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PubMed2004

Single nucleotide polymorphisms predict the change in left ventricular mass in response to antihypertensive treatment.

BACKGROUND: Our aim was to determine whether the change in left ventricular (LV) mass in response to antihypertensive treatment could be predicted by multivariate analysis of single nucleotide polymorphisms (SNPs) in candidate genes reflecting pathways likely to be involved in blood pressure control. METHODS: Patients with mild to moderate primary hypertension and LV hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta1 adrenoreceptor blocker atenolol (n = 49). A microarray-based minisequencing system was used for genotyping 74 SNPs in 25 genes. These genotypes were related to the change in LV mass index by echocardiography, after 12 weeks treatment as monotherapy, using stepwise multiple regression analysis. RESULTS: The blood pressure reductions were similar and significant in both treatment groups. Two SNPs in two separate genes (the angiotensinogen T1198C polymorphism, corresponding to the M235T variant and the apolipoprotein B G10108A polymorphism) for those treated with irbesartan, and the adrenoreceptor alpha2A A1817G for those treated with atenolol, significantly predicted the change in LV mass. The predictive power of these SNPs was independent of the degree of blood pressure reduction. CONCLUSION: SNPs in the angiotensinogen, apolipoprotein B, and the alpha2 adrenoreceptor gene predicted the change in LV mass during antihypertensive therapy. These results illustrate the potential of using microarray-based technology for SNP genotyping in predicting individual drug responses.

Adrenergic beta-Antagonists↗
PubMed2004

Asthma is associated with single-nucleotide polymorphisms in ADAM33.

BACKGROUND: The ADAM33 gene has recently been associated with asthma and bronchial hyper-reactivity. It codes for a disintegrin and metalloproteinase that triggers intra- and extracellular signalling by protein shedding. OBJECTIVE: We examined whether polymorphisms in ADAM33 are associated with asthma and related traits in two German populations. METHODS: We genotyped 15 intragenic single-nucleotide polymorphisms (SNPs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of allele-specific primer extension products. The transmission disequilibrium test was used for association analysis in the German asthma family study. Additionally, we tested for association of these SNPs in a case-control sample from the European Community Respiratory Health Study using Armitage's trend test. RESULTS: In both studies, we found SNPs that were significantly associated with asthma and related traits. In the family study, significant associations were observed for the SNPs F+1, ST+4 and ST+5 (with the lowest P-value for F+1, P=0.005). Remarkably, this association is seen even in the absence of linkage with two microsatellite markers from a previous genome scan either 3.1 million bases (Mb) up- or 5.6 Mb downstream. In the case-control study, SNP ST+7 (P=0.008) was significantly associated with asthma. Some of these SNPs overlapped with those found to be associated with elevated total IgE levels and bronchial hyper-responsiveness. CONCLUSION: This study replicates the recently published association between asthma and ADAM33 gene variants. However, most of the associated SNPs were at non-identical positions in the German, UK and US samples. As linkage disequilibrium is high among the tested SNPs, and there is no known functional polymorphism, either not-tested variants in ADAM33, unknown regulatory elements or a gene in close proximity is responsible for this association.

ADAM Proteins↗
PubMed1999

Single nucleotide polymorphism determination using primer extension and time-of-flight mass spectrometry.

The high frequency of single nucleotide polymorphisms (SNPs) in the human genome makes them a valuable source of genetic markers for identity testing, genome mapping, and medical diagnostics. Conventional technologies for detecting SNPs are laborious and time-consuming, often prohibiting large-scale analysis. A rapid, accurate, and cost-effective method is needed to meet the demands of a high-throughput DNA assay. We demonstrate here that analysis of these genetic markers can now be performed routinely in a rapid, automated, and high-throughput fashion using time-of-flight mass spectrometry and a primer extension assay with a novel cleavable primer. SNP genotyping by mass spectrometry involves detection of single-base extension products of a primer immediately adjacent to the SNP site. Measurement of the mass difference between the SNP primer and the extension peak reveals which nucleotide is present at the polymorphic site. The primer is designed such that its extension products can be purified and chemically released from the primer in an automated format. The reduction in size of the products as a result of this chemical cleavage allows more accurate identification of the polymorphic base, especially in samples from a heterozygotic population. All six possible heterozygotes are resolved unambiguously, including an A/T heterozygote with extension products differing by only 9 Da. Multiplex SNP determination is demonstrated by simultaneously probing multiple SNP sites from a single polymerase chain reaction (PCR) product as well as from multiplexed PCR amplicons. Samples are processed in parallel on a robotic workstation, and analyzed serially in an automated mass spectrometer with analysis times of only a few seconds per sample, making it possible to process thousands of samples per day.

DNA Primers↗
PubMed2005

Bioinformatics approaches and resources for single nucleotide polymorphism functional analysis.

Since the initial sequencing of the human genome, many projects are underway to understand the effects of genetic variation between individuals. Predicting and understanding the downstream effects of genetic variation using computational methods are becoming increasingly important for single nucleotide polymorphism (SNP) selection in genetics studies and understanding the molecular basis of disease. According to the NIH, there are now more than four million validated SNPs in the human genome. The volume of known genetic variations lends itself well to an informatics approach. Bioinformaticians have become very good at functional inference methods derived from functional and structural genomics. This review will present a broad overview of the tools and resources available to collect and understand functional variation from the perspective of structure, expression, evolution and phenotype. Additionally, public resources available for SNP identification and characterisation are summarised.

Algorithms↗
PubMed2006

Assessment of submicroscopic genetic lesions by single nucleotide polymorphism arrays in a child with acute myeloid leukemia and FLT3-internal tandem duplication.

The same FLT3-internal tandem duplication (ITD) positive clone was detected at diagnosis and relapse, but not at birth, in a child with M1 acute myeloid leukemia. Single nucleotide polymorphism arrays demonstrated that chromosome 13 acquired uniparental disomy, in association with del(9q), represented a progressive event in the course of the disease, and it was responsible for the homozygous FLT3-ITD at relapse.

Child↗
PubMed2003

Multiple single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase and its truncated pseudogene of 23 inbred strains of mice.

Reduced 5,10-methylenetetrahydrofolate reductase (MTHFR) results in a number of human diseases. To find a model mouse sensitive to these diseases, we analyzed single-nucleotide polymorphisms (SNPs) of the mouse Mthfr using 23 phylogenetically distant strains of mouse. We found five SNPs: two nonsynonymous and three synonymous. The CAST/Ei strain has the nonsynonymous SNP L350V and five strains (NMRI, KJR, SWN2, MSM, and JF1) have the nonsynonymous SNP S22G. The MTHFR activity of CAST/Ei and MSM showed no significant difference in activity or thermostability compared with that of C57BL/6J. We also found a pseudogene segment of the mouse Mthfr that was not present in human and was more frequently variable than the functional gene. These results suggest a possibility that the truncated pseudogene may buffer variations of the mouse Mthfr functional gene, and the mouse has evolved fewer variations of the gene than human.

Amino Acid Sequence↗
PubMed2002

Human histamine N-methyltransferase pharmacogenetics: gene resequencing, promoter characterization, and functional studies of a common 5'-flanking region single nucleotide polymorphism (SNP).

Histamine N-methyltransferase (HNMT) catalyzes one of two major metabolic pathways for histamine. The levels of HNMT activity and immunoreactive protein in human tissues are regulated primarily by inheritance. Previous studies of HNMT identified two common single nucleotide polymorphisms (SNPs), including a functionally significant nonsynonymous coding SNP (cSNP), (C314T, Thr105Ile), but that polymorphism did not explain all of the phenotypic variation. In the present study, a genotype-to-phenotype strategy was used to search for additional genetic factors that might contribute to the regulation of human HNMT activity. Specifically, we began by resequencing the human HNMT gene using 90 ethnically anonymous DNA samples from the Coriell Cell Repository and identified a total of eight SNPs, including the two that had been reported previously. No new nonsynonymous cSNPs were observed, but three of the six novel SNPs were located in the 5'-flanking region (5'-FR) of the gene-including a third common polymorphism with a frequency of 0.367 (36.7%). That observation directed our attention to possible genetic effects on HNMT transcription. As a first step in testing that possibility, we created and studied a series of reporter gene constructs for the initial 1kb of the HNMT 5'-FR. The core promoter and possible regulatory regions were identified and verified by electrophoresis mobility shift assays. We then studied the possible functional implications of the new common HNMT 5'-FR SNP. However, on the basis of reporter gene studies, that SNP appeared to have little effect on transcription. Phenotype-genotype correlation analysis performed with 112 human kidney biopsy samples that had been phenotyped for their level of HNMT activity confirmed that the common 5'-FR SNP was not associated with the level of HNMT activity in vivo. In summary, this series of experiments resulted in the identification of several novel HNMT polymorphisms, identification of the HNMT core promoter, and a comprehensive functional genomic study of a common HNMT 5'-FR SNP. These results represent an additional step in the definition of molecular genetic mechanisms involved in the regulation of this important autacoid-metabolizing enzyme in humans.

5' Flanking Region↗
PubMed2003

A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity.

Thymidylate synthase (TS) gene expression is modulated by a polymorphism in the 5' regulatory region of the gene. The polymorphism consists mainly of either two repeats (2R) or three repeats (3R) of a 28-bp sequence, yielding greater TS gene expression and protein levels with a 3R genotype. Two USF family E-box consensus elements are found within the tandem repeats of the 3R genotype, and one is found within the 2R genotype. These elements bind USF proteins in vitro by electrophoretic mobility shift analysis and in vivo by chromatin immunoprecipitation assay. We show that the additional USF consensus element within the 3R construct confers greater transcriptional activity relative to the 2R construct. Mutagenesis of the USF sites shows that the transcriptional regulation of TS is dependent, in part, on USF proteins binding within the tandem repeats. In addition, we identified a novel G-->C single nucleotide polymorphism in the second repeat of 3R alleles within the USF consensus element that alters the ability of USF proteins to bind and thus alters the transcriptional activation of TS gene constructs bearing this genotype. Through RFLP analysis, we determined the respective frequencies of the C allele (3RC) among all 3R alleles in non-Hispanic whites, Hispanic whites, African Americans, and Singapore Chinese to be 56%, 47%, 28%, and 37%, respectively. Based on our findings, this novel single nucleotide polymorphism should be considered when the 5' tandem repeat polymorphism is being used as a predictor of clinical outcome to TS inhibitors.

Base Sequence↗
PubMed2005

Improvement of single nucleotide polymorphism genotyping by allele-specific PCR using primers modified with an ENA residue.

When we placed an ENA residue into primers at the 3' end, or the n-1, n-2, or n-3 position, which included a single nucleotide polymorphism (SNP) site at the 3' end, only primers containing the ENA residue at the n-2 position were read by Taq DNA polymerase for amplification. The use of the ENA primers avoided the generation of undesired short products, which are thought to be derived from primer-dimers. A greater discrimination of the SNP site by these primers containing the ENA residue was observed compared with that of the corresponding unmodified DNA primers that are often used for allele-specific polymerase chain reaction (AS-PCR). This improvement is probably due to the difficulty of incorporating a nucleotide into the mismatched ENA primer by Taq DNA polymerase in the modified primer-template duplex. These results demonstrate that ENA primer-based AS-PCR would enable a rapid and reliable technique for SNP genotyping.

Alleles↗
PubMed2007

Intronic single-nucleotide polymorphisms in Bcl-2 are associated with chronic obstructive pulmonary disease severity.

BACKGROUND AND OBJECTIVE: COPD is a multifactorial disease influenced by genetic and environmental factors, and gene-by-environmental interactions. There is considerable variability in the degree of airflow obstruction, moreover only 10-15% of chronic smokers develop COPD. These observations indicate that additional risk factors, possibly genetic, contribute to not only the susceptibility to COPD but also the development and severity of COPD. Recent paradigms highlight the presence and causal role of apoptosis in emphysema. There is a large amount of information on the genes involved in the regulation of apoptosis and one of the most studied is Bcl-2. The aim of this study was to investigate the genetic association of Bcl-2 gene with the level of lung function, that is, the severity, of COPD. METHODS: The genetic association of Bcl-2 polymorphisms with lung function was investigated in 261 Japanese patients with COPD using 12 single-nucleotide polymorphisms (SNPs) in Bcl-2. RESULTS: Four SNPs showed a significant association between the high and low lung function groups in a dominant trait comparison. Subsequent linkage-disequilibrium mapping and analyses of haplotype structure also showed a significant association between the level of lung function and two haplotypes comprised of the associated SNPs in Bcl-2. CONCLUSIONS: Although the linkage between Bcl-2 gene and the susceptibility to COPD remains to be clarified, the findings of the current study indicate that Bcl-2 might be influencing the level of lung function, that is, the development and severity of COPD.

Aged↗
PubMed2006

Identification of coding single nucleotide polymorphisms and mutations by combination of genome tiling arrays and enrichment/depletion of mismatch cDNAs.

Genome tiling array technology combined with a method for both enrichment and depletion of mismatch-containing cDNA fragments offers a useful approach for detecting coding single nucleotide polymorphisms (cSNPs) and mutations in pooled cDNA samples. Enriched mismatch and perfect match cDNA samples from human primary melanoma cells and normal melanocytes were obtained by selection using mismatch repair thymine DNA glycosylase-bound beads. These cDNA samples were then labeled and hybridized to Encyclopedia of DNA Elements genome tiling arrays. The results revealed that the hybridization intensity values of potential cDNA variation regions of the enriched mismatch samples increased, whereas the hybridization intensity values of corresponding regions of the enriched perfect match samples decreased. Six potential mutations were confirmed by polymerase chain reaction product sequencing, including two novel heterozygous mutations in melanoma cells. We suggest that this strategy should increase the efficiency of both cSNP and mutation detection throughout the entire human genome and decrease the cost and complexity of genomewide analysis of cDNA variations.

Base Pair Mismatch↗
PubMed2004

Developments of geriatric autopsy database and Internet-based database of Japanese single nucleotide polymorphisms for geriatric research (JG-SNP).

To facilitate geriatric research on the roles of genetic polymorphisms of candidate genes, two databases were developed based on data obtained from autopsy examinations of elderly subjects: the geriatric autopsy database (GEAD) and the Japanese single nucleotide polymorphisms (SNP) database for geriatric research (JG-SNP) which is accessible on the Internet (http://www.tmgh.metro.tokyo.jp/jg-snp/english/E_top.html). The data for the GEAD were derived from 1074 consecutive autopsy cases (565 male and 509 female cases) with an average age of 80 years. The GEAD was installed on a stand-alone Windows 2000 server using Oracle 8i as the database application. The GEAD contains clinical diagnoses of 26 geriatric diseases, histories of smoking and alcohol consumption, pathological findings (720 items), severity of atherosclerosis, genetic polymorphism data, etc. On the JG-SNP website, case distribution corresponding to a specified SNP or disease can be searched or downloaded. Although there are several Internet-based SNP databases such as dbSNP, no databases are available at present on the web that contain both SNP data and phenotypic data. As autopsy studies can provide large amounts of accurate medical information, including the presence of undiagnosed diseases such as latent cancers, the GEAD is a unique and excellent database for research on genetic polymorphisms.

Aged↗
PubMed2005

Forensic assessment of 16 single nucleotide polymorphisms analyzed by hybridization probe assay.

Of a number of DNA marker typing techniques for personal identification in the field of forensic medicine, polymorphic short tandem repeat (STR) typing is currently the most frequently used technique. However, the multiplex STR method is time consuming. In contrast, single nucleotide polymorphism (SNP) detection methods are relatively rapid and amenable to high throughput. The discrimination power of each SNP is inferior to that of an STR, but a combination of many SNPs could realize a high discriminating power. In this regard, 16 highly informative SNP markers were selected in the introns of genes whose alleles had a proportion of 0.4-0.6 in the Japanese SNP database. The 16 SNPs were sequentially detected within 40 min using the hybridization probe assay on the LightCycler system. The allele and genotype frequencies of these SNPs were determined in a group comprising 64 unrelated Japanese subjects. Based on the frequency data of this group, the combined matching probability, defined as the estimated probability that two unrelated individuals selected at random would possess identical multilocus genotypes, was calculated with the 16 SNPs in the Japanese population and was found to be 2.025x10(-7). This system is an effective tool in the forensic medicine to obtain information on personal identification.

Alleles↗
PubMed2004

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

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

Black People↗
PubMed2004

Limited impact of multiple 5' single-nucleotide polymorphisms on the transcriptional control of the human beta 2-adrenoceptor gene.

The human beta(2)-adrenoceptor (beta(2)-AR) is subject to agonist-induced down-regulation. The degree of down-regulation is associated with certain single-nucleotide polymorphisms (SNPs) through yet unknown mechanisms. The 5'-leader sequence of the beta(2)-AR gene contains several SNPs that are in strong linkage disequilibrium. The -367 T/C polymorphism, in particular, has been shown to affect transcriptional activity in reporter gene assays. In the present study we analysed the impact of this -367 SNP on the transcription rate of the beta(2)-AR gene in the context of the complete natural locus. Taking advantage of the additional full disequilibrium with the +79 SNP in the beta(2)-AR coding sequence, allele-specific transcript quantification was performed in PBMCs of six -367 heterozygous mild asthmatic patients. Our data are in line with the reported impact of the -367 SNP and give no indication of additional haplotype-related effects on beta(2)-AR transcription. We further show that the -367 SNP affects the binding of a yet unidentified transcription factor complex, whose binding activity is not modulated by pharmacological compounds that induce or down-regulate beta(2)-AR expression, suggesting a role in constitutive steady state expression rather than in inducible expression. As the beta(2)-AR allele with a higher transcription rate associates with stronger agonist-induced down-regulation, it is not likely that the -367 SNP is causally related to the degree of down-regulation.

5' Untranslated Regions↗
PubMed2006

A single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1: Association with impairment of sustained attention.

BACKGROUND: The marker D1S251 of chromosome 1q42.1 showed significant association with schizophrenia in a Taiwanese sample. We used single nucleotide polymorphism (SNP) fine mapping to search for the vulnerability genes of schizophrenia. METHODS: We selected 120 SNPs covering 1 Mb around D1S251 from the public database. These selected SNPs were initially validated if allele frequency was >10%. Forty-seven validated SNPs were genotyped in 102 families with at least 2 siblings affected with schizophrenia. RESULTS: Two SNP blocks showed significant association with schizophrenia. Block 1 (five-SNP), located between intron 2 and intron 13 of the glyceronephosphate O-acyltransferase (GNPAT) gene, showed the most significant associations using single-locus TDT (z = -2.07, p = .038, df = 1) and haplotype association analyses (z = -1.99, p = .046, df = 1). Block 2 (two-SNP), located between intron 4 and intron 5 of the disrupted-in-schizophrenia 1 (DISC1) gene, also showed the most significant results in both the single-locus (z = -3.22, p = .0013, df = 1) and haplotype association analyses (z = 3.35, p = .0008, df = 1). The association of the DISC1 gene with schizophrenia was mainly in the patient group with sustained attention deficits as assessed by the Continuous Performance Test. CONCLUSIONS: Chromosome 1q42.1 harbors GNPAT and DISC1 as candidate genes for schizophrenia, and DISC1 is associated with sustained attention deficits.

Acyltransferases↗
PubMed2005

Pharmacological properties of the Cys23Ser single nucleotide polymorphism in human 5-HT2C receptor isoforms.

The human serotonin 2C (5-HT2C) receptor undergoes extensive RNA editing, generating multiple isoforms; the most prominent isoform in the human brain is the extensively edited VSV isoform. In addition, a naturally occurring single nucleotide polymorphism (SNP) is found in the coding region of the 5-HT2C receptor gene, which converts cysteine to serine at the 23rd amino acid (C23S). To elucidate the functional consequences, pharmacological properties were evaluated in cells expressing C23 or S23 in the nonedited, INI, or edited, VSV, isoform. Confocal imaging of HEK293 cells expressing the C23 and S23 variants revealed no apparent difference in cellular localization, which was confirmed in NIH-3T3 fibroblasts by surface biotinylation. Competition binding experiments revealed comparable high-affinity agonist binding for the C23 and S23 receptors and no difference in ligand affinities in either the INI or VSV backbones. The dose-response functions for 5-HT and (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI) to elicit phosphoinositide hydrolysis did not differ in either HEK293 or NIH-3T3 fibroblasts expressing the receptor variants. Constitutive activity, evaluated in COS-7 and HEK293 cells, also was not different. Lastly, fluorescence resonance energy transfer demonstrated homodimerization of C23 receptors, which was reproduced in cells expressing the S23 variant. We conclude that the C23S SNP in the 5-HT2C receptor has no functional consequences, even when evaluated in the most common, edited receptor backbone. Therefore, positive associations between this polymorphism and disease states may be a consequence of linkage disequilibrium with another SNP that is involved in the disease.

Animals↗
PubMed2006

Evaluation of the associations between the single nucleotide polymorphisms of the promoter region of the tumor necrosis factor-alpha gene and nasopharyngeal carcinoma.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine and may act as an endogenous tumor promoter. Single nucleotide polymorphisms (SNPs) of the TNF-alpha gene promoter region have been found to be associated with certain cancers. We conducted a case-control study to evaluate the association between these SNPs and nasopharyngeal carcinoma (NPC). METHODS: We used polymerase chain reaction followed by restriction fragment length polymorphism analysis to determine the -308 TNF-alpha promoter genotypes of 89 NPC patients and 360 healthy controls. In 23 NPC patients and 50 controls, we determined the sequence from -1065 to -101 nucleotides of the TNF-alpha gene promoter region to detect SNPs. RESULTS: In comparison with the controls, the NPC patients had higher proportions of men and carriage of IgA antibodies against the capsid antigen of Epstein-Barr virus, but had a similar carrier rate of the -308A allele (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.7-2.0). The carriage of the -308A allele was not associated with the occurrence of NPC in comparison with -308G homozygosity. We also found no significant differences in the distributions of allelic variants of the -1031, -863, -857, and -806 loci of the TNF-alpha promoter region, but observed a lower carrier rate of the novel -806T allele in the NPC patients (OR, 0.3; 95% Cl, 0.0-2.9). CONCLUSION: Allelic variants of the TNF-alpha promoter gene may not be used as biomarkers of susceptibility to NPC. The role of the -806T allele needs to be studied further.

Adult↗