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PubMed2005

Loss of heterozygosity analyzed by single nucleotide polymorphism array in cancer.

Neoplastic progression is generally characterized by the accumulation of multiple genetic alterations including loss of tumor suppression gene function. Loss of heterozygosity (LOH) has been used to identify genomic regions that harbor tumor suppressor genes and to characterize different tumor types, pathological stages and progression. LOH pattern has been detected by allelotyping using restriction fragment length polymorphism, and later by simple sequence length polymorphisms (SSLPs or microsatellite) for 10 years. This paper reviews the detection of LOH by recently developed single nucleotide polymorphism (SNP) arrays (all analyzed by Affymetrix array); furthermore, its advantage and disadvantage were analyzed in several kinds of cancer.

Genes, Tumor Suppressor↗
PubMed1999

Single nucleotide polymorphism (SNP) discovery and linkage mapping of bovine cytokine genes.

Polymorphic markers at bovine gene loci facilitate the integration of cattle genetic maps with those of humans and mice. To this end, 31 single nucleotide polymorphism (SNP) markers were developed for seven bovine chemokine genes. Loci were amplified from bovine genomic DNA by the polymerase chain reaction, and candidate amplicons were sequenced to determine their identity. Amplified loci from 24 founding parents and select progeny from a beef cattle reference population were sequenced and analyzed for SNPs. SNP haplotype alleles were determined by examining segregation patterns and used to establish the locus position on the bovine linkage map. Loci for growth-related proteins (GRO3, GRO1, and GROX) were clustered with the related CXC chemokine genes, interleukin (IL) 8, and epithelial cell inflammatory protein 1, at 84 cM from the centromeric end of the bovine chromosome (BTA) 6 linkage group. Bovine loci for a cluster of IL8 receptors, a stromal cell-derived factor 1, interferon-gamma, and tumor necrosis factor-alpha were mapped at 90, 55, 59, and 34 cM, respectively, from the centromeric ends of the BTA 2, 28, 5, and 23 linkage groups. The positions of these bovine loci were compared with those of orthologous loci on the human map to refine the boundaries of conserved synteny. These seven loci provide examples of SNP development in which the efficiency was largely dependent on the availability of bovine genomic or cDNA sequence. The polymorphic nature of these SNP haplotype markers suggests that they will be useful for mapping complex traits in cattle, such as resistance to infectious disease.

Animals↗
PubMed2003

Linkage disequilibrium and inference of ancestral recombination in 538 single-nucleotide polymorphism clusters across the human genome.

The prospect of using linkage disequilibrium (LD) for fine-scale mapping in humans has attracted considerable attention, and, during the validation of a set of single-nucleotide polymorphisms (SNPs) for linkage analysis, a set of data for 4,833 SNPs in 538 clusters was produced that provides a rich picture of local attributes of LD across the genome. LD estimates may be biased depending on the means by which SNPs are first identified, and a particular problem of ascertainment bias arises when SNPs identified in small heterogeneous panels are subsequently typed in larger population samples. Understanding and correcting ascertainment bias is essential for a useful quantitative assessment of the landscape of LD across the human genome. Heterogeneity in the population recombination rate, rho=4Nr, along the genome reflects how variable the density of markers will have to be for optimal coverage. We find that ascertainment-corrected rho varies along the genome by more than two orders of magnitude, implying great differences in the recombinational history of different portions of our genome. The distribution of rho is unimodal, and we show that this is compatible with a wide range of mixtures of hotspots in a background of variable recombination rate. Although rho is significantly correlated across the three population samples, some regions of the genome exhibit population-specific spikes or troughs in rho that are too large to be explained by sampling. This result is consistent with differences in the genealogical depth of local genomic regions, a finding that has direct bearing on the design and utility of LD mapping and on the National Institutes of Health HapMap project.

Alleles↗
PubMed2001

Coexistence of the methylenetetrahydrofolate reductase single-nucleotide polymorphism (C677T) in patients with the factor V Leiden or prothrombin G20210A polymorphisms.

Venous thromboembolism is a complex disease resulting from the interaction of a multitude of both genetic and environmental factors that can affect the cascade of biochemical reactions involved. Single-nucleotide polymorphisms in the genes that code for coagulation factors V (factor V Leiden) and II (prothrombin G20210A), as well as the methylenetetrahydrofolate reductase (MTHFR C677T) gene, have been implicated in the majority of cases of hereditary thrombophilia. In this study the authors evaluated the coexistence of the MTHFR polymorphism in 96 patients with a clinical suspicion for thrombosis who also have either the factor V Leiden polymorphism or the prothrombin G20210A polymorphism. Results indicate that the frequency of the MTHFR polymorphism was similar between the study and control groups with respect to heterozygosity (36.5% vs. 55.3%) and homozygosity (20.8% vs. 14.9%). These data suggest that the MTHFR polymorphism is not associated preferentially with patients who have had or who are at risk of developing a thrombotic event. In this study, patients with the factor V Leiden polymorphism or the prothrombin G20210A polymorphism were considered to be at risk.

DNA↗
PubMed2004

[Association of interferon-gamma + 874 gene single nucleotide polymorphism with susceptibility to intrauterine HBV infection].

OBJECTIVE: To explore the susceptibility of children to develop intrauterine hepatitis B virus (HBV) infection through studying the association between interferon gamma (IFN-gamma) + 874 single nucleotide polymorphism (SNP) and intrauterine HBV infection. METHODS: The subjects were selected from outpatients who were in our hepatitis B (HB) vaccine following-up clinics. The subjects whose mothers were HBV carriers were inoculated with HB vaccine or HB vaccine and hepatitis B immunoglobulin (HBIg). Intrauterine HBV infection was defined as peripheral blood HBsAg and/or HBV-DNA positive at birth and lasting for six months (group I). Normal immune children were defined as peripheral blood negative for HBV marker since birth and afterwards HBsAb titers were above protective level (group II). The subjects were composed of the following two groups. Group I consisted of 46 children with intrauterine HBV infection. Group II was composed of 73 normal children. A Taqman fluorescence polymerase chain reaction for the IFN-gamma + 874 SNP was performed for both groups. RESULTS: IFN-gamma + 874 SNP was tested successfully for every subject. Frequencies of AA, AT and TT genotype were 67.4%, 19.6% and 13.0% in the intrauterine HBV infection group, and 45.2%, 30.1% and 24.7% in the normal immune children group. A significant difference was found in the frequency distribution of IFN-gamma + 874 genotype between the two groups (chi(2) = 5.102, P = 0.02389). In the intrauterine HBV infection group the AA genotype was more common than in normal immune group. CONCLUSION: There is an association between IFN-gamma + 874 SNP and intrauterine HBV infection. This study suggested the possibility that IFN-gamma + 874 SNP might be important in determining an individual's susceptibility to development of intrauterine HBV infection.

Female↗
PubMedDate not supplied

Rolling circle amplification for scoring single nucleotide polymorphisms.

The analysis of the genetic basis of phenotypic traits is moving towards the complex diseases prevalent in wealthy populations. There is an increasing requirement for the detection of different types of sequence variation, particularly single-nucleotide polymorphisms (SNPs). SNPs occur about once every 100 to 300 bases. High-density SNP maps will help to identify the multiple genes associated with complex diseases such as cancer, diabetes, vascular disease, and some forms of mental illness.

DNA↗
PubMed2006

SNP2NMD: a database of human single nucleotide polymorphisms causing nonsense-mediated mRNA decay.

UNLABELLED: Elucidating the effects of genetic polymorphisms on genes and gene networks is an important step in disease association studies. We developed the SNP2NMD database for human SNPs (single nucleotide polymorphisms) that result in PTCs (premature termination codons) and trigger nonsense-mediated mRNA decay (NMD). The SNP2NMD Web interfaces provide extensive genetic information on and graphical views of the queried SNP, gene, and disease terms. AVAILABILITY: SNP2NMD is available from http://variome.net, or directly from http://bioportal.kobic.re.kr/SNP2NMD. SUPPLEMENTARY INFORMATION: http://bioportal.kobic.re.kr/SNP2NMD/Wiki.jsp?page=Statistics.

Chromosome Mapping↗
PubMed2005

The interleukin-6--174 single nucleotide polymorphism: cervical protein production and the risk of preterm delivery.

OBJECTIVE: The purpose of this study was to determine the associations between preterm delivery (PTD), cervical fluid interleukin-6 (IL-6) concentration, and the single nucleotide polymorphism at position -174 in the IL-6 gene. STUDY DESIGN: Cervical fluid samples were obtained from women 23 to 32 weeks' gestation with symptoms of preterm labor. Concentrations of IL-6 were determined by enzyme-linked immunosorbent assay (ELISA). IL-6 genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: One hundred thirty-seven women were enrolled, and complete information was available for 126. Cervical fluid IL-6 concentrations were not elevated in women destined to have a spontaneous PTD ( P = .86). IL-6 -174 genotype was not associated with PTD ( P = .62) or cervical fluid IL-6 concentration ( P = .36). Neonatal IL-6-174 genotype was not associated with PTD or IL-6 concentration. CONCLUSION: Cervical fluid concentrations of IL-6 were not elevated in symptomatic women destined to have a spontaneous PTD. The presence of maternal IL-6 -174C was not associated with cervical fluid concentration of IL-6 or risk of PTD.

Adult↗
PubMed2004

Evaluation of a new efficient procedure for single-nucleotide polymorphism genotyping: tetra-primer amplification refractory mutation system-polymerase chain reaction.

Tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) is a new efficient method for single-nucleotide polymorphism (SNP) genotyping. To determine the optimal conditions for ARMS-PCR we attempted to genotype ten SNPs. DNA was extracted from the peripheral blood of 168 unrelated healthy Japanese volunteers. Two problems inhibited uniform efficiency of the amplification of three bands. The first problem was the lower amplification efficiency of the shorter and allele-specific products compared with the largest product. This phenomenon was overcome by increasing the relative concentration of the inner primers. The second problem was non-specific amplification of the shorter products. To reduce the amplification of these non-specific bands, adjusting any one of the following PCR conditions was effective: i) reducing the ratio of the inner primer concentration relative to that of the outer primers; ii) increasing the annealing temperature for the initial 5-10 cycles; iii) hot start PCR. With these procedures all ten of the SNPs were successfully genotyped. Our present data may be useful in the further application of tetra-primer ARMS-PCR to SNP genotyping.

Asian People↗
PubMed2006

Global phylogeny of Mycobacterium tuberculosis based on single nucleotide polymorphism (SNP) analysis: insights into tuberculosis evolution, phylogenetic accuracy of other DNA fingerprinting systems, and recommendations for a minimal standard SNP set.

We analyzed a global collection of Mycobacterium tuberculosis strains using 212 single nucleotide polymorphism (SNP) markers. SNP nucleotide diversity was high (average across all SNPs, 0.19), and 96% of the SNP locus pairs were in complete linkage disequilibrium. Cluster analyses identified six deeply branching, phylogenetically distinct SNP cluster groups (SCGs) and five subgroups. The SCGs were strongly associated with the geographical origin of the M. tuberculosis samples and the birthplace of the human hosts. The most ancestral cluster (SCG-1) predominated in patients from the Indian subcontinent, while SCG-1 and another ancestral cluster (SCG-2) predominated in patients from East Asia, suggesting that M. tuberculosis first arose in the Indian subcontinent and spread worldwide through East Asia. Restricted SCG diversity and the prevalence of less ancestral SCGs in indigenous populations in Uganda and Mexico suggested a more recent introduction of M. tuberculosis into these regions. The East African Indian and Beijing spoligotypes were concordant with SCG-1 and SCG-2, respectively; X and Central Asian spoligotypes were also associated with one SCG or subgroup combination. Other clades had less consistent associations with SCGs. Mycobacterial interspersed repetitive unit (MIRU) analysis provided less robust phylogenetic information, and only 6 of the 12 MIRU microsatellite loci were highly differentiated between SCGs as measured by GST. Finally, an algorithm was devised to identify two minimal sets of either 45 or 6 SNPs that could be used in future investigations to enable global collaborations for studies on evolution, strain differentiation, and biological differences of M. tuberculosis.

Algorithms↗
PubMed2001

Single nucleotide polymorphisms in intron 2 of the human interleukin-1 receptor antagonist (IL-1Ra) gene: further definition of the IL-1 beta and IL-1Ra polymorphisms in North American Caucasians and Taiwanese Chinese.

Previous studies have suggested that a variable number tandem repeat (VNTR) polymorphism in the second intron of the interleukin-1 receptor antagonist (IL-1Ra) gene and the single nucleotide polymorphisms at positions -511 and +3954 of the IL-1beta gene might be associated with increased risks of chronic inflammatory diseases, autoimmune diseases and gastric cancer. In the present study, IL-1beta and IL-1Ra genotypes were analyzed among Asians in Taiwan and Caucasians in North America. We identified a novel polymorphism with 3 nucleotide substitutions in the IL-1Ra VNTR 2-repeat allele. One of the substitutions corresponds with the fourth 3' end nucleotide of the reverse primer that is often used for analysis of the IL-1Ra-associated VNTR locus. Mismatching between this primer and the 2-repeat allele can cause misleading amplification results when stringent conditions are used for annealing. The estimated haplotype frequencies of the variant IL-1 genes were significantly different between Taiwanese and Caucasians. The frequency of the pro-inflammatory IL-1Ra 2-repeat allele was significantly lower in Taiwanese than in Caucasians. In contrast, the frequencies of the pro-inflammatory IL-1beta -511T allele and +3954C allele were significantly higher among Taiwanese compared with Caucasians.

Asian People↗
PubMed2005

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance.

Hepatitis C virus (HCV) is an infectious blood-borne pathogen that usually persists as a chronic infection. However, approximately 15% of the time, patients can clear the virus, indicating that host differences could be critical in determining the course of HCV infection. The inflammatory response is crucial to resolving or failing to resolve an acute HCV infection. Some previous reports have implicated interleukin 10 (IL10) polymorphisms with successful anti-HCV therapy and natural viral clearance. We tested 54 single nucleotide polymorphisms (SNPs) in the IL10 region (+/-300 kb and 24 within the IL10 gene itself), which contains 13 genes including the IL10 immunomodulatory paralogs IL19, IL20, and IL24, for association with HCV clearance vs persistence. SNPs from two haplotype block regions, one at IL10 and the other from IL19/IL20, were associated with HCV clearance in African Americans (91 clearance cases and 183 chronically infected matched controls; P=0.05-0.002) while with expectation-maximization algorithm-reconstructed haplotypes, these associations remained (P=0.05-0.002). However, no significant associations were detected in European Americans (108 clearance and 245 chronic). Our results indicate that variants of the immunomodulatory IL10 and IL19/IL20 genes may be involved in natural clearance of HCV in the African-American population.

Black or African American↗
PubMed2005

New ovine PrP gene haplotypes as a result of single nucleotide polymorphisms in the PrP gene promoter.

Incidence of scrapie in sheep is strongly associated with PrP gene amino acid codon variants at positions 136, 154 and 171. However, there are breed differences in disease linkage and anomalous disease patterns which cannot obviously be explained by the '3 codon' genotype. Mouse studies indicate that PrP protein levels can influence scrapie disease progression and this prompted us to study the sheep PrP gene promoter region in a search for novel polymorphisms which may influence gene expression and hence disease susceptibility. The incidence of three single nucleotide polymorphisms (SNP) at positions C/A-5354, T/C-5382 and C/G-5622 within the PrP gene promoter region was determined from Neuropathogenesis Unit (NPU) and New Zealand (NZ) Cheviot and UK and NZ Suffolk sheep. The SNP variants A-5354 and G-5622 created consensus sequences for STAT and SP1 transcription factors, respectively, and C-5382 was within Motif 1, one of four conserved motifs found within the promoter region of mammalian PrP genes. The occurrence of C/A-5354 and T/C-5384 SNP exhibited differential associations with the PrP open reading frame (ORF) variants linked to scrapie susceptibility. A significant imbalance in the incidence of the C-5354/AXQ haplotype was found in the NPU Cheviot flock. C-5382 was not found in Suffolk sheep of either UK or NZ origin. The G-5622 SNP was found at a lower incidence in Suffolk sheep compared with Cheviots. The range of transcription factor binding motif profiles in the PrP gene promoter may act to modulate PrP gene activity and warrants further large-scale study.

Animals↗
PubMed2003

A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity.

To test the hypothesis that analyses of drug targets for polymorphism will help to establish gene-based information for the treatment of cancer patients, we investigated the functional single-nucleotide polymorphisms in the human cytidine deaminase (HDCA) gene. The cDNAs from 52 leukaemia/lymphoma samples and 169 control blood samples were direct-sequenced and analysed for the polymorphisms. Three different polymorphisms (A79C, G208A and T435C) were identified in the coding region of the HDCA gene and displayed allelic frequencies of 20.1%, 4.3% and 70.1%, respectively. No association with susceptibility to disease was observed. A novel polymorphism, G208A produced an alanine to threonine substitution (A70T) within the conserved catalytic domain. By introduction of the polymorphic HCDA genes into the yeast CDA-null mutants, the HCDA-70T showed 40% and 32% activity of prototype for cytidine and ara-C substrates, respectively (P < 0.01). The ara-C IC50 value of the yeast transformants carrying HCDA-70T was 757 +/- 33 micromol and was significantly lower (P < 0.01) than that of prototype (941 +/- 58 micromol). This study demonstrated a population characterized with 208A genotype for, which potentially leads one more sensitive to ara-C treatment than prototype. Accumulation of polymorphisms in the genes responsible for drug metabolism and determination of polymorphism-induced biological variations could provide the additional therapeutic strategies in risk-stratified protocols for the treatment of childhood malignancies.

Child, Preschool↗
PubMed2002

Lack of association of a single-nucleotide polymorphism of the mu-opioid receptor gene with anxiety-related traits: results from a cross-sectional study of adults and a longitudinal study of children.

There is evidence from animal experiments that the mu- and delta-opioid receptors may play a role in anxiety and depression. It might therefore be expected that functional polymorphisms of these genes in humans are associated with anxiety and depression. We investigated a single-nucleotide polymorphism (Asn40Asp) of the mu-opioid receptor gene (OPRM1). This association was investigated in two samples: 1) a cross-sectional survey of 867 community-living adults aged 18-79 years who were assessed for anxiety and depression symptoms and related personality traits; and 2) a longitudinal study of childhood temperament in which 660 children were followed from infancy to the mid-teens and assessed for anxiety-related temperament and behavior problems. The data did not support a role for the Asn40Asp polymorphism in anxiety and depression, despite adequate statistical power to detect small effects.

Adolescent↗
PubMed2002

CDS1 and promoter single nucleotide polymorphisms of the CTLA-4 gene in human myasthenia gravis.

The cytotoxic T lymphocyte associated protein 4 (CTLA-4) gene (Ctla-4) is a candidate gene for autoimmune disease. We here report results of two single nucleotide polymorphisms (SNPs) in the Ctla-4, a +49 A/G SNP in CDS1 and a C/T promoter SNP at position -318. There were no differences in these two SNPs between patients and healthy individuals. The frequency of allele G and genotype G/G at position +49 in CDS1 was increased in patients with thymoma when compared with patients with normal and hyperplastic thymic histopathology. Patients with the G/G genotype had signs of immune activation manifested as higher levels of serum IL-1beta and higher percentage of CD28(+) T lymphocytes. There was a strong linkage between the 86bp allele in the 3'-UTR and the A(+49) allele in CDS1. Our results suggest that the SNP at position +49 in CDS1 might be associated with the manifestations of MG.

3' Untranslated Regions↗
PubMed2002

Molecular haplotyping of genomic DNA for multiple single-nucleotide polymorphisms located kilobases apart using long-range polymerase chain reaction and intramolecular ligation.

Genetic polymorphisms are well-recognized causes of interindividual differences in disease risk and treatment response in humans. For genes containing multiple single-nucleotide polymorphisms (SNPs), haplotype structure is often the principal determinant of phenotypic consequences, and haplotype distribution represents the best approach for assessing patterns of linkage disequilibrium. To permit more widespread molecular determination of haplotypes, we developed a simple yet robust method to determine haplotype structure for multiple SNPs located up to 30 kb apart in genomic DNA using long-range polymerase chain reaction (LR-PCR) and intramolecular ligation. Complete concordance was shown between the new method and conventional approaches, such as family pedigree analysis or cloning and sequencing. The availability of a simple method to directly determine haplotype structure using genomic DNA, without family pedigree analysis, cloning or complex instrumentation, provides an important new tool for elucidating the genetic determinants of drug disposition and effects, disease risk, and molecular evolution.

Alleles↗
PubMed2001

Bioinformatic and experimental tools for identification of single-nucleotide polymorphisms in genes with a potential role for the development of the insulin resistance syndrome.

OBJECTIVES: Genes with a possible role for the development of the insulin resistance syndrome (IRS) were scanned for novel single-nucleotide polymorphisms (SNPs) using bioinformatics. METHODS: GenBank mRNA sequences were compared to the human EST database using gapped BLAST, software that is available on the internet. Mismatches between the search and the EST sequences indicated potential SNPs. Thirty-two SNPs in 13 genes were randomly chosen for experimental verification. PCR and direct sequencing were used to determine the 'true' SNPs. A random sample of 30 Swedish men with slightly elevated diastolic blood pressure (85-94 mmHg) obtained from a population-based study was selected for the sequencing. After completion of these stages, the potential SNPs were checked against the large and rapidly expanding SNP databases HGBASE and NCBI. RESULTS: EST searches of 146 genes revealed 106 potential SNPs in 44 genes. Experimental analysis of 32 of these potential SNPs verified two SNPs; endothelin receptor A 1471 G/C (3' UTR) and PAI-1 Trp514Arg from a T/C exchange. These two SNPs were also identified in the NCBI and HGBASE databases together with two polymorphisms that were not experimentally identified in our homogeneous Swedish population. Overall, the HGBASE and NCBI databases contained entries of 22% (23 out of 106) of the SNPs identified through our EST searches. CONCLUSIONS: In the search for genetic variations causing complex diseases like IRS in homogeneous populations (such as the Swedish one used here), important information can be obtained through bioinformatic searches of human genome databases and experimental verification.

Adult↗