Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “single nucleotide polymorphisms”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 991 records · Page 55Linked to original sources
PubMed2004

Single-nucleotide polymorphisms of vascular endothelial growth factor in psoriasis of early onset.

Vascular endothelial growth factor (VEGF)--a stimulus of angiogenesis--is produced by epidermal keratinocytes, and elevated levels have been found in plaques of psoriasis. Polymorphisms in the VEGF gene regulate production of VEGF. We postulated that patients with psoriasis may have altered systemic expression of VEGF consequent upon programming at the genomic level. We investigated the genetic basis of VEGF expression in patients with type 1 (onset before age 40 y) chronic plaque psoriasis compared to healthy controls and also measured plasma levels of VEGF and its receptors flt-1 and KDR. Patients with severe disease, and those with onset of psoriasis between the ages of 20 and 40 y showed significantly increased frequency of the +405 CC genotype (p=0.04 and p=0.02) and the C allele (p=0.03 and p=0.02), respectively, compared to healthy controls. Plasma levels of VEGF and flt-1 were significantly detectable in patients with psoriasis compared with controls (p<0.001); by contrast, mean plasma levels of KDR in psoriatic patients were comparable with controls. These results suggest that alterations in the biology of VEGF may be involved in the pathogenesis of psoriasis. VEGF, flt-1, and KDR could provide attractive targets for future psoriasis therapy.

Adolescent↗
PubMed2003

Methodologic quality and genotyping reproducibility in studies of tumor necrosis factor -308 G-->A single nucleotide polymorphism and bacterial sepsis: implications for studies of complex traits.

OBJECTIVE: Studies of genetic associations with common diseases, such as between cytokine gene polymorphisms and severe bacterial sepsis, have reached conflicting conclusions. Failure to follow methodologic standards may have contributed to discordant findings. The -308 G-->A transition in the tumor necrosis factor-alpha promoter has been genotyped by a variety of methods. Based on our observation of genotyping inaccuracies, we sought to determine whether published studies followed a series of acceptable methodologic standards and whether failure to follow the standard of genotyping reproducibility could lead to erroneous conclusions about gene-disease associations. DESIGN: Systematic review and reanalysis of banked genetic material. We applied a published series of seven methodologic standards to five reports of the association between this variant and bacterial sepsis. We then studied the accuracy of restriction fragment length polymorphism for the -308 site using DNA from a cohort of injury victims. SETTING: Surgery research laboratory. MEASUREMENTS AND MAIN RESULTS: We observed that methodologic quality was not uniform and that reproducibility of genotyping was infrequently met. In our subjects, we found that 4 of 46 heterozygotes analyzed by restriction fragment length polymorphism were actually GG-homozygotes (9% misclassified) according to alternative genotyping methods. CONCLUSIONS: Failure to confirm genotype may have led to conclusions that this polymorphism is not associated with sepsis or outcome. Our observations have implications for the conduct and evaluation of studies of complex genetic disease.

Genetic Techniques↗
PubMed2004

Development of the single nucleotide polymorphism marker of the wheat Lr1 leaf rust resistance gene.

The range of publicly available data on plant nucleotide sequences opens a new possibility in the design of SNP assays. The purpose of this study was to identify point mutations in genomic sequences closely linked to the Lr1 leaf rust resistance gene, and to develop SNP markers based on primer extension (SNuPE) facilitating efficient marker-based selection procedures, e.g. the pyramiding of resistance genes. Studies were performed on the panel of 37 wheat cultivars, the set of 41 Thatcher near-isogenic lines of spring wheat and on the 21 individuals derived from doubled-haploid (DH) lines derived from 'Henika' (Lr1) x 'IPG-SW-14'. A minisequencing reaction run with Lr1_98F primer detected four genotypes (T, C+T, C and "null") in the set of all Triticum aestivum varieties tested. In this study, it turned out that the T allele is associated with the Lr1 gene in a wide genetic background.

Base Sequence↗
PubMed2002

Single nucleotide polymorphisms in the 3' untranslated region of vascular endothelial growth factor gene in Japanese population with or without renal cell carcinoma.

We investigated native Japanese subjects whether C702T, C936T and G1612A polymorphisms in the 3' untranslated region (3'-UTR) of vascular endothelial growth factor (VEGF) gene are associated with the risk of renal cell carcinoma (RCC). Genomic DNAs from 145 RCC patients and 145 healthy controls were examined by polymerase chain reaction-based restriction fragment length polymorphism. Variant allele frequencies of C702T, C936T and G1612A were 0.00, 0.20 and 0.13 in the controls, respectively. The C702T and G1612A allele frequencies were significantly different between the Japanese population and the Caucasian population reported elsewhere. For each of C936T and G1612A polymorphisms, there was no statistically significant difference in the distribution of genotype frequencies between the cases and controls. Odds ratios and 95% confidence intervals computed by logistic regression analyses were not statistically significant. Stratification for the RCC cases according to pathological cell subtype, grade or stage failed to reveal any significant heterogeneity with respect to the genotype of each VEGF polymorphism. We revealed that there are significant ethnic differences in the C702T and G1612A allele frequencies, but suggested that C702T, C936T and G1612A polymorphisms in the 3'-UTR of VEGF gene are not associated with the risk of RCC, at least in Japanese population.

3' Untranslated Regions↗
PubMed2002

Single nucleotide polymorphisms of estrogen receptor alpha in human renal cell carcinoma.

Estrogens and their receptors (ERs) have been shown to play a role in various cancers. We hypothesize that polymorphisms and genotypic changes of the ERalpha gene are involved in renal cell carcinoma. To test this hypothesis, DNA samples from 113 cases of human renal cell cancer were analyzed by sequence-specific polymerase chain reaction to determine the genotypic frequency of six different polymorphic loci on ERalpha gene (codon 10 T-->C, codon 87 G-->C, codon 243 C-->T, codon 325 C-->G, codon 594 G-->A, and intron 1 C-->T). The relative risk of variant genotype was calculated by comparison with 200 healthy controls. The results of this study demonstrate that the distribution of genotypes on codon 10 differs between renal cancer patients and healthy normal controls (p<0.05). The relative risk of the genotype 10C/C was calculated as 2.51. No differences in genotypes were observed at all other loci. We also analyzed DNA from pairs of cancerous and normal tissues from 96 cases of human renal cell cancer to characterize genotypic changes at these loci. Genotypic changes were detected in nine cancer samples on exon 1 (codons 10 and 87) of ERalpha, although none were detected at other regions. The present study demonstrates for the first time that codon 10 polymorphism on exon 1 of ERalpha may be involved in renal cancer risk.

Carcinoma, Renal Cell↗
PubMed2003

The impact of single nucleotide polymorphisms of the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI antigen levels in healthy children and pediatric oncology patients.

The thrombin activatable fibrinolysis inhibitor (TAFI) influences the pathways regulating fibrin formation and deposition. The enormous TAFI plasma level variability present in adults may be explained by a combination of two polymorphisms in the TAFI gene (+1542C>G; 505G>A). We aimed to correlate these two polymorphisms with plasma TAFI antigen concentrations in healthy children and pediatric oncology patients with and without venous thrombosis who were supplied with Broviac central venous catheters. Polymorphisms were detected by restriction fragment length polymorphism (RFLP) analysis of polymerase chain reaction (PCR) amplification, whereas TAFI concentration was determined using a commercial enzyme-linked immunosorbent assay (ELISA). Samples from 57 controls and 67 pediatric patients (11 venous thrombotic complications) were studied. TAFI levels in healthy children and patients were not influenced by gender or age. Compared with the 505GG carriers (wild type), 505AA carriers as well as heterozygous 505GA carriers each exhibited significantly higher TAFI antigen concentrations. In contrast, the lowest TAFI levels were detected in homozygous carriers of the +1542GG polymorphism. A combination of the genotype 505AA (homozygous carrier) and +1542CC (wild type) was present in 13 probands and resulted in the highest TAFI levels. Although in oncologic patients the risk of thrombosis was markedly increased by the heterozygous factor V 1691G>A mutation, the two TAFI polymorphisms investigated exerted no thrombogenic influence.

Age Factors↗
PubMed2005

Sequence context analysis of 8.2 million single nucleotide polymorphisms in the human genome.

We analyzed n-mers (n=3-8) in the local environment of 8,249,446 human SNPs and compared their distribution with that in the genome reference sequences. The results revealed that the short sequences, which contained at least one CpG dinucleotide, occurred more frequently in the local SNP sequences than in the genome sequences. To exclude the hypermutability effect of the methylated CpG dinucleotides on the sequence context of SNPs, we examined the distribution patterns for each of the six categories of substitution. We observed the similar pattern (i.e., CpG-containing n-mers vs. non-CpG-containing n-mers) in SNP categories A/G, C/T and C/G but the opposite pattern in category A/T. We next identified 34,928 putative CpG islands in the human genome and located 133,591 SNPs within these islands. In the CpG islands, CpG SNPs were 3.92-fold less prevalent relative to the presence of CpG dinucleotides. Conversely, in the human genome, the frequency of CpG dinucleotides at the polymorphic sites was 6.09 times that in the genome reference sequences. These results support the previous views of mutational suppression at the CpG sites in the CpG islands and hypermutability of the methylated CpG dinucleotides that are prevalent in the non-CpG island sequences in the human genome. Our study represents a comprehensive investigation of the sequence context of SNPs in the human genome and in human CpG islands.

Base Composition↗
PubMed2006

Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function.

BACKGROUND: Hereditary mixed polyposis syndrome (HMPS) is characterised by colonic polyps of mixed histological types that are autosomal dominantly inherited and eventually lead to colorectal cancer (CRC). Study of the molecular basis of HMPS will enhance our knowledge of the genetic basis of the mixed polyposis-carcinoma sequence in both hereditary and sporadic CRC. METHODS/RESULTS: We performed a genomewide linkage search on 15 members of a three-generation HMPS family using the GeneChip Human Mapping 10K Array and identified a 7 cM putative linkage interval on chromosome 10q23. Subsequently, 32 members from two HMPS families were typed with nine microsatellite markers spanning the region and the linkage was confirmed with a maximum multi-point logarithm of the odds (LOD) score of 4.6 (p<0.001). The 10q23.1-10q23.31 haplotypes segregate with the disease in both families. We screened for mutations in four candidate genes within the linkage region and identified an 11 bp deletion in the bone morphogenesis protein receptor 1A (BMPR1A) gene in one family. CONCLUSIONS: Our results indicate that BMPR1A mutation accounts for HMPS. The data suggest that inactivating BMPR1A can initiate colorectal tumourigenesis via the mixed polyposis-carcinoma sequence.

Adenomatous Polyposis Coli↗
PubMed2004

Increased power for case-control studies of single nucleotide polymorphisms through incorporation of family history and genetic constraints.

Association studies assessing the relationship between a common polymorphism and disease generally compare allele frequencies in cases and controls. In such studies, a limited amount of information is often available about disease incidence in relatives. We hypothesised that more power could be obtained by incorporating the constraints imposed by the properties of a genetic polymorphism, and that power could be further increased by using family history (FH) information. We have developed a simple method for incorporating basic FH information from cases and controls into a genetic association study, assuming Hardy-Weinberg equilibrium (HWE) in the general population. We model the likelihood of the data in terms of the allele frequency and its relative risk (RR) of disease and perform likelihood ratio tests. Using simulations, we compared the power to detect an association using this approach with that of a 2 x 2 chi-squared test, for a range of disease models. The sample size required to detect an association is consistently lower for tests including the HWE constraint, with the largest reduction for more common alleles. The required sample size is reduced further by stratifying by FH. Stratifying by FH also improves the precision of the RR estimates. In situations where basic FH data are already available, this study shows that efficiency can be improved by the inclusion of even this small amount of extra information.

Alleles↗
PubMed2006

Single nucleotide polymorphisms and functional analysis of MxA promoter region in multiple sclerosis.

OBJECTIVE: Interferons (IFNs)-inducible myxovirus resistance protein A (MxA) has recently been used as an indirect marker of neutralizing antibody against IFN in patients with multiple sclerosis (MS). On the other hand, MxA inhibits the replication of viruses by means of modifying cellular function, including apoptotic pathway. Our objective is to investigate the genetic and pathological role of MxA in patients with MS. METHODS: We examined SNPs of MxA promoter region in 67 patients with MS. Moreover, to elucidate the functional roles of SNPs, we conducted Luciferase assay with pGL3-basic vector including patient-derived or artificially mutated MxA promoter region. RESULTS: A significantly higher frequency of the haplotype with -88T and -123A, which correlates with over-expression of MxA, was observed in MS. Moreover, we elucidated novel findings showing that nt -88 played a leading part with type I IFNs and that nt -123 played the same role independently without type I IFNs, respectively. CONCLUSION: SNPs on MxA promoter region may play an important role in the pathophysiology of MS and provide a novel strategy for the therapeutic resolutions of MS.

Adult↗
PubMed2004

Patterns of co-occurrence of three single nucleotide polymorphisms of the 5,10-methylenetetrahydrofolate reductase gene in kidney transplant recipients.

BACKGROUND: Recently, a new mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) encoding gene was first described (1793G > A). Only few reports have studied the prevalence of this polymorphism, especially in combination with other MTHFR mutations (677C > T, 1298A > C). METHODS: We cross-sectionally identified the novel MTHFR 1793G > A polymorphism in 730 kidney transplant recipients. MTHFR 677C > T and 1298A > C were also assessed and the frequency of each was described individually as well as in cross-tabulation with the other MTHFR genotypes. The expected number of patients for each MTHFR genotype combination was calculated and contrasted with the observed numbers. Fisher's exact test was used for statistical inference. RESULTS: The allelic frequency of MTHFR 1793G > A was 0.052. Seventy-two patients (9.9%) were heterozygous and two patients (0.3%) were homozygous. From the cross-tabulations, we identified 53 patients (expected: 33.6) with the MTHFR 1298AC/1793GA genotype and 17 patients (expected: 6.7) with the MTHFR 1298CC/1793GA genotype. Furthermore, we found two patients with double homozygosity for MTHFR 1793G > A and MTHFR 1298A > C (MTHFR 1793AA/1298CC genotype). The frequencies of these genotype combinations were substantially larger than could be expected (P < 0.001). CONCLUSIONS: These findings suggest a selection or survival advantage for individuals with combined MTHFR 1793G > A and MTHFR 1298A > C genotypes, possibly owing to a mutually stabilizing effect on MTHFR enzyme activity.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed2003

Direct detection of single nucleotide polymorphism (SNP) with genomic DNA by the ferrocenylnaphthalene diimide-based electrochemical hybridization assay (FND-EHA).

A ferrocenylnaphthalene diimide-based electrochemical hybridization assay (FND-EHA) was applied to the direct detection of a C-to-G transition in a codon (TCA) for Ser-447 of the human lipoprotein lipase (LPL) gene, which resulted in the termination of the LPL protein there. Either one of two 13-meric oligonucleotide probes, S447 WT and S447X MT, representing sequences complementary to those of the wild type (WT) and mutated (MT) forms, was immobilized on a gold electrode, followed by hybridization with chromosomal DNA extracted from human leukocytes under the condition in which both WT- and MT-type sequences can form a duplex. These two electrodes were soaked in an electrolyte containing FND under a condition [0.1 M HOAc/KOAc (pH 5.6) containing 0.1 KCl and 0.05 mM FND at 40 degrees C], in which only the MT duplex could undergo dissociation. FND was concentrated in proportion to the amount of the duplex formed on the electrode to give rise to a current signal. The electrochemical signal ratios obtained for WT/WT, WT/MT and MT/MT were close to the theoretical 2:1:0 with the S447 WT-modified electrode, and was again close to 0:1:2 with the S447X MT-modified one.

Base Sequence↗
PubMed2005

Disentangling linkage disequilibrium and linkage from dense single-nucleotide polymorphism trio data.

Parent-offspring trios are widely collected for disease gene-mapping studies and are being extensively genotyped as part of the International HapMap Project. With dense maps of markers on trios, the effects of LD and linkage can be separated, allowing estimation of recombination rates in a model-free setting. Here we define a model-free multipoint method on the basis of dense sequence polymorphism data from parent-offspring trios to estimate intermarker recombination rates. We use simulations to show that this method has up to 92% power to detect recombination hotspots of intensity 25 times background over a region of size 10 kb typed at density 1 marker per 2.5 kb and almost 100% power to detect large hotspots of intensity >125 times background over regions of size 10 kb typed with just 1 marker per 5 kb (alpha = 0.05). We found strong agreement at megabase scales between estimates from our method applied to HapMap trio data and estimates from the genetic map. At finer scales, using Centre d'Etude du Polymorphisme Humain (CEPH) pedigree data across a 10-Mb region of chromosome 20, a comparison of population recombination rate estimates obtained from our method with estimates obtained using a coalescent-based approximate-likelihood method implemented in PHASE 2.0 shows detection of the same coldspots and most hotspots: The Spearman rank correlation between the estimates from our method and those from PHASE is 0.58 (p < 2.2(-16)).

Computer Simulation↗
PubMed2006

Single nucleotide polymorphisms in DNA repair genes and basal cell carcinoma of skin.

In addition to environmental exposures like UV radiation and, in some cases, arsenic contamination of drinking water, genetic factors may also influence the individual susceptibility to basal cell carcinoma of skin (BCC). In the present study, 529 cases diagnosed with BCC and 533 controls from Hungary, Romania and Slovakia were genotyped for one polymorphism in each of seven DNA repair genes. The variant allele for T241M (C>T) polymorphism in the XRCC3 gene was associated with a decreased cancer risk [odds ratio (OR), 0.73; 95% confidence interval (CI), 0.61-0.88; P = 0.0007, multiple testing corrected P = 0.004]. The risk of multiple BCC was significantly lower among variant allele carriers than in non-carriers (P = 0.04). Men homozygous for the C-allele for E185Q (G>C) polymorphism in the NBS1 gene showed an increased BCC risk (OR, 2.19; 95% CI, 1.23-3.91), but not women (OR, 0.84; 95% CI, 0.49-1.47). In men, the age and nationality adjusted OR for the genotype CC (XRCC3)/CC (NBS1) was 8.79 (95% CI, 2.10-36.8), compared with the genotype TT (XRCC3)/GG (NBS1). The data from this study show overall risk modulation of BCC by variant allele for T241M polymorphism in XRCC3 and gender-specific effect by E185Q polymorphism in NBS1.

Adolescent↗
PubMed2006

Single-nucleotide polymorphisms of VEGF gene are associated with risk of congenital valvuloseptal heart defects.

BACKGROUND: Disturbed vascular endothelial growth factor (VEGF) production during early heart morphogenesis causes endocardial cushion malformation, which results in congenital heart disease (CHD). We tested whether functional VEGF -460T/C and +405G/C polymorphisms that have an impact on VEGF levels were associated with CHD. METHODS: Dried blood samples were collected from 102 CHD children and 112 healthy control neonates. Genotyping was done with polymerase chain reaction-restriction fragment length polymorphism (VEGF +405G/C) and real-time polymerase chain reaction methods (VEGF -460T/C). RESULTS: VEGF -460C allele frequency was similar in control and CHD subjects. VEGF +405C allele was less prevalent in controls than in CHD subjects (0.21 vs 0.42, P < .001). Having VEGF +405C presented increased risk for CHD (odds ratio [OR] 1.72, 95% CI 1.32-2.26). VEGF -460CT/+405CC allele associations did not occur in controls but in CHD patients (0% vs 13%, OR 2.26, 95% CI 1.93-2.64), whereas -460CT/+405GG allele association was more prevalent in controls (32% vs 16%, OR 0.58, 95% CI 0.37-0.89). CONCLUSIONS: VEGF gene and allele associations may be associated with increased risk of CHD.

Carrier State↗
PubMed2001

A single nucleotide polymorphism in the matrix metalloproteinase-1 (MMP-1) promoter influences amnion cell MMP-1 expression and risk for preterm premature rupture of the fetal membranes.

Interstitial collagen gives fetal membranes tensile strength, and membrane rupture has been attributed to collagen degradation. A polymorphism at -1607 in the matrix metalloproteinase-1 (MMP-1) promoter (an insertion of a guanine (G)) creates a core Ets binding site and increases promoter activity. We investigated whether this polymorphism is functionally significant for MMP-1 expression in amnion cells and whether it is associated with preterm premature rupture of the membranes (PPROM). The 2G promoter had >2-fold greater activity than the 1G allele in amnion mesenchymal cells and WISH amnion cells. Phorbol 12-myristate 13-acetate (PMA) increased mesenchymal cell nuclear protein binding with greater affinity to the 2G allele. Induction of MMP-1 mRNA by PMA was significantly greater in cells with a 1G/2G or 2G/2G genotype compared with cells homozygous for the 1G allele. When treated with PMA, the 1G/2G and 2G/2G cells produced greater amounts of MMP-1 protein than 1G/1G cells. A significant association was found between fetal carriage of a 2G allele and PPROM. We conclude that the 2G allele has stronger promoter activity in amnion cells, that it confers increased responsiveness of amnion cells to stimuli that induce MMP-1, and that this polymorphism contributes to the risk of PPROM.

Amnion↗
PubMed2006

Cytokine single nucleotide polymorphisms in Iranian patients with pulmonary tuberculosis.

BACKGROUND: Several genes coding for different cytokines may affect host susceptibility to tuberculosis. METHODS: In the present study, the allele and genotype frequencies of a number polymorphic genes coding for cytokines or cytokine receptors were investigated in Iranian patients with pulmonary tuberculosis (PTB). RESULTS: From the IL-1 cluster, a positive, significant difference was found at position -889, where the T/T genotype was over represented in PTB patients (p = 0.01); a positive, significant increase was found in the IL1R PstI 1970 C/C genotype, where the C allele was over represented in the PTB patients (p = 0.01). A significant negative association at codon 10 TGF-beta, T allele, was shown in our patients and the C allele and C/C genotype were over represented in the PTB patients (P<0.005). For TNF-alpha at position -238, we found a negative association for the G/A genotype and a positive association for the G/G genotype (p = 0.0009). Significant negative associations at position -590 IL-4, T allele and the T/T genotype were shown in our patients (p = 0.0007); also, the C allele and T/C genotype were significantly increased in our patients (P<0.05). With IL-6 at -174, G/G increased and G/C decreased significantly in the patients (P<0.005). CONCLUSION: Pro-inflammatory cytokines such as TNF-alpha and TGF-beta seem to be decreased, and IL-6 increased in PTB patients.

Case-Control Studies↗
PubMed2004

Maternal and fetal single nucleotide polymorphisms in the epoxide hydrolase and gluthatione S-transferase P1 genes are not associated with pre-eclampsia in the Coloured population of the Western Cape, South Africa.

Oxidative stress is thought to play an important role in the pathophysiology of pre-eclampsia. A defect in certain enzymes responsible for detoxification may cause prolonged exposure to reactive by-products and contribute to maternal endothelial as well as placental damage. Two polymorphisms affecting the function of the biotransformation enzymes epoxide hydrolase and glutathione S-transferase P1 were shown previously to be associated with pre-eclampsia in a Dutch population. The aim of this study was to determine if these two polymorphisms (maternal or fetal) contribute to pre-eclampsia in an anthropologically distinct population (the Western Cape region of South Africa) with a high incidence of the disease. Genomic DNA of mother - infant pairs with severe pre-eclampsia (n = 144), a population control group (n = 156) and control mother - infant pairs with uncomplicated pregnancy outcome (n = 45) were analysed for the EPHX and GSTP1 polymorphisms by polymerase chain reaction amplification and restriction enzyme digestion. Each polymorphism had a similar distribution in case and control subjects (mother and infant). The Val105/Val105 genotype of GSTP1 occurred at a higher frequency than reported for other populations. Neither maternal nor fetal EPHX Tyr113His and GSTP1 Ile105Val polymorphisms appear to contribute significantly to the pathophysiology of pre-eclampsia in the Coloured population of the Western Cape region of South Africa.

Alleles↗