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PubMed2003

Single nucleotide polymorphism genotyping using locked nucleic acid (LNA).

Locked nucleic acid (LNA) is a new class of bicyclic high affinity DNA analogs. LNA-containing oligonucleotides confer significantly increased affinity against their complementary DNA targets, increased mismatch discrimination (delta Tm) and allow full control of the melting point of the hybridization reaction. LNA chemistry is completely compatible with the traditional DNA phosphoramidite chemistry and therefore LNA-DNA mixmer oligonucleotides can be designed with complete freedom for optimal performance. These properties render LNA oligonucleotides very well suited for SNP genotyping and have enabled several approaches for enzyme-independent SNP genotyping based on allele-specific hybridization. In addition, allele-specific PCR assays relying on enzymatically-enhanced discrimination can be improved using LNA-modified oligonucleotides. The use of LNA transforms enzyme-independent genotyping approaches into experimentally simple, robust and cost-effective assays, which are highly suited for genotyping in clinical and industrial settings.

Alleles↗
PubMed2006

[Association of single nucleotide polymorphisms and haplotypes in DNA repair gene XRCC1 with susceptibility of breast cancer].

OBJECTIVE: To examine the contribution of the three most common single nucleotide polymorphisms (SNPs) in XRCC1 gene, C26304T, G27466A and G28152A, to susceptibility of breast cancer in Chinese Han population. METHODS: In this population-based case control study, 84 cases with breast cancer and 252 controls, matched to the cases in terms of habitation and age (5 years), were genotyped for the XRCC1 C26304T, G27466A and G28152A polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. The haplotype distribution was estimated and compared by EH linkage software 1. 2. RESULT: The distribution of basic characteristics, such as age, alcohol drinking, the family history of malignancy in first and second relatives except cigarette smoking, were not significantly different between cases and controls. However, the percentage of ever or current smokers was significantly higher in cases (7.1%) than that in controls (2.0%). The distributions of allelotype and genotype of C26304T, G27466A and G28152A polymorphisms were also not significantly different between cases and controls. There was no significant association between the risk of breast cancer and these three SNPs of XRCC1 gene. The genetic linkage disequilibrium existed in these three polymorphic sites both in cases and controls, in which the CGG, CGA, CAG and TGG haplotypes were the most common. There was also no significant association of XRCC1 haplotype with risk of breast cancer. CONCLUSION: XRCC1 C26304T, G27466A and G28152A SNPs may not be associated with the susceptibility of breast cancer. The CGG, CGA, CAG and TGG haplotypes might be the most common haplotypes in Chinese Han population.

Adult↗
PubMed2006

Detection of T:T mismatch base pair by fluorescence spectral change upon addition of mercury (II) cation: toward the efficient analyses of single nucleotide polymorphism.

We have already found that mercury (II) cation specifically binds to T:T mismatch base pair in heteroduplex, which increases the melting temperature of heteroduplex involving T:T mismatch base pair by about 4 degrees C. This result shows that addition of the metal cation is a promising strategy for the mismatch base pair detection in heteroduplex, but UV melting to determine the melting temperature is time-consuming. In the present study, to develop a more convenient way for the mismatch base pair detection, we examined the fluorescence spectral change of fluorescent-labelled duplex upon addition of the metal cation. Addition of mercury (II) cation to the heteroduplex involving the T:T mismatch base pair significantly changed the fluorescence intensity, but no significant change in the fluorescence intensity was observed for the duplexes involving other base pairs. Our results certainly support the idea that the fluorescence spectral change upon the addition of the metal cation could be a convenient strategy for the mismatch base pair detection by the heteroduplex analysis, and may eventually lead to progress in SNP genotyping.

Base Pair Mismatch↗
PubMed2004

Linkage analysis using single nucleotide polymorphisms.

We performed multipoint linkage analysis using 83 markers from the SNP Consortium (TSC) SNP linkage map in 3 regions covering 190 cM previously scanned with microsatellite markers and found to be linked to type 2 diabetes. Since the average linkage disequilibrium present in the TSC SNP marker clusters is relatively low, we assumed the intracluster genetic distances were a reasonable small nonzero distance (0.03 cM) and performed linkage analysis using GENEHUNTER PLUS and ASM linkage analysis software. We found that for the pedigree structures and missing data patterns in our samples the average information content in all three regions and the LOD score curves in two regions obtained from the TSC SNP markers were similar to results obtained from microsatellite marker maps with 10 cM average spacing. We also give an algorithm which extends the Lander-Green algorithm to permit multipoint linkage analysis of clusters of tightly linked markers with arbitrarily high levels of intracluster linkage disequilibrium.

Chromosome Mapping↗
PubMed2002

Identification of snails within the Bulinus africanus group from East Africa by multiplex SNaPshot trade mark analysis of single nucleotide polymorphisms within the cytochrome oxidase subunit I.

Identification of populations of Bulinus nasutus and B. globosus from East Africa is unreliable using characters of the shell. In this paper, a molecular method of identification is presented for each species based on DNA sequence variation within the mitochondrial cytochrome oxidase subunit I (COI) as detected by a novel multiplexed SNaPshotTM assay. In total, snails from 7 localities from coastal Kenya were typed using this assay and variation within shell morphology was compared to reference material from Zanzibar. Four locations were found to contain B. nasutus and 2 locations were found to contain B. globosus. A mixed population containing both B. nasutus and B. globosus was found at Kinango. Morphometric variation between samples was considerable and UPGMA cluster analysis failed to differentiate species. The multiplex SNaPshotTM assay is an important development for more precise methods of identification of B. africanus group snails. The assay could be further broadened for identification of other snail intermediate host species.

Animals↗
PubMed2006

Relationship between single nucleotide polymorphism in TNF-alpha gene promoter region and inhibitory effects of triptolide on TNF-alpha production in peripheral blood mononuclear cells of healthy humans.

The relationship between tumour necrosis factor-alpha (TNF-alpha) gene polymorphism and inhibitory effects of triptolide on TNF-alpha production from peripheral blood mononuclear cells (PBMC) of healthy humans was investigated. Genomic DNA from 41 healthy people was typed for TNF-alpha--308 polymorphism by allele-specific polymorphism chain reaction (AS-PCR). The TNF-alpha concentration in the supernatant was measured by ELISA. The results showed that the production of TNF-alpha from TNF-alpha--308 non-G/G genotype PBMC was higher than that from TNF-alpha--308 G/G genotype PBMC after stimulated by LPS. Triptolide could lower the production of TNF-alpha from G/ G genotype PBMC, but had no effect on the level of TNF-alpha from non-G/G genotype PBMC. It was concluded that TNF-alpha gene polymorphism was related to the TNF-alpha production from triptolide-inhibited PBMC culture in healthy humans.

Adult↗
PubMed2001

Lack of an association of a single nucleotide polymorphism in the promoter of the matrix metalloproteinase-1 gene in Czech women with pregnancy-induced hypertension.

In preeclampsia the cytotrophoblast invasion of the decidual vessels is reduced. The endothelia in the decidual vessels may influence cytotrophoblast invasion and remodeling of decidual spiral arteries. The decidual endothelial cells from preeclamptic placentas produce less matrix metalloproteinase-1 (MMP1) than those from normal placentas. MMPs form a group of enzymes that are capable of degrading components of extracellular matrix. The present study investigated the prevalence and possible association of an insertion of guanine in the promoter of the MMP1 gene in pregnancy-induced hypertension, preeclampsia and eclampsia in the Czech population. This was a case-control study. No differences were observed in genotype frequencies between cases and controls. The insertion of the guanine in the promoter of the MMP1 gene does not appear to increase the risk of development of pregnancy-induced hypertension, preeclampsia and eclampsia.

Adolescent↗
PubMed2002

Potential for the 2G single nucleotide polymorphism in the promoter of matrix metalloproteinase to enhance gene expression in normal stromal cells.

The 1G/2G polymorphism of matrix metalloproteinase 1 (MMP-1) affects activity of the promoter in transient transfections, and has been associated with the incidence or invasiveness of five types of cancer. In light of these findings, and because stromal cells may contribute to tumor cell invasion, we used quantitative real-time reverse transcription-PCR to measure endogenous MMP-1 mRNA expression in 34 human foreskin fibroblasts homozygous or heterozygous for the 1G and 2G alleles. We measured basal, cytokine, and growth factor induced MMP-1 mRNA expression. The genotype of the MMP-1 promoter polymorphism was not predictive of mean MMP-1 mRNA expression. However, within the population of cell lines with at least one 2G polymorphism, there were more individuals with higher levels of MMP-1 mRNA after treatment with a cytokine or growth factors. Our data suggest that the presence of the 2G polymorphism does not significantly affect mean expression levels of a population but may increase the potential for an individual to have higher MMP-1 expression in response to growth factors and cytokines.

Alleles↗
PubMed2004

Detection of single nucleotide polymorphisms in the mannose-binding lectin gene using minor groove binder-DNA probes.

Structural point mutations in exon 1 at codons 52, 54 and 57 and a promotor polymorphism at -221 bp of the mannose-binding lectin (MBL) gene are associated with increased susceptibility to various infectious diseases. We developed a genotyping method based on the 5' nuclease (TaqMan) assay in combination with the use of minor-groove-binder (MGB) probes in screening for these mutations/polymorphisms. In contrast to conventional probes, MGB probes have a short length and can be used for detection of mutations that are in close proximity to each other, as is the case for the structural mutations in exon 1 of the MBL gene. Results obtained with the 5' nuclease assay using MGB probes were identical with results obtained with classical techniques such as restriction fragment length polymorphism, allele-specific PCR, and sequencing. In conclusion, the 5' nuclease assay using MGB probes is useful for large-scale screening of point mutations/polymorphisms, even when they are in close proximity.

DNA Primers↗
PubMed2005

Detection of functional single-nucleotide polymorphisms that affect apoptosis.

Human EBV-transformed B lymphocyte cell lines (LCLs) were used to measure the apoptotic response of individuals to gamma radiation. The responses form a normal distribution around a median of 35.5% apoptosis with a range of 12-58%. This heterogeneous response has a genetic basis. LCLs from Caucasian donors and African American donors form distinct distributions of apoptotic response; all of the 11 LCLs comprising the lowest responding group (exhibiting between 12-20% apoptosis) are from Caucasian donors. The assay is capable of detecting significant effects of SNPs in two genes, MDM2 and AKT1, whose products are involved in controlling the p53 pathway and cellular response to DNA damage, suggesting that these data and this assay can be used to identify novel SNPs in other genes whose products impact the cellular response to radiation. Finally, the LCLs in the lowest apoptotic response group have the highest concentration of AKT1 protein and all harbor a haplotype in AKT1 that is present in Caucasians but absent in African Americans.

Apoptosis↗
PubMed2001

The discovery of single-nucleotide polymorphisms--and inferences about human demographic history.

A method of historical inference that accounts for ascertainment bias is developed and applied to single-nucleotide polymorphism (SNP) data in humans. The data consist of 84 short fragments of the genome that were selected, from three recent SNP surveys, to contain at least two polymorphisms in their respective ascertainment samples and that were then fully resequenced in 47 globally distributed individuals. Ascertainment bias is the deviation, from what would be observed in a random sample, caused either by discovery of polymorphisms in small samples or by locus selection based on levels or patterns of polymorphism. The three SNP surveys from which the present data were derived differ both in their protocols for ascertainment and in the size of the samples used for discovery. We implemented a Monte Carlo maximum-likelihood method to fit a subdivided-population model that includes a possible change in effective size at some time in the past. Incorrectly assuming that ascertainment bias does not exist causes errors in inference, affecting both estimates of migration rates and historical changes in size. Migration rates are overestimated when ascertainment bias is ignored. However, the direction of error in inferences about changes in effective population size (whether the population is inferred to be shrinking or growing) depends on whether either the numbers of SNPs per fragment or the SNP-allele frequencies are analyzed. We use the abbreviation "SDL," for "SNP-discovered locus," in recognition of the genomic-discovery context of SNPs. When ascertainment bias is modeled fully, both the number of SNPs per SDL and their allele frequencies support a scenario of growth in effective size in the context of a subdivided population. If subdivision is ignored, however, the hypothesis of constant effective population size cannot be rejected. An important conclusion of this work is that, in demographic or other studies, SNP data are useful only to the extent that their ascertainment can be modeled.

Bias↗
PubMed2004

Molecular and functional differences induced in thrombospondin-1 by the single nucleotide polymorphism associated with the risk of premature, familial myocardial infarction.

A serine (Ser-700) amino acid rather than an asparagine (Asn-700) at residue 700 of thrombospondin-1 has been linked to an increased risk for development of premature, familial heart attacks. We now have identified both functional and structural differences between the Ser-700 and Asn-700 thrombospondin-1 variants. The Ser-700 variant increased the rate and extent of platelet aggregation and showed increased surface expression on platelets compared with the Asn-700 variant. These differences could be ascribed to an enhanced interaction of the Ser-700 variant with fibrinogen on the platelet surface and are consistent with a prothrombotic phenotype in Ser-700 individuals. The Ser-700 variant thrombospondin-1 was conformationally more labile than the Asn-700 variant as demonstrated by increased susceptibility to proteolytic digestion and enhanced susceptibility to unfolding by denaturants. These data suggest a potential molecular and cellular basis for a genetic risk factor associated with early onset myocardial infarction.

Asparagine↗
PubMed2005

Single nucleotide polymorphisms in the corticotrophin-releasing hormone and pro-opiomelancortin genes are associated with growth and carcass yield in beef cattle.

A single nucleotide polymorphism (SNP) in the corticotrophin-releasing hormone gene (CRH C22G) alters the fourth amino acid in the signal sequence from proline to arginine. Two other SNPs (CRH A145G and C240G) occur in the propeptide region at residue positions 45 and 77, respectively, that result in serine/asparagine and histidine/aspartic acid substitutions respectively. These SNPs, as well as SNPs in pro-opiomelancortin (POMC), leptin (LEP) and melanocortin-4 receptor (MC4R), were evaluated for associations with average daily gain, end-of-test rib-eye area, shipping weight and hot carcass weight in a group of 256 steers using a general linear model. The CRH C22G SNP was associated with end-of-test rib-eye area (P < 0.034) and hot carcass weight (P < 0.0015). The SNP in POMC was associated with shipping weight (P < 0.0078) and hot carcass weight (P = 0.006) while it approached significance for average daily gain (P < 0.07). The SNP in MC4R approached significance for hot carcass weight (P < 0.085) while no significance was observed between the leptin SNP and the above listed traits. Because both CRH and POMC regulate appetite, potential interaction effects between these two genes were assessed. The absence of an interaction effect between CRH and POMC with hot carcass weight suggests that these genes act independently to increase carcass yield. These gene effects used singularly or together could result in an economic benefit to the beef industry.

Animals↗
PubMed2003

A single nucleotide polymorphism in the Emp3 gene defines the H4 minor histocompatibility antigen.

Minor histocompatibility antigens (minor H antigen) elicit strong T-cell-mediated responses during both graft rejection and graft versus leukemia (GvL) among MHC-matched individuals (where MHC is major histocompatibility complex). Employing expression-cloning methodology, we have identified a cDNA clone, MI-35, encoding the immunodominant H4b minor H antigen within the classical mouse H4 complex. The minimal antigenic epitope derived from H4b presented on Kb class I MHC is SGIVYIHL (SYL8) and the polymorphism is due to C-->T nucleotide modification in p3 resulting in the change of threonine (ACT) to isoleucine (ATT). The results presented here demonstrate that amino acid variation in the allelic epitopes results in the low abundance of H4a peptide. The differential peptide copy number resulted in an immunodominant cytotoxic T cells (CTL) response directed against H4b while the anti-B6 response directed against H4a was easily dominated. These results provide a molecular mechanism for the H4 minor H antigen and suggest a novel mechanism by which alloantigenic disparity caused by conservative amino acid changes can be augmented by posttranslational antigen processing events.

Amino Acid Sequence↗
PubMed2002

The discovery and confirmation of single nucleotide polymorphisms in the human p53R2 gene by EST database analysis.

The human expressed sequence tag (EST) database provides a wealth of resources, which can be used to rapidly screen for potential polymorphisms in proteins of physiological interest. The human p53R2 gene, a recently identified ribonucleotide reductase, plays an important role in DNA repair and is involved in the pathway of p53 activity in response to the presence of DNA damage. On the basis of the alignment of human EST sequences, we identified three candidate polymorphisms at nt 2752, 2759 and 4696 in the 3'-untranslated region of the p53R2 gene. The presence of these polymorphisms was confirmed in a Caucasian population (n = 82) by allele-specific PCR and PCR/restriction fragment length polymorphism analyses. The rare allele frequency at position 4696 (15.5%) is higher than either rare allele frequency at position 2752 or 2759 (6 and 6%). Our results suggest that the human EST data may serve as a valuable source for the rapid identification of genetic variation.

3' Untranslated Regions↗
PubMed2004

Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma.

Toll-like receptor 6 (TLR6) is one of a series of highly conserved innate immune receptors. We resequenced TLR6 in DNA samples from 24 African Americans, 23 European Americans, and 24 Hispanic Americans, identifying 53 SNPs, 22 with an allele frequency >5%. Significant differences in SNP frequencies among the three populations were noted. In all, 11 SNPs caused amino-acid changes, including one with a frequency >5% in all three populations. Utilizing this SNP (Ser249Pro), we performed exploratory nested case-control disease-association studies, including one involving 56 African Americans with asthma and 93 African American controls. The minor allele of this SNP was associated with decreased risk for asthma (odds ratio 0.38, 95% CI 0.16-0.87, P=0.01), an effect consistent with the known biology of the toll-like receptors. Although replication of this finding in other, larger samples is needed, variation in TLR6 may have relevance to the pathogenesis of immunologically mediated diseases.

Asthma↗
PubMed2006

Disparate distribution of 16 candidate single nucleotide polymorphisms among racial and ethnic groups of pediatric heart transplant patients.

BACKGROUND: Allograft failure in African-Americans remains higher than in Caucasians. Single nucleotide polymorphisms (SNPs) have been associated with altered allograft outcomes. METHODS: In this multi-center study we compared SNP frequencies in 364 pediatric heart recipients from three ethnic/racial groups: Caucasian (n = 243), African-American (n = 39), and Hispanic (n = 82). The target genes were: tumor necrosis factor-alpha, interleukin (IL)-10, IL-6, interferon (IFN)-gamma, vascular endothelial growth factor (VEGF), transforming growth factor-beta1, Fas, FasL, granzyme B, ABCB1, CYP3A5. RESULTS: Compared to Caucasians, African-Americans exhibited a higher prevalence of genotypes associated with low expression of IFN-gamma (24% vs. 45.7%, P < 0.001) and IL-10 (33% vs. 57.1%, P = 0.052). African-Americans also exhibited an increased prevalence of high IL-6 (82.9% vs. 38.1%; P < 0.001). VEGF -2578 C/C and -460 C/C genotypes were found more frequently in African-Americans and Hispanics as compared to Caucasians (P < 0.001). G/G genotype of Fas and T/T genotype of FasL were expressed more often by African-American recipients. The prevalence of Granzyme B (-295A/G) genotype was differentially distributed in the three groups. Compared with Caucasians, African-Americans were twice as likely to carry the ABCB1 2677 G/G genotype (78.6% vs. 33.7%, P < 0.0025), and they were more frequent carriers of the CYP3A5 *1/*1 genotype (35.7% vs. 0.6% in Caucasians and 7.2% in Hispanics; P < 0.001). CONCLUSION: African-Americans have a genetic background that may predispose to proinflammatory/lower regulatory environment, reduced drug exposure and immunosuppressive efficacy. In this ongoing multicenter study, these gene polymorphisms differences among ethnic/racial groups are being documented so that therapeutic strategies can be devised to optimize outcomes for pediatric transplant recipients.

Adolescent↗
PubMed2001

Single nucleotide polymorphism in prohibitin 3' untranslated region and breast-cancer susceptibility.

The RNA encoded by the 3' untranslated region of the prohibitin gene arrests cell proliferation by blocking the transition between the G1 and S phases of the cell cycle. The product of a variant allele (T allele) is inactive. We did a case-control study of prohibitin genotype in 205 women with breast cancer and 1046 healthy controls. The results showed an association between the T allele and breast cancer in women who reported a first-degree relative with the disease (odds ratio 2.5, p=0.005). An even stronger association was found in a subset of women diagnosed at or before age 50 years (4.8, p=0.003). These data suggest that prohibitin genotyping has value in assessing risk of breast cancer in women aged 50 years or younger with at least one first-degree relative with the disease.

Adult↗