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PubMed2003

Single-nucleotide polymorphism analysis using fluorescence resonance energy transfer between DNA-labeling fluorophore, fluorescein isothiocyanate, and DNA intercalator, POPO-3, on bacterial magnetic particles.

To develop an analytical system for single-nucleotide polymorphisms (SNPs), the fluorescence resonance energy transfer (FRET) technique was employed on a bacterial magnetic particle (BMP) surface. A combination of fluorescein isothiocyanate (FITC; excitation 490 nm/emission 520 nm) labeled at the 5' end of DNA and an intercalating compound (POPO-3, excitation 534 nm/emission 570 nm) was used to avoid the interference from light scattering caused by nanoparticles. After hybridization between target DNA immobilized onto BMPs and FITC-labeled probes, fluorescence from POPO-3, which was excited by the energy from the FITC, was detected. The major homozygous (ALDH2*1), heterozygous (ALDH2*1/*2), and minor homozygous (ALDH2*2) genotypes in the blood samples were discriminated by this method. The assay described herein allows for a simple and rapid SNP analysis using a fully automated system.

Bacterial Proteins↗
PubMed2002

Single nucleotide polymorphism detection: allelic discrimination using TaqMan.

Candidate gene studies are one of the most widely used approaches in the dissection of the genetic basis of disease. High-throughput methods for genotyping single nucleotide polymorphisms (SNPs) are necessary to perform large-scale association studies. We describe the use of the TaqMan or 5' nuclease allelic discrimination assay for genotyping polymorphisms of the collagen I alpha 1 (COLIA1) and vitamin D receptor (VDR) genes. The basis for the assay is an allele specific oligonucleotide probe, labelled with a fluorescent reporter dye and a quencher dye, which is cleaved during the amplification process generating an increase in the intensity of fluorescence related to the accumulation of PCR product which is measured directly in the reaction well. Suitable for the discrimination of alleles differing by a single base change, this technique is robust, accurate, cost effective, and sufficiently high-throughput for a medium sized laboratory performing association analyses.

Alleles↗
PubMed2002

MitoAnalyzer, a computer program and interactive web site to determine the effects of single nucleotide polymorphisms and mutations in human mitochondrial DNA.

MitoAnalyzer provides information about the effects of single nucleotide polymorphisms (SNPs) and mutations in human mitochondrial DNA (mtDNA). This program determines if a single base pair (bp) change is in the non-coding or coding region, in the first, second or third bp of the codon, in a rRNA, tRNA or a protein, causes an amino acid (aa) change, the nature of that change, the position of the aa change in the protein, and the new aa sequence of the changed protein. Mutations associated with published mitochondrial diseases are noted. This program, thus, facilitates rapid analysis and evaluation of SNPs and mutations in human mtDNA.

Journal Article↗
PubMed2003

Sequence context at human single nucleotide polymorphisms: overrepresentation of CpG dinucleotide at polymorphic sites and suppression of variation in CpG islands.

Human polymorphisms originate as mutations, and the influence of context on mutagenesis should be reflected in the distribution of sequences surrounding single nucleotide polymorphisms (SNPs). We have performed a computational survey of nearly two million human SNPs to determine if sequence-dependent hotspots for polymorphism exist in the human genome. Here we show that sequences containing CpG dinucleotides, which occur at low frequencies in the human genome, are 6.7-fold more abundant at polymorphic sites than expected. In contrast, polymorphisms in CpG sequences located within CpG islands, important regulatory regions that modulate gene expression, are 6.8-fold less prevalent than expected. The distribution of polymorphic alleles at CpGs in CpG islands is also significantly different from that in non-island regions. These data strongly support a role for 5-methylcytosine deamination in the generation of human variation, and suggest that variation at CpGs in islands is suppressed.

5-Methylcytosine↗
PubMed2006

Single nucleotide polymorphism C677T in the methylenetetrahydrofolate reductase gene might be a genetic risk factor for infertility for Chinese men with azoospermia or severe oligozoospermia.

AIM: To analyze the distribution of the single nucleotide polymorphism (SNP) C677T in the methylenetetrahydrofolate reductase (MTHFR) gene in 355 infertile Chinese patients with idiopathic azoospermia or severe oligozoospermia and 252 fertile Chinese men as controls to explore the possible association of the SNP and male infertility. METHODS: Using the polymerase chain reaction (PCR)-restriction fragment length polymorphism technique, the allele and genotype distribution of SNP C677T in the MTHFR gene were investigated in both patients and controls. RESULTS: The frequencies of allele T (40.9% vs 30.4%, P = 0.002, odds ration [OR] = 1.58, 95% confidence interval [CI]: 1.24-2.02) and mutant homozygote (TT) (18.3% vs. 11.5%, P=0.023, OR=1.72, 95% CI: 1.07-2.76) as well as carrier with allele (TT + CT) (63.4% vs. 49.2%, P = 0.0005, OR = 1.79, 95% CI: 1.29-2.48) in infertile patients were significantly higher than those in controls. After patient stratification, the significant differences in distribution of the SNP between each patient subgroup and control group still remained. CONCLUSION: Our findings indicate that there is an association of SNP C677T in the MTHFR gene with male infertility, suggesting that this polymorphism might be a genetic risk factor for male infertility in Chinese men.

Adult↗
PubMed2004

Single nucleotide polymorphisms in the promoter region of the interleukin-6 gene and the risk of recurrent pregnancy loss in Japanese women.

OBJECTIVE: To investigate the relationships between recurrent pregnancy loss and single nucleotide polymorphisms (-634C-->G and -174G-->C genotypes) in the promoter region of the interleukin (IL)-6 gene in the Japanese population. DESIGN: A case-control study. SETTING: Obstetrics and gynecology department of a university hospital. PATIENT(S): Cases were 76 women with recurrent pregnancy loss; controls were 93 fertile women. INTERVENTION(S): Determination of IL-6 promoter gene polymorphisms performed by polymerase chain reaction and gel electrophoresis. MAIN OUTCOME MEASURE(S): Frequency and distribution of the promoter region of the IL-6 gene allele. RESULTS: There was a significant difference in the -634C-->G genotype frequency (CC vs. CG/GG) between women with recurrent pregnancy loss and controls. The risk of recurrent pregnancy loss was lower in the carriers of the G allele than in women with the wild type (CC) (odds ratio = 0.46; 95% confidence interval = 0.24-0.91). On the other hand, we did not detect any carrier of -174C among the 169 subjects. CONCLUSION(S): The results suggest that, in the Japanese population, women carrying the -634G allele of the IL-6 gene might have a decreased risk of recurrent pregnancy loss.

Abortion, Habitual↗
PubMed2001

Using single nucleotide polymorphisms to investigate association between a candidate gene and disease.

A range of study designs, using unrelated or family controls, were used to investigate the pattern of association with disease of single nucleotide polymorphisms (SNPs) within candidate gene 1 (simulated data). Strong evidence of disease association at the functional locus was detected using all study designs, and in the "general" but not the "isolated" population the functional polymorphism displayed considerably higher association than surrounding SNPs. There was much variation in the strength of association of SNPs with disease, up to 70% of which was explained by SNP allele frequency and distance from the functional polymorphism. Some common polymorphisms very close to the functional locus however showed no association with disease. Analysis of short haplotypes of SNPs reduced but did not totally remove this feature.

Adult↗
PubMed2006

Single nucleotide polymorphism (SNP) discovery in duplicated genomes: intron-primed exon-crossing (IPEC) as a strategy for avoiding amplification of duplicated loci in Atlantic salmon (Salmo salar) and other salmonid fishes.

BACKGROUND: Single nucleotide polymorphisms (SNPs) represent the most abundant type of DNA variation in the vertebrate genome, and their applications as genetic markers in numerous studies of molecular ecology and conservation of natural populations are emerging. Recent large-scale sequencing projects in several fish species have provided a vast amount of data in public databases, which can be utilized in novel SNP discovery in salmonids. However, the suggested duplicated nature of the salmonid genome may hamper SNP characterization if the primers designed in conserved gene regions amplify multiple loci. RESULTS: Here we introduce a new intron-primed exon-crossing (IPEC) method in an attempt to overcome this duplication problem, and also evaluate different priming methods for SNP discovery in Atlantic salmon (Salmo salar) and other salmonids. A total of 69 loci with differing priming strategies were screened in S. salar, and 27 of these produced approximately 13 kb of high-quality sequence data consisting of 19 SNPs or indels (one per 680 bp). The SNP frequency and the overall nucleotide diversity (3.99 x 10-4) in S. salar was lower than reported in a majority of other organisms, which may suggest a relative young population history for Atlantic salmon. A subset of primers used in cross-species analyses revealed considerable variation in the SNP frequencies and nucleotide diversities in other salmonids. CONCLUSION: Sequencing success was significantly higher with the new IPEC primers; thus the total number of loci to screen in order to identify one potential polymorphic site was six times less with this new strategy. Given that duplication may hamper SNP discovery in some species, the IPEC method reported here is an alternative way of identifying novel polymorphisms in such cases.

Animals↗
PubMed2000

Single nucleotide polymorphism and linkage disequilibrium within the TCR alpha/delta locus.

Much attention is being given to the identification of common disease genes through whole-genome linkage disequilibrium (LD) screens with single nucleotide polymorphisms (SNPs). Simulation studies have suggested that useful LD is unlikely to extend beyond 3 kb, and that > 500,000 SNPs may be needed for comprehensive coverage of the genome. The TCR alpha/delta locus on chromosome 14q contains many V, J and D segments that combine with constant domains to produce either an alpha or a delta chain of the T cell receptor. Multiple SNPs have been recognized within the V segments, and it has been suggested that variation within the locus may modify the course of autoimmune and allergic diseases. We have examined LD within an 850 kb section of the TCR alpha/delta locus on chromosome 14q by typing 24 V gene segment SNPs and two microsatellites. One hundred and fifty-nine nuclear and extended families were genotyped in order to derive haplotypes, and the pair-wise LD between SNPs was investigated in 600 haplotypes from unrelated individuals (the parents). The mean extent of useful LD was much greater than suggested by simulations: significant LD was relatively common at 250 kb and was detectable beyond 500 kb. The mean extent of LD was twice as far between alleles of low frequency than between common alleles. The distribution of LD was highly irregular and concentrated in three distinct islands. The results differ from those obtained by simulation, and if they are typical of other genomic regions, suggest that the minimum number of markers necessary for comprehensive LD mapping may be reduced by at least an order of magnitude.

Alleles↗
PubMed2004

DNA microarray-based analysis of single nucleotide polymorphisms may be useful for assessing the risks and benefits of hormone therapy.

OBJECTIVE: To determine what percentage of women can be given individualized counseling based on genetic information, as single nucleotide polymorphisms (SNPs) are associated with risks and benefits of estrogen therapy and hormone therapy such as thrombosis, myocardial infarction, breast cancer, and bone protection. DESIGN: Cross-sectional study. SETTING: Academic research institution. PATIENT(S): A consecutive series of 2,507 perimenopausal and postmenopausal women. INTERVENTION(S): Peripheral venous puncture and multiplex polymerase chain reaction on a microarray system. MAIN OUTCOME MEASURE(S): Analysis of 22 SNPs of 17 genes: AGTMet235Thr, APOECys112Arg, APOEArg158Cys, COMTVal158Met, CYP17-34T>C, CYP191558C>T, CYP19Arg264Cys, CYP1A16235T>C, CYP1A1Ile462Val, CYP1B1Leu432Val, CYP1B1Asn453Ser, HSD17B1-27A>C, ER-alphaIVS-401T>C, prothrombin20210G>A, factor V Leiden, eNOS-786T>C, eNOSGlu298Asp, MRSer810Leu, MTHFR677C>T, PAI 15G>4G, SRD5A2Val89Leu, and VDRb>B. RESULT(S): Among the women in the study, 66% had at least two homozygous mutant SNPs of interest. A thrombophilic disposition was found in 9.9% of women, and 23% of women had at least two SNPs associated with an increased risk of breast cancer (COMT, CYP17, CYP19, CYP1A1, and CYP1B1). The SNPs predisposing women to cardiovascular pathologies (e.g., APOE, AGT, eNOS, and PAI 1) were found in 12.3% of women. Carriage of SNPs predisposing to early postmenopausal bone loss and osteoporosis (ER-alpha and VDR) were found in 26.7% of women. CONCLUSION(S): These data suggest that the assessment of SNPs associated with risks and benefits of estrogen/hormone therapy may be a new means to individualize counseling about and prescription of estrogen/hormone therapy in up to 66% of women.

Breast Neoplasms↗
PubMed2001

Genotyping single nucleotide polymorphisms using intact polymerase chain reaction products by electrospray quadrupole mass spectrometry.

Both single nucleotide polymorphisms (SNPs) and mutations are commonly observed in the gene encoding the tumor suppressor protein, p53. SNPs occur at specific locations within genes whereas mutations may be distributed across large regions of genes. When determining nucleotide differences, mass spectrometry is the only method other than Sanger sequencing which offers direct structural information. Electrospray ionization (ESI) quadrupole mass spectrometry (MS) analysis of intact polymerase chain reaction (PCR) products was performed following a simple purification and on-line heating to limit ion adduction. The PCR products were amplified directly from genomic DNA rather than plasmids, as in our previous work. Two known polymorphisms of the p53 gene were genotyped. A cytosine (C) or guanine (G) transversion, designated C <--> G (G <--> C on the opposite strand), were each detected by a 40.0 Da change upon ESI quadrupole MS analysis. Using known PCR products as standards, the genotypes determined for 10 human samples corresponded with restriction fragment length polymorphism (RFLP) analysis. Cytosine/thymine (T) transitions, designated C <--> T (G <--> A on the opposite strand), were also genotyped by ESI-MS. This SNP is discriminated by a 15.0 Da change on one strand (C <--> T) and a 16.0 Da change on the other (G <--> A). Appropriate sample preparation and instrumental configuration (including heated sample inlet syringe and MS source), to limit adducts, are both vital for successful ESI quadrupole MS analysis of intact PCR products.

DNA↗
PubMed2000

Genetic identification by mass spectrometric analysis of single-nucleotide polymorphisms: ternary encoding of genotypes.

An approach to genetic identification using biallelic single-nucleotide polymorphism (SNP) genetic markers is described in which the three possible genotypes, AA, Aa, or aa, where "A" and "a" represent the two SNP alleles, are assigned a ternary (base 3) digit of 0, 1, or 2, respectively. Genotyping an individual over a panel of separate SNP markers produces a composite ternary genetic code that can be converted to an easily stored, decimal (base 10) genetic identification number. The unambiguous identification of 11 individuals is demonstrated using ternary genetic codes generated from MALDI-TOF mass spectrometric genotyping data from 7 different SNP markers.

Alleles↗
PubMed2003

Twelve novel single nucleotide polymorphisms in the CES2 gene encoding human carboxylesterase 2 (hCE-2).

Twelve novel single nucleotide polymorphisms (SNPs) were found in the CES2 gene from 153 Japanese individuals, who were administered irinotecan or steroidal drugs. The detected SNPs were as follows:1) SNP, MPJ6_CS2001; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-CTGGAACAACTCG/CCTCCCCTCGGAA-3'. 2) SNP, MPJ6_CS2002; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-AACCACCACCGCT/CGATCCTAGCAGG-3'. 3) SNP, MPJ6_CS2003; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-AAATGTTTGTCAA/GGTGGATAAATGA-3'. 4) SNP, MPJ6_CS2004; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-CCTCCTATCGATC/GCCCCAGCGCGCT-3'. 5) SNP, MPJ6_CS2005; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-GCCAGTCCCATCC/TGGACCACACACA-3'. 6) SNP, MPJ6_CS2006; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-GCTGGGCAACCCG/AGGCTGAGCGGGG-3'. 7) SNP, MPJ6_CS2007; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-CAAGCACGCAACC/TGGCAACTGGGGC-3'. 8) SNP, MPJ6_CS2008; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-CATGGAGAGTGGC/TGTGGCCCTCCTG-3'. 9) SNP, MPJ6_CS2009; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-CCTGTTCTTGGCC/TAGGGCCTTGGGC-3'. 10) SNP, MPJ6_CS2010; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-CCCATCCCCAGCT/AACAGACTCTCTC-3'. 11) SNP, MPJ6_CS2011; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-TCCACCTGGGGTA/GGATGTTGCCTCC-3'. 12) SNP, MPJ6_CS2013; GENE NAME, CES2; ACCESSION NUMBER, NT_010498.13; LENGTH, 25 bases; 5'-GGACTGGGGACCG/AAGGTCTCGGGGG-3'The frequencies were 0.029 for MPJ6_CS2004 and CS2013, 0.026 for MPJ6_CS2009, 0.013 for MPJ6_CS2001, 0.007 for MPJ6_CS2003, and 0.003 for the other 7 SNPs. Among these SNPs, MPJ6_CS2005 (100C>T) resulted in an amino acid alteration (R34W), and MPJ6_CS2007 (579C>T) and MPJ6_CS2008 (765C>T) were synonymous (T193T and G255G, respectively). Furthermore, MPJ6_CS2011 (IVS8-2A>G) resulted in variation at ther 3' splice acceptor site.

Journal Article↗
PubMed2004

Association of single nucleotide polymorphisms in the eosinophil peroxidase gene with Japanese cedar pollinosis.

BACKGROUND: Japanese cedar pollinosis is the most common form of hay fever in spring in Japan. We have previously demonstrated that single nucleotide polymorphism Pro358Leu of exon 7 in the eosinophil peroxidase (EPO) gene is associated with cedar pollinosis, although the association has not been confirmed by analysis of the whole gene in a different population. METHODS: We sequenced all exons of the EPO gene in 60 children with pollinosis and their parents using the PCR-restriction fragment length polymorphism method. RESULTS: We found 8 polymorphisms, Ile40Met, Gln122His, Arg202Arg (A660G), Asn303Asn (C909T), Arg326Pro, Arg326His, Pro358Leu, and Asn572Ty, in the EPO gene. As a result of the transmission disequilibrium test, we recognized significant transmissions of 202Arg (660G) in exon 6 in addition to 358Leu of exon 7 in the EPO gene of affected children. CONCLUSIONS: Our results might indicate that polymorphisms of the EPO gene are associated with Japanese cedar pollinosis.

Adolescent↗
PubMed2006

The interleukin-1 beta +3953 single nucleotide polymorphism: cervical protein concentration and preterm delivery risk.

PROBLEM: To determine the associations between preterm delivery <37 weeks (PTD), cervical fluid interleukin-1beta (IL-1beta) concentration, and its +3953 single nucleotide polymorphism (SNP). METHOD OF STUDY: Cervical fluid, peripheral blood, and cord blood samples were obtained from a cohort of women 23-32 weeks gestation with preterm labor symptoms and intact membranes. RESULTS: Increased cervical fluid concentrations of IL-1beta were associated with PTD (P = 0.017) and spontaneous PTD (P = 0.001). Maternal IL-1beta +3953 SNP genotype was associated neither with PTD (P = 0.43) nor with cervical fluid IL-1beta concentrations (P = 0.35). Neonatal IL-1beta +3953 SNP genotype was associated neither with PTD nor cervical IL-1beta concentrations. CONCLUSIONS: Cervical fluid concentrations of IL-1beta were elevated in symptomatic women destined to have a spontaneous PTD. The gene dosage of maternal IL-1beta +3953 allele 2 was associated neither with increased cervical fluid concentrations of IL-1beta nor with risk of PTD.

Adult↗
PubMed2003

Association analysis of bone mineral density and single nucleotide polymorphisms in two candidate genes on chromosome 1p36.

Two candidate genes for bone mineral density (BMD), tumor necrosis factor alpha receptor 2 (TNFRSF1B) and lysyl hydroxylase (PLOD1), have been scanned for single nucleotide polymorphisms (SNPs) within their coding and promoter regions. These two genes, separated by about 200 kb, are located within the chromosomal interval 1p36.2-1p36.3 that has been linked to femoral neck BMD. In a patient population (n = 104) of European descent, there were four SNPs within TNFRSF1B and six SNPs within PLOD1 that occurred with greater than 5% frequency. There was significant linkage disequilibrium within both genes. Single marker analysis revealed significant association for one SNP located in intron 6 of PLOD1 and lumbar spine BMD (P = 0.01). Allelic haplotypes that encompassed the four SNPs in TNFRSF1B or the six SNPs in PLOD1 were assigned using a Bayesian algorithm as implemented in the program Haplotyper. Association of TNFRSF1B haplotypes with femoral neck BMD was statistically significant (P = 0.01). Similarly, PLOD1 haplotypes demonstrated a statistically significant association with spinal BMD (P = 0.04). These findings strengthen the potential importance of chromosome 1p36.2-1p36.3 in contributing to BMD variation, and are consistent with genetic variation in either PLOD1, TNFRSF1B or nearby genes playing a role in the phenotype.

Antigens, CD↗
PubMed2004

Characterization of two SNPs (single nucleotide polymorphisms) in the porcine INSL3 gene and their exclusion as a common genetic basis of hernia inguinalis in pigs.

The INSL3 gene encoding Leydig cell insulin-like hormone is an important candidate gene for congenital disorders of the reproductive tract in pigs. Comparative sequencing using phenotypically hernia inguinalis affected and unaffected animals showed that the porcine gene is remarkably conserved. No polymorphisms were found in the two exons or in the intron. Two single-nucleotide polymorphisms (SNPs) were detected in the promoter region (G-224A and A-164C) of the sequenced pigs and fast screening methods were developed for large scale studies. Some significant breed differences exist for allele frequencies at both SNPs in the INSL3 gene. Screening of the two SNPs in a population of hernia inguinalis affected full and half sib piglets (n = 223) revealed that the SNPs can be excluded as a common genetic basis for this congenital disorder in this pedigree.

Animals↗
PubMed2005

Single nucleotide polymorphisms of the IL18 gene are associated with atopic eczema.

BACKGROUND: Human IL-18 is an inflammatory cytokine that plays a role in atopic diseases, such as atopic eczema (AE), by enhancing IL-4 and IL-13 production and stimulating the synthesis of IgE. OBJECTIVE: To evaluate associations of polymorphisms in the IL18 gene on chromosome 11q22 with AE, we performed genotyping for single nucleotide polymorphisms (SNPs) in the IL18 gene in 225 patients with AE and 175 healthy control volunteers. METHODS: Genotyping was performed by means of restriction fragment length polymorphism analysis. RESULTS: Analyses revealed significant associations of SNPs +113[t/g] and +127[c/t] in exon 1, -137[g/c] in promoter region 1, and -133[c/g] in promoter region 2 with AE. These associations were not directly dependent on a specific subtype of AE or the concomitant manifestation of allergic rhinitis or asthma. On the functional level, the amount of IL-18 in the supernatants of PBMCs of patients with AE stimulated with Staphylococcus aureus enterotoxin B was significantly higher than that in healthy control subjects. In parallel, the amount of active IL-18 in the sera of patients with AE was enhanced at the exacerbation of their disease. CONCLUSION: In conclusion, our data suggest that SNPs in the IL18 gene might be involved in the development of AE by contributing to a functional dysregulation of the IL-18 production in vivo .

Adult↗