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At least 1,531 records · Page 85Linked to original sources
PubMed2004

A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.

Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting approximately 1% of the adult population worldwide, with an estimated heritability of 60%. To identify genes involved in RA susceptibility, we investigated the association between putative functional single-nucleotide polymorphisms (SNPs) and RA among white individuals by use of a case-control study design; a second sample was tested for replication. Here we report the association of RA susceptibility with the minor allele of a missense SNP in PTPN22 (discovery-study allelic P=6.6 x 10(-4); replication-study allelic P=5.6 x 10(-8)), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as "Lyp." We show that the risk allele, which is present in approximately 17% of white individuals from the general population and in approximately 28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation. The minor allele of this SNP recently was implicated in type 1 diabetes, suggesting that the variant phosphatase may increase overall reactivity of the immune system and may heighten an individual carrier's risk for autoimmune disease.

Arthritis, Rheumatoid↗
PubMed2006

High-throughput loss-of-heterozygosity study of chromosome 3p in lung cancer using single-nucleotide polymorphism markers.

Loss of DNA copy number at the short arm of chromosome 3 is one of the most common genetic changes in human lung cancer, suggesting the existence of one or more tumor suppressor genes (TSG) at 3p. To identify most frequently deleted regions and candidate TSGs within these regions, a recently developed single-nucleotide polymorphism (SNP)-mass spectrometry-genotyping (SMSG) technology was applied to investigate the loss of heterozygosity (LOH) in 30 primary non-small-cell lung cancers. A total of 386 SNP markers that spanned a region of 70 Mb at 3p, from 3pter to 3p14.1, were selected for LOH analysis. The average intermarker distance in the present study is approximately 180 kb. Several frequently deleted regions, including 3p26.3, 3p25.3, 3p24.1, 3p23, and 3p21.1, were found. Several candidate TSGs within these frequently detected LOH regions have been found, including APG7L at 3p25.3, CLASP2 at 3p23, and CACNA2D3 at 3p21.1. This study also showed that SMSG technology is a very useful approach to rapidly define the minimal deleted region and to identify target TSGs in a given cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed2003

[Coding single nucleotide polymorphism is an ideal marker for detecting gene imprinting by 5' nuclease assay].

OBJECTIVE: To establish a novel approach for quick and high throughput verification of human gene imprinting. METHODS: By use of a pair of dye-labeled probes, 5' nuclease assay was combined with reverse transcriptase-PCR(RT-PCR) to genotype a coding single nucleotide polymorphism (cSNP), rs705(C/T) of a known imprinted gene, small nuclear ribonucleotide protein N (SNRPN), on both genomic DNA and cDNA of human lymphoblast cell lines. RESULTS: Allele discrimination showed a clear monoallelic expression pattern of SNRPN, which was confirmed by RT-PCR based restriction fragment length polymorphisms. Pedigree analysis verified the paternal origin of expressed allele, which is in consistency with previous report. CONCLUSION: Coding SNP is an ideal marker for detecting gene imprinting by 5' nuclease assay. This approach has also a potentiality to discover differential allele expression of non-imprinted genes in order to find gene cis-acting functional polymorphism.

Alleles↗
PubMed2006

Identification of single nucleotide polymorphisms in FOXJ1 and their association with allergic rhinitis.

Forkhead-box J1 (FOXJ1) is a presumed transcription factor that can suppress T cell activity, at least partially, through the repression of NFkappaB activity. Thus, dysregulation of FOXJ1 is thought to be associated with autoimmune diseases and/or other inflammatory diseases. To investigate the association between single nucleotide polymorphisms (SNPs) of human FOXJ1 and allergic rhinitis, we scanned the whole human FOXJ1 gene, including the promoter region, by direct sequencing of DNA from 32 individuals. We identified seven SNPs, three of which (g.-460C>T, g.1805G>T, and g.3375G>C) were chosen for large sample size genotyping (n=713), and to assess the genotype frequencies of these SNPs between controls and allergic rhinitis patients. We also investigated the relationships of each genotype with serum total IgE levels in allergic rhinitis patients, and compared the frequencies of haplotypes constructed by these SNPs between the two groups. Our results suggest that the SNPs g.-460C>T, g.1805G>T and g.3375G>C in the human FOXJ1 gene might be associated with susceptibility to allergic rhinitis (P=0.0184, 0.0076, and 0.0143, respectively). The main haplotype, CGG, also revealed a significant association with allergic rhinitis (P=0.000018). However, no significant association was found between serum total IgE levels and the genotypes of these polymorphisms.

Adult↗
PubMed2004

Influence of single-nucleotide polymorphisms in the multidrug resistance-1 gene on the cellular export of nelfinavir and its clinical implication for highly active antiretroviral therapy.

Protease inhibitors (PIs) such as nelfinavir (NFV) suppress HIV replication. PIs are substrates of P-glycoprotein (P-gp), the product of the multidrug-resistance-1 (MDR1) gene. Three single-nucleotide polymorphisms (SNPs) are present in exons of the MDR1 gene: MDR1 1236, MDR1 2677 and MDR1 3435. We speculated that these genetic polymorphisms affected PI concentration in the cell. To verify this hypothesis, we first genotyped these SNPs in 79 Japanese patients by the SNaPshot method and found incomplete linkage disequilibrium between the SNPs. Because the SNP at MDR1 3435 has been reported to be associated with P-gp expression, we evaluated the effect of that SNP on the export of NFV from HIV-positive patients' lymphoblastoid cell lines by measuring time-dependent decrease in the amount of intracellular NFV by high-performance liquid chromatography. We found the intracellular concentration of NFV in lymphoblastoid cell lines (LCLs) with the homozygous T/T genotype at MDR1 3435 were higher than that with C/C genotype with statistical significance. This suggests that the activity of P-gp in patients' LCL cells with the MDR1 3435 T/T genotype was lower. In a retrospective study we evaluated the effect of the SNPs on CD4 cell count recovery in response to antiretroviral treatment with PIs, and obtained statistically significant evidence that suggested marginal association of the SNP at MDR1 1236 but not at MDR1 2677 or MDR1 3435. As in vitro results were not consistent with the clinical evaluation, clinical importance of MDR1 genotyping for antiretroviral therapy remains to be investigated in a larger, case-controlled study.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Genotype frequencies of the +874T-->A single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis.

In the light of the key role played by interferon (IFN)-gamma in the control of tuberculosis, in the present paper we have evaluated the distribution of the functional +874T --> A IFN-gamma single nucleotide polymorphism (SNP) in Sicilian patients affected by tuberculosis. Our aim was to determine whether there is an association between the TT genotype, which has been suggested to be linked to an increased production of IFN-gamma, and resistance to chronic tuberculosis. DNA samples were obtained from 45 patients and 97 healthy controls. Polymorphism at +874 was identified using amplification refractory mutational system methodology. The +874T SNP was less frequent in patients than in controls (0.42 vs. 0.50) but the difference was not significant. The +874TT genotype, which has been suggested to be associated with high IFN-gamma production, was significantly decreased in the patients. Thus, resistance to chronic lung tuberculosis might be associated with a genetically determined high IFN-gamma production capacity. In conclusion, the present data add another piece of evidence to the complex puzzle of genetic and environmental factors involved in control of infectious diseases. Studies on cytokine gene polymorphisms may elucidate the complex network of trans-interactive genes influencing the type and strength of responses to environmental stressors and may help to identify the genetic factors that affect survival in humans.

Adult↗
PubMed2003

Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene.

The variable number of tandem repeat (VNTR) of thymidylate synthase (TS) gene, mainly 2 repeat (2R) and 3 repeat (3R), is one of the genetic variations that can potentially predict the effectiveness of 5-fluorouracil-based chemotherapy. In this study we identified an additional single nucleotide polymorphism (SNP) in the VNTR of TS, followed by functional and clinical analysis of the SNP. Two-hundred fifty eight tumor samples were obtained from patients with primary colorectal adenocarcinoma. We observed three different patterns of electrophoresis by analysis of the VNTR with 2R/3R heterozygote. The sequencing results revealed a SNP, G/C polymorphism, within the 28-bp repeat component of TS VNTR. Each polymorphic allele was assigned as 2G, 2C, 3G, or 3C according to the combination of SNP and VNTR. Functional analysis showed that the plasmid construct with 3G sequence had three to four times greater efficiency of translation than other polymorphic sequences. 3R allele in colorectal cancer was subdivided into around half by the SNP, indicating its commonness among Japanese. TS genotypes of the patients with colorectal cancer were classified into high expression type (2R/3G, 3C/3G, and 3G/3G) and low expression type (2R/2R, 2R/3C, and 3C/3C). The patients who received oral fluoropyrimedines survived longer than the patients with no treatment in the group of low expression type. No benefit of oral fluoropyrimedines was observed in the group of high expression type. These results suggest that the double polymorphism in the TS tandem repeat sequence, the SNP and the VNTR, may provide a potential for more effective prediction of the clinical outcome of 5-fluorouracil-based chemotherapy.

Adenocarcinoma↗
PubMed2002

Establishment of the genomic structure and identification of thirteen single-nucleotide polymorphisms in the human RECK gene.

The human RECK gene, mapped at 9p13-->p12, is known as a tumor suppressor gene and as a key regulator of extracellular matrix integrity and angiogenesis. We have established the entire genomic structure of this gene, which spans more than 87 kb and consists of 21 exons and 20 introns, and identified thirteen single nucleotide polymorphisms (SNPs). Four SNPs were identified in the coding region of the gene (exons 1, 9, 13 and 15), and the remaining nine in introns 5, 8, 10, 12, 15 and 17. The availability of the genomic organization of the RECK gene and the identification of polymorphisms throughout its entire genome will facilitate the evaluation of its role in several disorders and also contribute to the assignment of genes to the several diseases mapped to this chromosomal region.

Base Sequence↗
PubMed2002

Single nucleotide polymorphisms and microsatellite alleles of tumor necrosis factor alpha and interleukin-10 genes and the risk of advanced chronic alcoholic liver disease.

BACKGROUND: Only a minority of ethanol abusers develop advanced chronic alcoholic liver disease (CALD). In CALD there is a imbalance between TNF alpha and IL-10, which may be modulated by several polymorphisms at both genetic loci. Our aim has been to elucidate the possible relation between these polymorphisms and the risk of CALD. PATIENTS AND METHODS: 147 patients with advanced CALD and 355 healthy controls (all white Spaniards) were included. TNF alpha biallelic single nucleotide polymorphisms (SNP) at positions -238, -308, and -376 and IL-10 biallelic SNP at positions -597, - 824, and - 1087 were investigated by polymerase chain reaction (PCR) amplification and dot blot hybridization. Moreover, polymorphic microsatellites TNFa, TNFb, IL-10.R and IL-10.G were investigated in a multiplex PCR and alleles were estimated in an automatic sequencer. RESULTS: No differences were found in the distribution of any of the studied polymorphisms, except by an excess of the haplotype formed by the allele 11 of the microsatellite IL-10.G and the GCC arrangement of the SNPs at the promoter of IL-10 gene in patients (15.7 vs. 8.24%, odds ratio: 2.08, 95% C.I. = 1.31-3.31). CONCLUSIONS: The studied polymorphisms at TNF alpha and IL-10 genetic loci are not clearly related to the risk of CALD. The excess of G11-GCC haplotype found in CALD patients needs independent confirmation.

Adult↗
PubMed2004

A novel single nucleotide polymorphism (SNP) of the CYP2C19 gene in a Japanese subject with lowered capacity of mephobarbital 4'-hydroxylation.

We sequenced all nine exons and exon-intron junctions of the cytochrome P450 2C19 (CYP2C19) gene from a Japanese subject with a lowered capacity of CYP2C19-mediated 4'-hydroxylation after an oral administration of mephobarbital. We found a novel single nucleotide polymorphism (SNP) of CYP2C19 gene as follows: SNP, 040110MoritaJ001; GENENAME: CYP2C19; ACCESSION NUMBER: NT_030059.8; LENGTH; 25 bases; 5'-GAGGGCCTGGCCC/TGCATGGAGCTGT-3'. The SNP (168946C>T) induced an amino acid alteration (Arg442Cys) located in exon 9 close to the heme-binding region of CYP2C19, which may result in the decrease in the catalytic properties of CYP2C19. A new allele having this SNP was designated as CYP2C19*16.

Amino Acid Sequence↗
PubMed1999

Identification of candidate coding region single nucleotide polymorphisms in 165 human genes using assembled expressed sequence tags.

Using assembled expressed sequence tags (ESTs) from 50 different cDNA libraries, we have identified contigs that represent the complete coding sequences of 850 known human genes, and have scanned these for high quality sequence substitutions. We report the identification and characteristics of 201 candidate single nucleotide polymorphisms found in the coding sequences (cSNPs) of 165 of these genes. Using a conservative calculation, coding region nucleotide diversity (the average number of differences between any pair of chromosomes) was found to be 3 per 10,000 bp based on this data. This analysis reveals that assembled ESTs from multiple libraries may provide a rich source of comparative sequences to search for cSNPs in the human genome.

Amino Acid Substitution↗
PubMed2005

Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia.

The complications of sickle cell disease are probably determined by genes whose products modify the pathophysiology initiated by the sickle haemoglobin mutation. Priapism, one vaso-occlusive manifestation of sickle cell disease, affects more than 30% of males with the disease. We examined the possible association of single nucleotide polymorphisms (SNPs) in 44 candidate genes of different functional classes for an association with the occurrence of priapism. One hundred and forty-eight patients with sickle cell anaemia and incident or a confirmed history of priapism were studied, along with 529 controls that had not developed priapism. Polymorphisms in the KLOTHO gene (KL; 13q12) showed an association with priapism by genotypic [reference SNP cluster identifier number (rs)2249358; odds ratio (OR) = 2.6 (1.4-5.5); rs211239; OR = 1.7 (1.2-2.6)] and haplotype analyses [rs211234 and rs211239; OR = 2.3 (1.5-3.4)]. These findings may have broader implications in sickle cell disease, as KL encodes a membrane protein that regulates many vascular functions, including vascular endothelial growth factor expression and endothelial nitric oxide release.

Adult↗
PubMed2003

Genetic variation and hematology: single-nucleotide polymorphisms, haplotypes, and complex disease.

In the course of generating a draft sequence of the human genome, we now recognize the enormous scope of genetic variation among humans, which can be used to probe the genetics of complex diseases such as leukemia or thrombosis. There is already mounting evidence of new susceptibility genes and genes that interact with environmental factors. Genetic variants, especially single-nucleotide polymorphisms (SNPs), also can be utilized to investigate potential modifiers of disease. Genetic variation can be applied to study pharmacogenomics, which could eventually drive the choice of therapeutic and interventional strategies. The genomic revolution ultimately should give insights into key mechanisms in hematological disorders that can be translated into targeted therapies.

Genetic Predisposition to Disease↗
PubMed2005

Application of the regression of offspring on mid-parent method to detect associations between single-nucleotide polymorphisms and the beta 2 electroencephalogram phenotype in the COGA data.

The beta 2 electroencephalogram (EEG) phenotype is used as a quantitative measure related to alcoholism, and evidence of linkage and association has previously been reported in the Collaborative Study on the Genetics of Alcoholism data. In this study, associations between the beta 2 EEG phenotype and single nucleotide polymorphisms from whole-genome Illumina and Affymetrix panels were investigated with the regression of offspring on mid-parent method to identify significant genetic effects and to estimate their heritability. Separate regressions on father and mother were performed to identify parent-specific effects. Estimates of the heritability of the beta 2 EEG phenotype were 0.68 +/- 0.12 and 0.52 +/- 0.07 based on father-offspring and mother-offspring pairs, respectively. Significant associations at the 0.0005 level, some of which were parent-specific, were found on chromosomes 1, 2, 5, 6, 7, 8, 11, 12, 15, 16, 17, 18, and 19 with heritability attributable to each SNP ranging from 0.01 to 8%.

Adolescent↗
PubMed2004

A single nucleotide polymorphism in the CD40 gene on chromosome 20q (GD-2) provides no evidence for susceptibility to Graves' disease in UK Caucasians.

OBJECTIVE: A genome-wide screen in Graves' disease (GD) has shown linkage to chromosome 20q, designated GD-2. The gene encoding CD40, which stimulates lymphocyte proliferation and differentiation, maps to this region, and a single nucleotide polymorphism (SNP) at position -1 of the Kozak sequence within the gene has been reported to be associated with GD. The aim of this study was to determine whether this SNP of the CD40 gene confers susceptibility to GD in UK Caucasians. DESIGN: A large case-control cohort consisting of 800 patients with GD, and 785 control subjects with no history of autoimmune disease, was used to genotype this SNP by polymerase chain reaction restriction fragment length polymorphism. RESULTS: Despite adequate power (> 99%) to detect an effect, if present (odds ratio of 1.5), no significant difference in allele or genotype frequency of the CD40 SNP was observed between patients with GD and control subjects (P = 0.087 and P = 0.145, respectively). CONCLUSIONS: These data suggest that this polymorphism of the CD40 gene is not associated with GD in the UK and is therefore not contributing to disease susceptibility in the chromosomal region designated GD-2.

Alleles↗
PubMed2005

Thermodynamic analyses of the specific interaction between C:C mismatch base pair and silver (I) cation: toward the efficient detection of single nucleotide polymorphism.

We examined the effect of silver (I) cation on the thermal stability of heteroduplex and homoduplex. Addition of silver (I) cation increased the melting temperature of heteroduplex containing C:C mismatch base pair by about 4 degrees C. The thermal stability of homoduplex and heteroduplexes containing other kinds of mismatch base pairs was not significantly changed by the addition of silver (I) cation. Isothermal titration calorimetric study demonstrated that silver (I) cation directly bound to C:C mismatch base pair in heteroduplex at a molar ratio of 1:1. The binding constant and the enthalpy change for the binding of silver (I) cation to C:C mismatch base pair was approximately 10(6) M(-1) and -3 kcal mol(-1), respectively. We conclude that silver (I) cation directly binds to C:C mismatch base pair in heteroduplex with high affinity and specificity. Our results certainly support the idea that the addition of silver (I) cation to C:C mismatch base pair in heteroduplex could be a convenient strategy for heteroduplex analysis and may eventually lead to progress in single nucleotide polymorphism genotyping.

Base Pair Mismatch↗
PubMed2003

Analysis of single nucleotide polymorphism C3435T of the multidrug resistance gene MDR1 in acute lymphoblastic leukemia.

Multidrug resistance is an important mechanism responsible for refractoriness of leukemia and worse outcome of patients. Overexpression of the multidrug resistance gene, MDR1, is of prognostic relevance in acute myeloid leukemia, while its role in acute lymphoblastic leukemia (ALL) is still under debate. Single nucleotide polymorphisms (SNP) have been detected in the MDR1 gene. The C3435T polymorphism in this gene seems to have functional and clinical consequences. In the present investigation, we have analyzed the role of the C3435T SNP for drug resistance and prognosis of human ALL. The C3435T SNP was analyzed in 20 T-ALL cell lines and in blood samples from 53 ALL patients and 7 healthy donors. The cell line panel consisted of cell lines not prior exposed in vitro to cytostatic drugs as well as of drug-resistant lines which were selected in vitro by exposure to doxorubicin, vincristine, methotrexate, or hydroxyurea. We have developed a highly sensitive matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS)-based genotyping approach to survey the C3435T SNP. Furthermore, mRNA expression was determined by real time reverse-transcribed polymerase chain reaction and doxorubicin sensitivity by a growth inhibition assay. Surprisingly, we did not find a significant correlation between C3435T homo- or heterozygote genotypes and MDR1 mRNA expression of cell lines or blood samples from patients and healthy donors. Furthermore, there was no relationship between the response of the cell lines to doxorubicin and the C3435T genotypes. Homo- or heterozygosity did not correlate to survival of patients in the Kaplan-Meier analysis. In conclusion, we do not have reason to assume that the C3435T SNP contributes to drug resistance of ALL and prognosis of ALL patients.

Antineoplastic Agents↗
PubMed2004

Thermodynamic analyses of the specific interaction between T:T mismatch base pair and mercury (II) cation: toward the efficient detection of single nucleotide polymorphism (1).

We examined the effect of mercury (II) cation on the thermal stability of heteroduplex and homoduplex. Addition of mercury (II) cation increased the melting temperature of heteroduplex containing T:T mismatch base pair by about 4 degrees C. The thermal stability of homoduplex and heteroduplexes containing other kinds of mismatch base pairs was not significantly changed by the addition of mercury (II) cation. Isothermal titration calorimetric study demonstrated that mercury (II) cation directly bound to T:T mismatch base pair in hcteroduplex at a molar ratio of 1:1. The binding constant and the enthalpy change for the binding of mercury (II) cation to T:T mismatch base pair was approximately 10(6) M(-1) and -6 kcal mol(-1), respectively. We conclude that mercury (II) cation directly binds to T:T mismatch base pair in heteroduplex with high affinity and specificity. Our results certainly support the idea that the addition of mercury (II) cation to T:T mismatch base pair in heteroduplex could be a convenient strategy for heteroduplex analysis and may eventually lead to progress in single nucleotide polymorphism genotyping.

Base Pair Mismatch↗