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PubMed2004

Seven novel single nucleotide polymorphisms in the human SLC22A1 gene encoding organic cation transporter 1 (OCT1).

Twenty genetic variations, including seven novel ones, were found in the human SLC22A1 gene, which encodes organic cation transporter 1, from 116 Japanese individuals. The novel variations were as follows: -94C>A in the 5'-untranslated region (A of the translation start codon is numbered +1 in the cDNA sequence; MPJ6_OC1001), 350C>T (MPJ6_OC1004), IVS1-35T>C (MPJ6_OC1006), 561G>A (MPJ6_OC1010), IVS6+75C>G (MPJ6_OC1014), IVS8+108A>G (MPJ6_OC1017), and 1671_1673delATG (MPJ6_OC1020). The frequencies were 0.082 for IVS1-35T>C, 0.022 for IVS6+75C>G, 0.009 for 561G>A, and 0.004 for the other 4 variations. Among them, 350C>T resulted in the amino acid substitution Pro117Leu, which is located in the large extracellular loop between transmembrane domains 1 and 2. Also, we detected the four previously reported nonsynonymous variations, 123C>G (Phe41Leu), 480C>G (Phe160Leu), 1022C>T (Pro341Leu), and 1222A>G (Met408Val) with frequencies of 0.004, 0.086, 0.168, and 0.810, respectively.

Genetic Variation↗
PubMed2005

Loss of heterozygosity testing using real-time PCR analysis of single nucleotide polymorphisms.

PURPOSE: Colon cancer is a genetic disease, caused by mutations in different oncogenes and tumor-suppressor genes. The aim of this study is to evaluate the usefulness of real-time PCR SNP analysis as a new technique in the loss of heterozygosity (LOH) analysis at the E-cadherin gene locus in sporadic colon cancer. METHODS: One-hundred cases of human sporadic colon cancer and corresponding normal tissue samples were analyzed using two flanking polymorphic markers commonly used in the LOH analysis at the E-cadherin gene locus by conventional VNTR-LOH analysis. Two intragenic E-cadherin SNP markers were analyzed using real-time PCR SNP analysis. RESULTS: LOH (17.6%) was detected using flanking markers, however, no LOH was detected when the intragenic E-cadherin SNP markers were introduced into our study. Since these markers are intragenic they more accurately represent the status of the E-cadherin gene than the previously used flanking markers. CONCLUSION: In conclusion, real-time PCR SNP analysis was found to be more accurate, faster, simpler, and a more high-throughput method than the conventional VNTR-LOH analysis.

Biomarkers, Tumor↗
PubMed2006

Label-free detection of single nucleotide polymorphisms utilizing the differential transfer function of field-effect transistors.

We present a label-free method for the detection of DNA hybridization, which is monitored by non-metallized silicon field-effect transistors (FET) in a microarray approach. The described method enables a fast and fully electronic readout of ex situ binding assays. The label-free detection utilizing the field-effect is based on the intrinsic charge of the DNA molecules and/or on changes of the solid-liquid interface impedance, when biomolecules bind to the sensor surface. With our sensor system, usually a time-resolved, dc readout is used. In general, this FET signal suffers from sensor drift, temperature drift, changes in electrolyte composition or pH value, influence of the reference electrode, etc. In this article, we present a differential ac readout concept for FET microarrays, which enables a stable operation of the sensor against many of these side-parameters, reliable readout and a possibility for a quick screening of large sensor arrays. We present the detection of point mutations in short DNA samples with this method in an ex situ binding assay.

Biosensing Techniques↗
PubMed2005

Association of interferon-gamma +874(T/A) single nucleotide polymorphism with the rate of tryptophan catabolism in healthy individuals.

Abstract Mechanisms induced by tryptophan (trp) catabolism are important in the regulation of both normal and pathogenetic immune responses. The key enzyme is indoleamine-pyrrole 2,3-dioxygenase (EC 1.13.11.42) (IDO) which converts trp to kynurenine (kyn), the main toxic metabolite. It is known that interferon-gamma (IFN-gamma) is able to activate IDO. We wanted to analyse whether the strength of this mechanism would be under genetic control. To this end, we analysed the IFN-gamma+874(T/A) genotypes, which are known to have an effect on IFN-gamma production, of 309 healthy blood donors and correlated these to the levels of trp and kyn in their blood. The data obtained demonstrate that the presence of the high producer T allele was associated with increased IDO activity (i.e. elevated kyn and kyn/trp levels), but this effect was observed only in females. These data show that trp catabolism is genetically controlled by the IFN-gamma gene and may thus be operative in those disease conditions associated with the polymorphisms of the IFN-gamma gene.

Adult↗
PubMed2006

[Association study of single nucleotide polymorphism of interleukin 6 receptor gene and type 2 diabetes in Chinese Han population].

OBJECTIVE: To determine the association of the promoter and exon 9 of interleukin 6 receptor gene IL6R and the susceptibility of type 2 diabetes mellitus in Chinese Han population. METHODS: A total of 183 unrelated subjects, including 87 type 2 diabetes and 96 normal glucose tolerant (NGT) controls, were recruited. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were employed to screen the polymorphism. RESULTS: In the normal glucose tolerant control group, the genotype frequencies and allele frequencies of D358A were AA 31.2%, AC 41.7%, CC 27.1%, A 52.1%, C 47.9%, while the corresponding frequencies in the type 2 diabetes group were AA 44.8%, AC 41.4%, CC 13.8%, A 65.5%, C 34.5% respectively, the CC genotype frequency and C allele frequency of normal glucose tolerant control was higher than that of type 2 diabetes (Chi2 test=4.900, P< 0.05; Chi2 test=6.784, P< 0.01). No differences were found in the genotype frequencies and allele frequencies of -183(G --> A). CONCLUSION: The above results suggest that the D358A polymorphism of IL6R maybe correlate with type 2 diabetes in Chinese Han population.

Adult↗
PubMed2003

Unusual pattern of single nucleotide polymorphism at the exuperantia2 locus of Drosophila pseudoobscura.

We have investigated the pattern of DNA sequence variation at the exuperantia2 locus in Drosophila pseudoobscura. This adds to the increasing dataset of genetic variation in D. pseudoobscura, a useful model species for evolutionary genetic studies. The level of silent site nucleotide diversity and the divergence from an outgroup Drosophila miranda are comparable with those for other X-linked loci. One peculiar pattern at the exu2 locus of D. pseudoobscura is a complete linkage disequilibrium between two SNPs, one of which is a replacement site. As a result, there are two distinct haplotype groups in our dataset. Based upon the comparisons with the outgroup sequences from D. miranda and Drosophila persimilis, we show that the newly derived haplotype group has lower diversity than the ancestral haplotype group. The pattern of protein evolution at exu2 shows some deviation from the neutral model. Together, these and other characteristics of the exu2 locus suggest the action of selection on the pattern of SNP variation, consistent with a partial selective sweep associated with the newly derived haplotype.

Animals↗
PubMed2003

A single nucleotide polymorphism in the human H-ras proto-oncogene determines the risk of urinary bladder cancer.

Acquired mutations and inherited polymorphisms in the H-ras gene may modulate the risk of urinary bladder cancer. In DNA isolated from bladder cancer tissue, we screened the coding sequence of H-ras, including the exon-intron-junctions, for exon 1 (n = 68 patients), exon 2 (n = 50), and exons 3 and 4 (n = 25). Acquired mutations at codons 12 and 13 (exon 1) and codon 61 (exon 2), which had been described earlier in bladder cancer tissue, were not found in any of the tumors, but we identified a frequent polymorphism at nucleotide 81T-->C (exon 1) in a wobble position. The clinical impact of this polymorphism was investigated in a case-control study in which 312 patients with histologically verified bladder cancer were compared with 254 hospital controls; 13.5% of the cases but only 7.1% of controls were homozygous for the 81C-variant of this polymorphism [odds ratio (OR), 2.04; 95% confidence interval (CI), 1.15-3.61; P = 0.014]. The homozygous 81C genotype was overrepresented, particularly in the patient groups with poorly differentiated tumors (n = 145, >or=G3; OR, 2.22; 95% CI, 1.15-4.27; P = 0.017), muscle-invasive tumors (n = 107, >or=T(2); OR, 2.65; 95% CI, 1.35-5.23; P = 0.005), and flat transitional cell carcinoma (n = 45; OR, 3.69; 95% CI, 1.60-8.51; P = 0.002). In general, 81CC occurred more frequently in advanced types of bladder cancer. We conclude that individuals harboring the homozygous 81C-genotype of the H-ras proto-oncogene are at an increased risk of bladder cancer.

Adult↗
PubMed2004

Genotyping of three single nucleotide polymorphisms following whole genome preamplification of DNA collected from buccal cells.

Collection of genomic DNA from buccal cells is a simple and convenient procedure for genotyping individuals. One disadvantage is that the amount of genomic DNA may be inadequate for genotyping projects that require a large number of determinations per sample. Primer Extension Preamplification (PEP) methods that can amplify the entire genome 100-fold or more offer a potential solution to this problem. To test whether the preamplified DNA product retains the original allelic distribution of the genomic DNA sample from which it was derived, we compared PEP buccal DNA with genomic buccal DNA from 94 pairs of monozygotic twins. Using the 5' nuclease (Taqman) method, we genotyped three SNPs that are of wide interest in behavioral and psychiatric genetic studies. The percent agreement between allele calls using PEP DNA samples and those using genomic DNA samples ranged between 99% and 100% depending on SNP assay. These data complement our earlier findings with respect to microsatellite markers and variable number tandem repeat (VNTR) polymorphisms and indicate that whole-genome preamplification is an appropriate method for providing DNA for SNP genotyping these and possibly other loci.

Aryl Hydrocarbon Hydroxylases↗
PubMed2005

A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter enhances oral squamous cell carcinoma susceptibility in a Chinese population.

We genotyped 96 oral squamous cell carcinoma (OSCC) patients for the 1G/2G polymorphism of matrix metalloproteinase-1 (MMP-1) promoter -1607 bp using PCR-RFLP. A control population of 120 frequency-matched subjects was also genotyped for the same polymorphism. The detection frequency of 2G allele was significantly higher in OSCC subjects (76%) than in the control group (56.7%). The frequency of 2G allele had a significant difference between the OSCC and controls group (p = 0.00, Odds Ratio, OR = 2.232, 95% CI = 1.477-3.372). The genotype 2G/2G was found in 57.3% of the OSCC, and 34.2% in the controls. The proportion of 2G homozygote (2G/2G) was significantly higher in the OSCC group when compared to controls (p = 0.001, OR = 2.585, 95% CI = 1.487-4.494). OSCC patients were stratified by clinicopathological parameters including gender, smoking, clinical stage and lymph node metastasis, but the only statistically significant association with MMP-1 genotype was with smoking. The results showed that a SNP in the MMP-1 promoter -1607 bp was associated with OSCC susceptibility in a Chinese population.

Adult↗
PubMed2005

A single-nucleotide polymorphism in human angiotensinogen gene is associated with essential hypertension and affects glucocorticoid induced promoter activity.

Hypertension is a serious health problem particularly for African-Americans. Previous studies have suggested that angiotensinogen (AGT) gene locus is involved in human essential hypertension. We have recently shown that an A/G polymorphism at -217 in the promoter of the AGT gene is associated with essential hypertension especially in African-Americans. We report here that A/G polymorphism at -217 affects the glucocorticoid-induced promoter activity of the human AGT gene. We show that recombinant glucocorticoid receptor (GR) binds strongly to the AGT gene promoter when nucleoside A is present at -217, and dexamethasone treatment increases the interleukin 6 induced promoter activity of reporter constructs containing nucleoside A at -217. Similarly cotransfection of GR and C/EBP beta or C/EBP delta increases the promoter activity of reporter construct containing nucleoside A at -217. Since AGT is an acute phase protein, we propose that increased expression of -217A allele of the AGT gene by glucocorticoids and C/EBP family of transcription factors may be involved in essential hypertension.

Angiotensinogen↗
PubMed2002

A single-nucleotide polymorphism in C-type natriuretic peptide gene may be associated with hypertension.

We conducted an association study between genetic variants of C-type natriuretic peptide gene (CNP) and hypertension in a Japanese population. We found four genetic variants, two in the promoter region, one missense mutation, and one in the 3'-untranslated region (3'-UTR), and genotyped all four variants in 2,006 subjects recruited from the Suita study. One of the variants, G2628A in 3'-UTR, was found to be associated with blood pressure. Multiple logistic analyses indicated that the genotype of the G2628A polymorphism (GG=1, GA+AA=2) (p=0.0034), sex (p=0.0288), alcohol consumption (p=0.0002), age (p<0.0001), and body mass index (p<0.0001) were predictors of hypertension. The odds ratio of the GA+AA genotype over the GG genotype for hypertension was 1.40 (p=0.0034, 95% confidence interval (CI) 1.12-1.75). Multiple logistic analyses in a younger subpopulation aged below 65 years indicated that the odds ratio of the GA+AA genotype over the GG genotype for hypertension was 1.58 (p=0.0024, 95%CI 1.18-2.12). Thus, the CNP G2628A polymorphism made an even greater contribution to hypertension in the younger subpopulation.

Age Distribution↗
PubMed2005

Typing of single nucleotide polymorphisms by MALDI mass spectrometry: principles and diagnostic applications.

BACKGROUND: After the completion of the human genome sequencing project human genetics has now shifted its focus to DNA variation. DNA variation analysis is considered to be a key in partly understanding the mechanisms of complex diseases or varying patient responses in drug treatment. One of the major goals in genetics is finding the DNA variants that can act as diagnostic markers for predisposition to specific diseases. Moreover, in microbiology DNA variation has long been known to help discriminate and identify bacterial strains and viruses. Diagnostics based on DNA or RNA detection might be advantageous as an early-stage indication can be provided. METHODS: Many simple and efficient methods for the analysis of nucleic acids are already available. Consequently, the last few years have seen an increased in the use of large-scale analysis of nucleic acids, in basic DNA variation studies along with diagnostics. Mass spectrometry techniques such as matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) can be of great use for genome variation analysis. In particular high-throughput SNP analysis by MALDI can be performed using fully integrated platforms. CONCLUSIONS: Mass spectrometry-based procedures have promise for SNPs analysis especially for clinical diagnostics.

Chemistry, Clinical↗
PubMed2003

Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data.

We introduce a new statistical model for patterns of linkage disequilibrium (LD) among multiple SNPs in a population sample. The model overcomes limitations of existing approaches to understanding, summarizing, and interpreting LD by (i) relating patterns of LD directly to the underlying recombination process; (ii) considering all loci simultaneously, rather than pairwise; (iii) avoiding the assumption that LD necessarily has a "block-like" structure; and (iv) being computationally tractable for huge genomic regions (up to complete chromosomes). We examine in detail one natural application of the model: estimation of underlying recombination rates from population data. Using simulation, we show that in the case where recombination is assumed constant across the region of interest, recombination rate estimates based on our model are competitive with the very best of current available methods. More importantly, we demonstrate, on real and simulated data, the potential of the model to help identify and quantify fine-scale variation in recombination rate from population data. We also outline how the model could be useful in other contexts, such as in the development of more efficient haplotype-based methods for LD mapping.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Single-nucleotide-polymorphism genotyping for whole-genome-amplified samples using automated fluorescence correlation spectroscopy.

Whole-genome amplification (WGA) methods were adopted for single-nucleotide-polymorphism (SNP) typing to minimize the amount of genomic DNA that has to be used in typing for thousands of different SNPs in large-scale studies; 5-10 ng of genomic DNA was amplified by a WGA method (improved primer-extension-preamplification-polymerase chain reaction (I-PEP-PCR), degenerated oligonucleotide primer-PCR (DOP-PCR), or multiple displacement amplification (MDA)). Using 1/100 to 1/500 amounts of the whole-genome-amplified products as templates, subsequent analyses were successfully performed. SNPs were genotyped by the sequence-specific primer (SSP)-PCR method followed by fluorescence correlation spectroscopy (FCS). The typing results were evaluated for four different SNPs on tumor necrosis factor receptor 1 and 2 genes (TNFR1 and TNFR2). The genotypes determined by the SSP-FCS method using the WGA products were 100% in concordance with those determined by nucleotide sequencing using genomic DNAs. We have already carried out typing of more than 300 different SNPs and are currently performing 7,500-10,000 typings per day using WGA samples from patients with several common diseases. WGA coupled with FCS allows specific and high-throughput genotyping of thousands of samples for thousands of different SNPs.

Genome, Human↗
PubMed2003

A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter is associated with conventional renal cell carcinoma.

Matrix metalloproteinase (MMP)-1 is associated with tumor cell invasion and metastasis, and its promoter polymorphism has been shown to influence the transcriptional level. Our study explored the association between this polymorphism and renal cell carcinoma in a Japanese population. DNA was extracted from peripheral blood and normal tissue of 119 patients with conventional renal cell carcinoma (RCC) and from 210 age- and sex-matched healthy volunteers. Genotyping was carried out using direct sequencing. In the MMP-1 gene promoter polymorphism, it was demonstrated that the frequency of the 2G/2G genotype, which is associated with higher enzyme activity, was significantly higher in patients with RCC than in controls (p = 0.0015; OR = 2.082; 95% CI 1.317-3.293). When stratified for gender, only men showed a significant association of the polymorphism with RCC (p = 0.0028; OR = 2.307; 95% CI 1.333-3.990). However, no significant association was observed between the 2G/2G genotype and clinicopathologic parameters including age, gender, tumor grade and pathologic stage. Our present data suggest that the MMP-1 promoter polymorphism may be linked to susceptibility for conventional RCC.

Adult↗
PubMed2004

Single nucleotide polymorphism analysis and functional characterization of the human Ah receptor (AhR) gene promoter.

The aryl hydrocarbon receptor (AhR) mediates biological and toxicological actions of e.g., halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Although much is known about the biochemical and molecular mechanisms of AhR action, little is known about the control of the expression of the AhR gene itself. Therefore, we aimed at the identification and characterization of regions important for constitutive AhR gene expression. First, we screened 2.6 kb of the 5(')-flanking region of the AhR gene in 91 healthy Caucasian volunteers for naturally occurring genetic variants. Seven variants were detected. However, they do not seem to influence AhR gene expression in lymphocytes. Using a 2.7 kb AhR promoter luciferase reporter gene construct and various deletion constructs, a putative regulatory region was identified and characterized further by electrophoretic mobility shift assays and site-directed mutagenesis. These investigations were confirmed by cotransfection experiments in Drosophila SL2 cells. The obtained results prove an involvement of Sp1 in AhR gene regulation.

5' Flanking Region↗
PubMed2003

A functional single nucleotide polymorphism (V158M) in the COMT gene is associated with aggressive personality traits.

BACKGROUND: Suicidal behavior is often correlated with other-directed aggression, which is partially mediated by catecholaminergic neurotransmission. Catechol-O-methyltransferase (COMT) is an enzyme involved in catecholamine inactivation. In this study, we examined the influence of a functional COMT (V158M) polymorphism on suicidal behavior and anger-related traits. METHODS: This polymorphism was examined in 149 German suicide attempters and 328 German control subjects. Both groups were administered self-report questionnaires for anger-related traits. RESULTS: There was no overall difference in allele/genotype frequency between patients and control subjects; however, the low-activity L-allele and genotype frequencies were higher among violent suicide attempters. For anger-related traits, a multivariate effect of the COMT genotype was observed after controlling for age and educational level. LL-carriers expressed their anger more outwardly, whereas HH-carriers expressed it more inwardly and reported more state anger, as assessed by the self-report questionnaire. CONCLUSIONS: These findings support the hypothesis that the functional polymorphism in the COMT gene may modify the phenotype of suicide attempts and anger-related traits. This, however, being a novel finding, should warrant further investigation.

Adult↗
PubMed2006

Effects of a single nucleotide polymorphism on the expression of human tumor necrosis factor-alpha.

Tumor necrosis factor (TNF)-alpha plays a prominent role in inflammations and is a proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. Recent association studies have found that the TNF-alpha-857T allele was associated with several disorders. Here we demonstrate, with reporter genes under the control of the two allelic TNF-alpha promoters, that the minor allele -857T is a much stronger transcriptional activator than the major allele -857C in RAW264.7 cell line in response to lipopolysaccharide stimulation. However, the result was not consistent in HeLa cell line. Furthermore, for the quantitative analysis of TNF-alpha synthesis between the -857C/C genotype from healthy subjects and the -857C/T genotype from AS patients, the quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed separately. There was no significant difference between the two groups at the level of mRNA and protein. These results show that this polymorphism may have a direct effect on TNF-alpha regulation in a tissue-specific manner, and apart from the polymorphism at -857 in the TNF-alpha promoter, there may be other factors affecting the expression of TNF-alpha.

Adult↗