Identification of frequent chromosome copy-number polymorphisms by use of high-resolution single-nucleotide-polymorphism arrays.
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Chromosome Aberrations↗
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Investigation of HER-2 codon 655 single nucleotide polymorphism frequency and c-ErbB-2 protein expression alterations in gastric cancer patients.
AIM: To investigate both whether the risk of gastric cancer is associated with the Ile/Val single nucleotide polymorphism (SNP) of human epidermal growth factor receptor-2 (HER-2) transmembrane domain-coding region at codon 655 and the suggested existence of HER-2 expression in gastric cancer cases in a Turkish patient group. METHODS: Polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) strategy was used to analyze the presence of HER-2 SNP at codon 655. c-erbB-2 expression pattern was analyzed by immunohistochemistry. The results were compared between gastric carcinoma group and chronic gastritis group, as well as between clinicopathological parameters and carcinoma. RESULTS: Results showed that Ile/Val genotype accounted for 20% within the Turkish gastric carcinoma group, and none in chronic gastritis group, and this genotyping was associated with stage IV gastric cancers (P=0.04). Positive membranous HER-2 immunoreactivity, on the other hand, accounted for 24% within the Turkish gastric carcinoma group and none from chronic gastritis cases; further, it was correlated with intestinal type carcinomas (P=0.007), and stage III-IV carcinomas (P=0.004). CONCLUSION: These observations imply that the tested HER-2 SNP may participate in the development and progression of gastric cancer. Thus, after confirming these results with large sample groups, HER-2 codon 655 SNP and/or c-erbB-2 overexpression may also be used as a poor prognostic indicator for gastric carcinomas.
Adult↗
Defining haplotype blocks and tag single-nucleotide polymorphisms in the human genome.
Recent studies suggest that the genome is organized into blocks of haplotypes, and efforts to create a genome-wide haplotype map of single-nucleotide polymorphisms (SNPs) are already underway. Haplotype blocks are defined algorithmically and to date several algorithms have been proposed. However, little is known about their relative performance in real data or about the impact of allele frequencies and parameter choices on the detection of haplotype blocks and the markers that tag them. Here we present a formal comparison of two major algorithms, a linkage disequilibrium (LD)-based method and a dynamic programming algorithm (DPA), in three chromosomal regions differing in gene content and recombination rate. The two methods produced strikingly different results. DPA identified fewer and larger haplotype blocks as well as a smaller set of tag SNPs than the LD method. For both methods, the results were strongly dependent on the allele frequency. Decreasing the minor allele frequency led to an up to 3.7-fold increase in the number of haplotype blocks and tag SNPs. Definition of haploytpe blocks and tag SNPs was also sensitive to parameter changes, but the results could not be reconciled simply by parameter adjustment. These results show that two major methods for detecting haplotype blocks and tag SNPs can produce different results in the same data and that these results are sensitive to marker allele frequencies and parameter choices. More information is needed to guide the choice of method, marker allele frequencies, and parameters in the development of a haplotype map.
Algorithms↗
Three novel single nucleotide polymorphisms (SNPs) of the CYP2B6 gene in Japanese individuals.
We sequenced all exons and exon-intron junctions of the CYP2B6 gene from 200 Japanese individuals. We found three novel single nucleotide polymorphisms (SNPs) (1375A>G, 1427G>A and 1454A>T) causing amino acid substitutions (Met(459)Val, Gly(476)Asp and Gln(485)Leu in exon 9), respectively. The detected SNP was as follows: 1) SNP, 031226Hiratsuka01; GENE NAME, CYP2B6; ACCESSION NUMBER, AC023172; LENGTH, 25 base; 5'-CAGAACTTCTCCA/GTGGCCAGCCCCG-3'. 2) SNP, 031226Hiratsuka02; GENE NAME, CYP2B6; ACCESSION NUMBER, AC023172; LENGTH, 25 base; 5'-CCCAGGAGTGTGG/ATGTGGGCAAAAT-3'. 3) SNP, 031226Hiratsuka03; GENE NAME, CYP2B6; ACCESSION NUMBER, AC023172; LENGTH, 25 base; 5'-CCCCAACATACCA/TGATCCGCTTCCT-3'.
Amino Acid Substitution↗
How valid is single nucleotide polymorphism (SNP) diagnosis for the individual risk assessment of breast cancer?
The number of reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency single nucleotide polymorphisms (SNPs) has increased in recent years. Evidence is accumulating defining specific individual variations in breast cancer susceptibility. Genetic variations of estradiol and xenobiotics metabolisms as well as genes involved in cell-cycle control have been described as significant contributors to breast cancer susceptibility, with variations depending on ethnic background and co-factors such as smoking and family history of breast cancer. In sum, the highest level of evidence to date linking SNPs and breast cancer comes from nested case-control studies within the prospective Nurses' Health Study. These data establish seven SNPs - hPRB +331G/A, AR CAG repeat, CYP19 (TTTA)10, CYP1A1 MspI, VDR FOK1, XRCC1 Arg194Trp and XRCC2 Arg188His - as small but significant risk factors for spontaneous, non-hereditary breast cancer. In addition, meta-analysis of data in the literature establishes the TGFBR1*6A, HRAS1, GSTP Ile105Val and GSTM1 SNPs as low-penetrance genetic risk factors of sporadic breast cancer. The clinical consequences of such a risk elevation may be detailed instruction of the patient as to general measures of breast cancer prevention such as a low-fat diet, optimization of body mass index, physical exercise, avoidance of alcohol and long-term hormone replacement therapy, and participation in a breast cancer screening program between the ages of 50 and 70 years. Specific surgical or drug interventions such as prophylactic mastectomy and oophorectomy or prophylactic intake of tamoxifen are not indicated based on SNP analysis at this time.
Breast Neoplasms↗
High-throughput genotyping of single nucleotide polymorphisms using new biplex invader technology.
The feasibility of large-scale genome-wide association studies of complex human disorders depends on the availability of accurate and efficient genotyping methods for single nucleotide polymorphisms (SNPs). We describe a new platform of the invader assay, a biplex assay, where both alleles are interrogated in a single reaction tube. The assay was evaluated on over 50 different SNPs, with over 20 SNPs genotyped in study cohorts of over 1500 individuals. We assessed the usefulness of the new platform in high-throughput genotyping and compared its accuracy to genotyping results obtained by the traditional monoplex invader assay, TaqMan genotyping and sequencing data. We present representative data for two SNPs in different genes (CD36 and protein tyrosine phosphatase 1beta) from a study cohort comprising over 1500 individuals with high or low-normal blood pressure. In this high-throughput application, the biplex invader assay is very accurate, with an error rate of <0.3% and a failure rate of 1.64%. The set-up of the assay is highly automated, facilitating the processing of large numbers of samples simultaneously. We present new analysis tools for the assignment of genotypes that further improve genotyping success. The biplex invader assay with its automated set-up and analysis offers a new efficient high-throughput genotyping platform that is suitable for association studies in large study cohorts.
Biotechnology↗
The A118G single nucleotide polymorphism of the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans.
Responses to painful stimuli are characterized by tremendous interindividual variability, and genetic factors likely account for some proportion of this variability. However, few studies have identified genetic contributions to experimental pain perception in humans. This experiment investigated whether the A118G single nucleotide polymorphism of the mu-opioid receptor gene ( OPRM1 ) was associated with responses to three different experimental pain modalities in a sample of 167 healthy volunteers (96 female, 71 male). Responses to thermal, mechanical, and ischemic pain were assessed in all subjects, and genotyping of OPRM1 was performed, which revealed that the rare A118G allele occurred in 24 females (25%) and 12 males (17%). Statistical analyses indicated that subjects with a rare allele had significantly higher pressure pain thresholds than those homozygous for the common allele. Also, a sex by genotype interaction emerged for heat pain ratings at 49 degrees C, such that the rare allele was associated with lower pain ratings among men but higher pain ratings among women. These data indicate an association of a common single nucleotide polymorphism of OPRM1 with mechanical pain responses and that this genotype may be associated with heat pain perception in a sex-dependent manner. This study examines the association of the A118G SNP of OPRM1 to experimental pain sensitivity. The results indicate that the rare allele is associated with higher pressure pain thresholds. These results support previous contentions that OPRM1 may be a pain-relevant gene; however, replication of these findings is needed.
Adult↗
A single nucleotide polymorphism on the promoter of eotaxin1 associates with its mRNA expression and asthma phenotypes.
Eotaxin1 plays a pivotal role in eosinophil-associated inflammation. Previously, we demonstrated 14 single-nucleotide polymorphisms (SNPs) in the human eotaxin1 gene and the association between the EOT+67G>A allele and the level of IgE. In this study, we investigated the association between the SNPs and plasma eotaxin1 levels, peripheral blood eosinophil counts, and PC20 methacholine values in normal and asthmatic subjects, and the effects of SNPs on the process of eotaxin1 production. The EOT-576C>T and EOT-384A>G polymorphisms and haplotypes (ht1 and ht4) were significantly associated with plasma eotaxin1 levels in the asthmatics (p < 0.001-0.040). The log [plasma eotaxin1] values correlated with the log [serum total IgE] values in the asthmatics and the normal controls (p = 0.012 and p = 0.004, respectively), and with the log [PC20 methacholine] values in the asthmatics (p = 0.014). A DNA-protein complex was formed with EOT-384A>G, but not with the other SNPs of the promoter. The interaction was stronger with the minor allele than with the common allele, and was reduced upon TNF-alpha exposure. TNF-alpha-stimulated PBMCs from the asthmatics with the minor allele homozygote expressed significantly lower levels of eotaxin1 mRNA than those from individuals with the common allele. The EOT+67G>A polymorphism, which substitutes alanine with threonine, did not affect eotaxin1 production or activity. Our data suggest that the EOT-384A>G SNP participates in the regulation of eotaxin1 expression by providing a potential binding site for a repressor, and that the ANOVA of EOT-384A>G may predict asthma phenotypes.
Adult↗
Rapid detection of single nucleotide polymorphisms related with lung cancer susceptibility of Chinese population.
Genetic variations have been thought to contribute to individual differences in lung cancer susceptibility. In our study, the possibility of an association of CYP1B1, GSTP1 and hOGG1 genetic polymorphisms with lung cancer was investigated in Chinese population of Nanjing, by a new single nucleotide polymorphism (SNP) typing approach of di-allele-specific-amplification with artificially modified primers (diASA-AMP) technique. A matched case-control study of 227 patients with lung cancer was conducted to detect CYP1B1 Leu432Val, GSTP1 Ile105Val and hOGG1 Ser326Cys polymorphisms. Genotypes were analyzed by diASA-AMP technique. Results did not show a significant difference in distributions of allele frequencies or genotypes of CYP1B1, GSTP1 and hOGG1 between two groups. However, stratifying on smoking status demonstrated that CYP1B1 432Val genotype had a slightly combined effect on lung cancer with smoker subjects (OR=2.78, 95%CI=1.46-5.29). The interaction between GSTP1 105Val mutation and smoking in the development of lung cancer were not detected, nor was hOGG1 326Cys mutation. Variant allele frequencies of CYP1B1, GSTP1 and hOGG1 in control group were similar to other reports of Chinese population. The sequencing results of CYP1B1, GSTP1 and hOGG1 matched the ones of diASA-AMP technique. CYP1B1 432Val polymorphism may modulate the individual susceptibility of lung cancer among smokers in Chinese population. GSTP1 Ile105Val and hOGG1 Ser326Cys polymorphisms were not found to be risk factors of lung cancer in this study. The method diASA-AMP is rapid, specific and cost-effective. It can be used for rapid detection of the genes related with tumor susceptibility of population.
Adult↗
Analysis of Hemicentin-1, hOgg1, and E-selectin single nucleotide polymorphisms in age-related macular degeneration.
PURPOSE: Age-related macular degeneration (AMD) is a common disease in which both environmental and genetic factors have been implicated. Various single nucleotide polymorphisms (SNPs) have been correlated, through candidate gene association studies, with age-related diseases, including AMD. Recently we identified an association between AMD and two SNPs in CX3CR1, which encodes a chemokine receptor. This study investigates the Hemicentin-1 (an extracellular matrix protein) Q5345R, hOgg1 (DNA repair gene) S326C, and E-selectin (an adhesion molecule) S149R SNPs in association with AMD. METHODS: Genomic DNA was extracted from peripheral blood of 89 patients with advanced AMD, 97 age-matched controls without clinical AMD, and 170 random unscreened healthy volunteers. DNA was subjected to polymerase chain reaction amplification coupled with the restriction fragment length polymorphism assay. RESULTS: The distribution of the Hemicentin-1 Q5345R, hOgg1 S326C, and E-selectin S149R SNPs did not differ significantly (all P values > .05) between the AMD patients and controls. Hemincentin-1 5345R was not found in any subject. hOgg1 326C allele frequency was 21.35% (38 of 178) in the AMD group compared with 19.12% (65 of 340) in the random controls and 19.59% (38 of 194) in the age-matched controls. E-selectin 149R allele frequencies were 8.99% (16 of 178) in AMD cases, 9.41% (32 of 340) in random controls, and 10.82% (21 of 194) in age-matched controls. CONCLUSIONS: We were not able to demonstrate an association between the Hemicentin-1, hOgg1, and E-selectin SNPs and AMD development in the currently available cases and controls. Further candidate genes, particularly those involved in extracellular matrix, oxidative stress, and immune system functions, are currently being screened in our laboratory.
Adult↗
Host TNF-alpha-1031 and -863 promoter single nucleotide polymorphisms determine the risk of benign ulceration after H. pylori infection.
OBJECTIVES: This study tested whether host genotypes of the tumor necrosis factor-alpha (TNF-alpha) promoter single nucleotide polymorphism (SNP) could determine clinical and histological outcomes after Helicobacter pylori infection. METHODS: A total of 524 dyspeptic patients, 424 with and 100 without H. pylori infection, were checked for TNF-alpha promoter SNP over the locus on -1031(T/C), -863(C/A), -857(C/T), -806(C/T), and -308(G/A) by sequence-specific oligonucleotide probe. Each patient received panendoscopy to take gastric biopsy to detect H. pylori infection and its related histology using the updated Sydney's system. Gastric TNF-alpha expressions were stained by immunohistochemistry. RESULTS: In H. pylori-infected patients, -1031C or -863A carriers of TNF-alpha promoter had more severe gastric neutrophil infiltration and TNF-alpha gastric staining than individuals with -1031TT or -863CC genotype, respectively (p<0.05). The multivariate logistic regression verified both -1031C and -863A carriers were independent risk factors to have duodenal ulcers and gastric ulcer without IM in the H. pylori-infected hosts (p<0.05). As compared to -863CC and -1031TT genotype combinations, the ulcer risk after H. pylori infection was 2.46 (95% CI: 1.32-4.59, p<or=0.00001) for the carriers with either -1031C or -863A allele, and even elevated to 6.06 (95% CI: 3.57-10.21, p<or=0.00001) for the individuals harboring both -863A and -1031C alleles. For patients with gastric ulcer, the 863CC genotype had a higher rate to have intestinal metaplasia than -863A carrier (p<or=0.005). CONCLUSIONS: TNF-alpha-1031 and -863 promoter SNP should be novel host factors to determine the gastric inflammation and risk of peptic ulceration upon H. pylori infection.
Biopsy↗
Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma.
Asthma is the most common chronic childhood disease in the developed nations, and is a complex disease that has high social and economic costs. Studies of the genetic etiology of asthma offer a way of improving our understanding of its pathogenesis, with the goal of improving preventive strategies, diagnostic tools, and therapies. Considerable effort and expense have been expended in attempts to detect specific polymorphisms in genetic loci contributing to asthma susceptibility. Concomitantly, the technology for detecting single nucleotide polymorphisms (SNPs) has undergone rapid development, extensive catalogues of SNPs across the genome have been constructed, and SNPs have been increasingly used as a method of investigating the genetic etiology of complex human diseases. This paper reviews both current and potential future contributions of SNPs to our understanding of asthma pathophysiology.
Animals↗
Genomic diversity in Mycobacterium avium: single nucleotide polymorphisms between the S and C strains of M. avium subsp. paratuberculosis and with M. a. avium.
Following identification of large genomic polymorphisms in a previous study, a polymerase chain reaction and sequencing strategy was used to identify single nucleotide polymorphisms (SNPs) in 25 genes in the sheep (S) and cattle (C) strains of Mycobacterium avium subsp. paratuberculosis (M. a. paratuberculosis) and between M. a. paratuberculosis and M. a. avium. From 12,117 bp of sequence representing 26 loci across 25 genes, 11 SNPs were identified between the S and C strains in eight genes: hsp65, sodA, dnaA, dnaN, recF, gyrB, inhA, and pks8. An in silico comparison of these M. a. paratuberculosis sequences and the M. a. avium 104 genome revealed 86 SNPs, which corresponded well with similar studies of SNPs in the M. avium complex.
Animals↗
[Single nucleotide polymorphisms in NOS3 A-922G, T-786C and G894T: a correlation study of the distribution of their allelic combinations with hypertension in chinese Han population].
To study single nucleotide polymorphisms (SNP) in A-922G, T-786C and G894T of endothelial nitric oxide synthase (NOS3) and to correlate the distribution of their allelic combinations with hypertension in Chinese Han nationality population, genomic DNA was isolated from venous blood leukocytes from 192 unrelated patients with hypertension (95 females and 97 males) and 122 healthy unrelated individuals (46 females and 76 males) as controls. SNPs of NOS3 A-922G, T-786C and G894T were genotyped by allele-specific primer (ASP) PCR. The distribution of genotype combinations of three SNPs was determined by clustering analysis. There were no difference in allele genotype distribution frequency and haplotype frequency of NOS3 G894T, NOS3 A-922G and NOS3 T-786C between the essential hypertension group and the healthy population (P>0.05). According to sex stratification, no association between essential hypertension and SNP of NOS3 A-922G,NOS3 T-786C or NOS3 G894T has been found in either the male subgroup or the female subgroup. In respect of allele genotype combination frequency in the natural distribution of NOS3 A-922 G, NOS3 T-786C and NOS3 G894T SNP, there was significant difference only in the allele genotype combination frequency of NOS3 G894G+A-922G+T-786T between the hypertension group and the healthy group (P<0.05, Chi2=4.5944). According to sex stratification, there were no significant difference in all above allele genotype combination frequency in three sites of NOS3 SNP between the hypertension male subgroup and the healthy male subgroup (P>0.05). There was significant difference in the allele combination frequency of NOS3 G894G +A-922G+T-786C between the hypertension female subgroup and the healthy female subgroup(P<001, Chi2=8.502). There was no association of SNP in NOS3 A-922G, NOS3 T-786C or NOS3 G894T with hypertension in the Chinese Han nationality population, nor was there a sex difference. The combination frequency of allele NOS3 G894G + A-922G + T-786C in the hypertension female subgroup was much lower than that in the healthy female subgroup, suggesting that female population with this combination genotype may be less susceptible to hypertension.
Adult↗
Identification of coding single-nucleotide polymorphisms in human taste receptor genes involving bitter tasting.
T2Rs comprise a G-protein-coupled receptor superfamily that contains functionally defined bitter taste receptors. Here we report the tissue expressions and coding single-nucleotide polymorphisms (cSNPs) in human T2R genes (hT2R3, hT2R4, and hT2R5) on chromosome 7q31. We first demonstrated that hT2R3, hT2R4, and hT2R5 are actually expressed in the circumvallate papillae of the human tongue by reverse transcription-polymerase chain reaction (RT-PCR). We identified six cSNPs within the T2R receptor genes. The hT2R4 and hT2R5 contained four and one cSNPs that cause missense mutations, respectively, while hT2R3 included one silent nucleotide mutation. However, we could not find any nonsense mutations that resulted in a frameshift or a premature stop codon within the open reading frames. Genotype frequencies of each cSNP were in Hardy-Weinberg equilibrium. The identification of nucleotide diversity and amino acid polymorphisms in human T2R receptors could help clarify individual differences in the acceptability and sensitivity to bitter compounds.
Base Sequence↗
Whole-genome association analysis to identify markers associated with recombination rates using single-nucleotide polymorphisms and microsatellites.
Recombination during meiosis is one of the most important biological processes, and the level of recombination rates for a given individual is under genetic control. In this study, we conducted genome-wide association studies to identify chromosomal regions associated with recombination rates. We analyzed genotype data collected on the pedigrees in the Collaborative Study on the Genetics on Alcoholism data provided by Genetic Analysis Workshop 14. A total of 315 microsatellites and 10,081 single-nucleotide polymorphisms from Affymetrix on 22 autosomal chromosomes were used in our association analysis. Genome-wide gender-specific recombination counts for family founders were inferred first and association analysis was performed using multiple linear regressions. We used the positive false discovery rate (pFDR) to account for multiple comparisons in the two genome-wide scans. Eight regions showed some evidence of association with recombination counts based on the single-nucleotide polymorphism analysis after adjusting for multiple comparisons. However, no region was found to be significant using microsatellites.
Female↗
Three TNFalpha single nucleotide polymorphisms in the Japanese population.
BACKGROUND: Tumour necrosis factor-alpha (TNFalpha) is an essential regulator of immune responses and is implicated to relate to several types of disease susceptibilities. Population information on polymorphisms is essential for the study of genetic diseases. AIM: To obtain accurate information about single nucleotide polymorphisms (SNPs) in the TNFalpha gene in the Japanese population. SUBJECTS AND METHODS: The entire TNFalpha gene was screened for SNPs by directly sequencing 48 chromosomes derived from 24 unrelated Japanese individuals. Allele frequencies of each polymorphism were determined and compared with those previously reported in other populations. RESULTS: Three SNPs, -308G/A at nt -308, IVS1 + 125G/A at nt 492 and IVS3 + 104G/A at nt 1359 were observed, of which one (IVS3 + 104G/A at nt 1359) was novel. In addition, allele frequencies of -308G/A were remarkably different from those presented in the NCBI dbSNP, indicating a significant ethnic difference. CONCLUSIONS: The polymorphisms and allele frequencies obtained in this study will be useful for genetic studies of common diseases such as osteoporosis and rheumatoid arthritis in the Japanese population.
Alleles↗
Quantitative approach to single-nucleotide polymorphism analysis using MALDI-TOF mass spectrometry.
Pooling of DNA samples before genotyping is a valuable means of streamlining large-scale genotyping efforts in disease association studies, single-nucleotide polymorphism (SNP) validation or mutant allele screening programs. In this report, we explore the application of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to quantitative analysis of SNPs. The measurements are based on MALDI-TOF MS analysis of primer extension assays performed on standard mixtures of pooled PCR products at several test loci. The inherent high molecular weight resolution of MALDI-TOF MS conveys high specificity and good signal-to-noise ratio for performing accurate quantitation. The methods described maximize the sensitivity and quantitative capacity of MALDI-TOF MS while preserving the throughput and economic advantages of the MALDI-TOF platform. Using the format described, we demonstrate that allele frequencies as low as 5% can be detected quantitatively and unambiguously.
Alleles↗