observed in the frequency of the haplotypes along the ethnic groups, no statistical differences were observed in haplotype frequencies between MB and PB patients. The BI analyses showed a lower bacteriological index among the -308 carriers, while the BI of the -238 carriers was higher. Although no significance has been achieved in this analysis regarding the influence of the polymorphisms to the development of the clinical outcome, it seems that in a different stage (among the MB patients) the polymorphisms could contribute to the degree of severity observed.

Black People↗
PubMed2003

Low frequency of mutated methylenetetrahydrofolate reductase 677C-->T and 1298A-->C genetics single nucleotide polymorphisms (SNPs) in Sub-Saharan populations.

5,10-Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are two of the key enzymes in the folate/vitamin B12-dependent remethylation of homocysteine to methionine. The frequencies of MTHFR single nucleotide polymorphisms (SNPs), 677C-->T, 1298A-->C, 1317T-->C and of MTR, 2756A-->G, have been widely studied in Caucasians, but they have never been reported simultaneously in a large population from Sub-Saharan Africa. Presently, we report the prevalence of these SNPs and their relationship to homocysteine in 240 subjects recruited in West Africa. The frequencies of the mutant genotypes 677TT (0.8%) and 1298CC (2%) were lower than that usually observed in Caucasians, while the frequency of the mutant 1317CC was higher (16%). We formed a systematic association of the mutated MTHFR 677C-->T SNP with a 1298A/1317T common haplotype. The MTHFR mutant genotype 677TT was associated with an intermediate hyperhomocysteinemia (92.4 +/- 6.0 micromol/l) higher than that described in Caucasians. The 2756A-->G SNP in the MTR was similarly distributed in Africans compared to Caucasians. In conclusion, the MTHFR 677TTor 1298CC genotypes are much rarer in Africans than in Caucasians. The 677TT low frequency may be related to the high effect of this mutation on homocysteine metabolism in the environmental conditions of this African region.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2002

How many SNPs does a genome-wide haplotype map require?

We derive and compare several estimates of the number of SNPs that would be required to form the basis of a complete haplotype survey of the human genome. Our estimates make use of reports published by Stephens et al. [1], Patil et al. [2] and Daly et al. [3]. The estimated number of SNPs required for a genome-wide haplotype survey ranges from 180K (based on a European sample of 16 chromosomes) to 600K (based on an ethnically diverse sample of 164 chromosomes). We discuss the implications of using cohorts of different size and ethnic composition and the usefulness of public SNP databases for this effort. Finally, we estimate the experimental effort and cost required to complete a genome-wide haplotype survey.

Algorithms↗
PubMed2001

Towards high-throughput genotyping of SNPs by dynamic allele-specific hybridization.

Analysis of single nucleotide polymorphisms (SNPs)--the most common form of variation in the human genome--has become a popular strategy for discovering genes involved in complex diseases such as Alzheimer's disease, obesity and diabetes. It is also widely anticipated that SNPs will play a major role in pharmacogenomics, where the identification of variations in specific genes relevant to drug efficacy, toxicity and metabolism will help to establish optimal therapeutic strategies for individual patients. Reflecting these expectations, many new SNP-related technologies have appeared over the past few years, each with unique advantages, but all with the common goal of simplifying and expediting SNP analysis. We recently introduced a technique termed dynamic allele-specific hybridization (DASH), a convenient method for SNP (and insertion-deletion) genotyping, which is highly applicable to both basic research and clinical diagnostics. Commercial DASH devices are now available, making the technology affordably accessible for all laboratories.

Alleles↗
PubMed2003

Two novel single nucleotide polymorphisms (SNPs) of the FMO3 gene in Japanese.

We sequenced all exons and exon-intron junctions of the flavin-containing monooxygenase 3 (FMO3) gene from 27 Japanese individuals who are trimethylaminuria volunteers judged by self-reported analysis. We found two novel single nucleotide polymorphisms (SNPs) (21246 T>A and 21265 C>T) causing amino acid substitutions (Asp(198)Glu and Arg(205)Cys in exon 5), respectively. The Asp(198)Glu allele also presented together with known SNPs (20852 C>T in exon4, 20960_20962 CTT deletion, 21115 G>A in intron 4, and 21243_21244 TG deletion in exon 5) in the same allele of the FMO3 gene to form a novel haplotype. These sequences are as follows:1) SNP, 030609Fujieda019; GENE NAME, FMO3; ACCESSION NUMBER, AL021026; LENGTH, 25 base; 5'-TTCGGGCTG(TG/-)AT/AATTGCCACAGAA-3'.2) SNP, 030609Fujieda020; GENE NAME, FMO3; ACCESSION NUMBER, AL021026; LENGTH, 25 base; 5'-ACAGAACTCAGCC/TGCACAGCAGAAC-3'.

Journal Article↗
PubMed2006

Single-tube-genotyping of gastric cancer related SNPs by directly using whole blood and paper-dried blood as starting material.

AIM: To demonstrate an inexpensive method for typing gastric cancer related single nucleotide polymorphisms (SNPs) using whole blood or paper-dried blood as starting materials. METHODS: PCR amplification is directly carried out from the whole blood or paper-dried blood sample without any DNA extraction step. Before PCR, a blood sample, four primers, and all of biological reagents necessary for PCR were added at a time; After PCR, the amplified products were directly separated by slab gel electrophoresis or microchip CE without any purification. SNP typing was performed by tetra-primer PCR with two inner primers specific to each allele and two outer primers defining the length of allele-specific amplicons. Genotypes were directly discriminated by the size of amplicons specific to each allele, thereby avoiding any post-PCR process. RESULTS: Using a special PCR buffer, inhibitory substances in blood (including the anticoagulant in blood) and filter paper were effectively suppressed; a "true" single-tube-genotyping is thus realized. We successfully determined genotypes IL-1B-511 and IL-1B-31 polymorphisms at the gene IL-1B by using whole-blood and paper-dried blood samples as starting materials respectively. The method is so sensitive that 0.5-1.0 microL of blood sample is enough to give a satisfactory typing results. The genotyping results were confirmed by RFLP-PCR using purified genome DNA, indicating that amplification specificity was not affected by inhibitory components (including coagulants) in blood or filter paper. CONCLUSION: Compared with SNP typing methods based on purified DNA, the proposed method is labor-saving, simple, inexpensive, and less cross-contaminated. It is promising to use this method to type other SNPs.

Cost Control↗
PubMed1999

Mining SNPs from EST databases.

There is considerable interest in the discovery and characterization of single nucleotide polymorphisms (SNPs) to enable the analysis of the potential relationships between human genotype and phenotype. Here we present a strategy that permits the rapid discovery of SNPs from publicly available expressed sequence tag (EST) databases. From a set of ESTs derived from 19 different cDNA libraries, we assembled 300,000 distinct sequences and identified 850 mismatches from contiguous EST data sets (candidate SNP sites), without de novo sequencing. Through a polymerase-mediated, single-base, primer extension technique, Genetic Bit Analysis (GBA), we confirmed the presence of a subset of these candidate SNP sites and have estimated the allele frequencies in three human populations with different ethnic origins. Altogether, our approach provides a basis for rapid and efficient regional and genome-wide SNP discovery using data assembled from sequences from different libraries of cDNAs.

DNA, Complementary↗
PubMed2000

Candidate gene analysis in Rett syndrome and the identification of 21 SNPs in Xq.

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that affects females. Exclusion mapping studies using a new family with maternal inheritance of RTT defined Xq28 as the candidate region for the RTT gene. Six candidate genes were selected for mutation analysis based on their established expression patterns and known functions in the CNS. These are: Glutamate receptor subunit 3 (GLUR3), GABA receptor subunit alpha 3 (GABRA3), GABA receptor subunit e1 (GABRE1), Vacuolar ATPase subunit 1 (VATPS1, XAP3), the human homologue of plexin 3-SEX (XAP6) and the Synaptobrevin-like protein (SYBL1). Major rearrangements involving these genes were excluded by Southern analysis. No disease-causing mutations were found, but several single-nucleotide polymorphisms (SNPs) were detected. These SNPs will be useful in future linkage analysis and whole-genome association studies for other diseases. The genomic characterization of GLUR3 and GABRA3 will allow mutational analysis of these genes as candidates for other X-linked neurological disorders mapping to Xq25-Xq26 and Xq28.

Base Sequence↗
PubMed2003

Easy, accurate and reliable screening for SNPs by ion pair/reverse phase HPLC: simultaneous detection of factor V G1691A, prothrombin G20210A and methylenetetrahydrofolate reductase C677T variants.

We have set up allele specific PCR in combination with high-performance liquid chromatography as a method to simultaneously detect three SNPs, factor V (G1691A), factor II/prothrombin (G20210A) and methylenetetrahydrofolate reductase (C677T) genes, all suspected to be inherited risk factors for deep vein thrombosis. Allele specific multiplex PCR technique was used to generate PCR products of different sizes which were specific for each genotype analyzed in this study. PCR products were analyzed on the WAVE Nucleic Acid Analysis platform by means of a gradient ion pair/reverse phase chromatography without any further purification. This method allows concurrent genotyping of the PCR products of the three mutations within 8 minutes, clearly reduces working time and costs in a routine laboratory, and can easily be adapted to the analysis of any other SNP or the combination of different other SNPs. The assay established here has been validated on more than a hundred samples and gave correct and highly reproducible intra- and interday results, allowing the application of this easy, accurate and reliable test in routine settings and in clinical trials and epidemiological surveys.

Chromatography, High Pressure Liquid↗