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PubMed2006

High-resolution characterization of linkage disequilibrium structure and selection of tagging single nucleotide polymorphisms: application to the cholesteryl ester transfer protein gene.

Full characterization of intragenic variation may improve candidate gene associations. This study selected tagging (t) single nucleotide polymorphisms (SNPs) to comprehensively represent genetic variability in the cholesteryl ester transfer protein (CETP) gene. Nineteen SNPs were identified in 50 unrelated individuals in the SNP discovery phase, and 13 intronic SNPs were added from the literature. These 32 SNPs were genotyped in 339 apparently healthy individuals and 190 coronary artery disease (CAD) patients. Using phased haplotypes, linkage disequilibrium (LD) structure was characterized and tSNPs selected using a principal component analysis (PCA) method. In healthy individuals, seven LD groups were identified that accounted for 93.4% of the observed genetic variation. These LD groups highlighted a complex LD structure for CETP, including both recombination and mutation, and eleven tSNPs were selected. Among CAD patients the results were essentially the same. Results from PCA using diploid genotype data were reasonably comparable. Finally, the selected tSNPs successfully represented the association evidence discovered for all of the other SNPs studied. This study provides an optimal set of tSNPs for association analyses of CETP. The observed complexity of LD structure highlights the importance of using methods, such as PCA, that allow for multiple dynamics in intragenic LD structure.

Aged↗
PubMed2001

Single nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene are common in US Caucasian and Hispanic American populations.

To investigate the prevalence of the C677T and A1298C single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in Caucasian and Hispanic populations, EDTA-anticoagulated whole blood specimens were collected from a total of 100 random patients, 50 Caucasians and 50 Hispanics of Puerto Rican dissent. The prevalence of the two MTHFR SNPs was determined by polymerase chain reaction (PCR) mediated restriction fragment length polymorphism analysis. In the Caucasian population, homozygosity for the MTHFR A1298C SNP was detected in 4% (2/50) of the individuals tested, while 42% (21/50) were heterozygous for this SNP. Among Hispanics, 4% (2/50) were homozygous and 38% (19/50) heterozygous for the A1298C SNP. Homozygosity for the C677T MTHFR SNP was detected in 16% (8/50) and 10% (5/50) of Caucasians and Hispanics, respectively. In this study, the frequency of the C677T heterozygotes was very high at 56% (28/50) and 52% (26/50) Caucasians and Hispanics, respectively. C677T and A1298C are common SNPs in the MTHFR gene. The high prevalence of these SNPs in both Caucasian and Hispanic populations demonstrates the possibility of compounding effects of these SNPs in the pathogenesis of human diseases. While subgroups of patients may exhibit some clinical phenotype linked to these SNPs, our analysis demonstrates the need for careful interpretation of SNP data in the context of population screening.

DNA↗
PubMed2005

A comparison between microsatellite and single-nucleotide polymorphism markers with respect to two measures of information content.

Using the Genetic Analysis Workshop 14 (GAW14) simulated dataset, we compare microsatellite and single-nucleotide polymorphism (SNP) markers in terms of two measures of information content, the traditional entropy-based information content measure, and a new "relative information" measure. Both attempt to measure the amount of information contained in the markers about the identity-by-descent (IBD) sharing among relatives. The performance of the two information measures are compared based on their variability and ability to predict change in the LOD score (Delta LOD) as map density increases for SNP markers. Although in a linked region, LOD scores are correlated with measures of information, we observe that none of the measures predict the LOD score itself very well. In an unlinked region, the LOD score is not related to either measures of information. The information content of microsatellite markers with 7.5-cM spacing is slightly higher than that of SNP markers with 3-cM spacing. At these map densities, microsatellites are found to be uniformly more informative than SNPs irrespective of their level of heterozygosity. For SNPs, we found that as the level of heterozygosity increases, the information content increases. As reported in all other previous studies, we also found that high-density SNPs have higher information content compared to low-density microsatellites. Performance of both the two information measures considered here are similar, but the relative information measure predicts Delta LOD as marker density increases better than the traditional entropy-based information measure.

Genetic Markers↗
PubMed2003

Single nucleotide polymorphisms in promoter of angiotensin II type 1 receptor gene associated with essential hypertension and coronary heart disease in Chinese population.

AIM: To discover single nucleotide polymorphisms (SNPs) in the promoter region of angiotensin II type 1 receptor (AT1) gene and evaluate their associations with the occurrence of essential hypertension (EH) and coronary heart disease (CHD) in Chinese Han population. METHODS: SNPs detection was performed by PCR-sequencing. The genotype was determined by the same method in a total number of 473 unrelated patients including 160 EH cases, 128 CHD cases, and 185 EH combined with CHD cases as well as 160 healthy controls. RESULTS: Six SNPs were discovered in the promoter region of AT1 gene. -810A/T was almost in completely linkage disequilibrium with -713G/T, -214A/C, -213G/C, and -153A/G polymorphisms. No statistically association was found in our population between -810A/T polymorphism and EH, the association of -810A allele and CHD was of borderline significant (chi2=3.649, P=0.056). However, significant differences of genotype distributions were observed in the EH combined with CHD group (TT=126, TA=51, AA=8) compared with the EH patients (TT=127,TA=26, AA=7, chi2=6.410, P=0.041) and the healthy controls (TT=130, TA=24, AA=6, chi2=7.742, P=0.021). The EH combined with CHD patients had a significantly increased A allele frequency than the normal references (0.181 vs 0.106, chi2=7.690, P=0.006) and the EH subjects (0.181 vs 0.125, chi2=4.119, P=0.042). Hypertensive patients carrying TA genotype (OR=1.977, 95 % CI 1.160-3.354, P=0.011) or A allele (OR=1.548, 95 % CI 1.015-2.361, P=0.043) had an increased risk for CHD morbidity. CONCLUSION: we firstly report that -810A/T polymorphism in the promoter region of AT1 gene might be a genetic risk factor for the pathogenesis of CHD complicated with EH in Chinese Han population.

Aged↗
PubMed2005

[Significance of -191G/C single nucleotide polymorphisms in the promoter region of ATP-binding cassette transporter gene in coronary artery disease].

OBJECTIVE: To investigate the effect of -191G/C single nucleotide polymorphisms (SNP) in the promoter region of ATP-binding cassette transporter A1(ABCA1) gene on plasma lipids and its significance in coronary artery disease (CAD). METHODS: By polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), -191G/C SNP in the promoter region of ABCA1 gene was analyzed in 204 patients with CAD and 114 control subjects and the distribution of the -191G/C genotypes compared between the two groups and also between different clinical phenotypes of CAD. The clinical indexes associated with CAD were also compared between the patients with the three genotypes of CAD. RESULTS: The frequency distribution of GG, GC, and CC genotypes significantly differed between CAD group and the control group, and the former group had obvious higher CC genotype frequency and the C allele frequency (P<0.05 and P<0.01, respectively). In CAD patients, the frequency distribution of GG, GC, and CC genotypes varied significantly between those with acute coronary syndrome (ACS) and those with stable angina pectoris (SAP). The CC genotype showed obviously higher frequency in ACS group than in SAP group and the C allele was more frequent in the former group (P<0.05 and P<0.01, respectively). However, no significant difference was noted in the body mass index, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, or very low-density lipoprotein cholesterols between the three genotypes. CONCLUSIONS: The -191G/C SNP in the promoter region of ABCA1 is associated with increased CAD and the C allele may relate to the stability of CAD without detectable changes in plasma lipids.

ATP Binding Cassette Transporter 1↗
PubMed2003

Extension of the GOOD assay for genotyping single nucleotide polymorphisms by matrix-assisted laser desorption/ionization mass spectrometry.

Over the past years several methods using mass spectrometry for high-throughput genotyping of single nucleotide polymorphisms (SNPs) have been developed. Most of these procedures require stringent purification. Only the GOOD assay does not need any sample purification. Here, several new implementations of this assay are presented. The molecular biological procedure of the GOOD assays is based on the principle that the analysis of DNA by matrix-assisted laser desorption/ionization (MALDI) is strongly dependent on the charge state. A 100-fold increase in sensitivity can be achieved if the analyzed DNA product is conditioned by a chemical procedure termed 'charge-tagging'. The GOOD assay starts with a PCR; allele-specific DNA molecules are generated by extension of modified primers. These contain up to three phosphorothioates and optionally a quaternary ammonium charged group with ddNTPs or alpha-S-ddNTPs. Then the unmodified part of the primers is digested by phosphodiesterase II and the negative charges of the phosphorothioates are neutralized by an alkylation reaction resulting in charge-tagged DNA products. Through the use of a novel DNA polymerase for the primer extension, which preferably incorporates ddNTPs over dNTPs, an enzymatic degradation of residual dNTPs from the PCR is not required. Additionally, the unique property of charge-tag technology is demonstrated to detect specifically on the same sample allele-specific DNA products carrying a positive charge-tag in the positive ion mode while products carrying a negative charge-tag are analyzed in the negative ion mode. We also generated zwitterionic allele-specific products that were detectable with high sensitivity in positive ion mode. The findings of this study raise interesting questions about the ionization process of nucleic acids in MALDI. The new variations of the GOOD assay were applied to genotype SNPs of a candidate gene for cardiovascular disease.

Base Sequence↗
PubMed2000

Single nucleotide polymorphism analyses of the human proliferating cell nuclear antigen (pCNA) and flap endonuclease (FEN1) genes.

The products of proliferating cell nuclear antigen (PCNA) and flap endonuclease (FEN1) genes are multifunctional proteins that are involved in DNA replication and damage repair. Yeast models suggest association of mutant forms of PCNA and FEN1 with genomic instability. In our study, we have determined the single nucleotide polymorphisms in human PCNA and FEN1 genes. We sequenced the coding region and adjacent noncoding region of both the PCNA and FEN1 genes in 120 alleles (60 individuals). In the PCNA gene, we detected 9 sequence variants with Hardy-Weinberg allele frequency ranging from 0.008 to 0.088. No polymorphism was detected in the FEN1 gene. The sequence variants in the PCNA gene included 7 intronic single nucleotide polymorphisms (SNP) and 2 synonymous exonic SNPs. All the intronic SNPs were located in introns 1 and 4, which contain several regulatory elements involved in the control of PCNA gene expression. Six of the 7 intronic SNPs showed complete linkage disequilibrium. We confirmed this allelic linkage disequilibrium by allele-specific PCR sequencing. We genotyped 117 additional individuals belonging to 3 population subgroups using the PCR-RFLP method. Finally, to see if the detected polymorphisms are associated with any cancer type, we genotyped cases with melanomas (37 cases), breast cancers (118 cases) and lung cancers (100 cases). We did not find statistical difference in frequency of polymorphism in any cancer type compared with healthy controls, although in breast cancer the frequency was low. Our results suggest that the coding regions of the PCNA and FEN1 genes are highly conserved when compared with other DNA repair genes. The potential of some of the detected intronic polymorphisms to effect regulation of the PCNA gene expression remains to be determined.

Alleles↗
PubMed2006

Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial moyamoya disease.

OBJECTIVE: The genes encoding tissue inhibitor of metalloproteinase (TIMP) 4 and TIMP2 span chromosomes 3p24.2-p26 and 17q25, respectively, which are the locations of familial moyamoya disease (FMMD) genes. We investigated single nucleotide polymorphisms of the TIMP2 and TIMP4 genes in FMMD patients to determine genetic predispositions. METHODS: Eleven blood samples from FMMD patients were recruited. Controls included 50 blood samples from patients with nonfamilial moyamoya disease (MMD) and another 50 blood samples from non-MMD persons. We evaluated the promoter regions, exon-intron junctions, and the exons of the TIMP2 and TIMP4 genes by direct sequencing, and compared single nucleotide polymorphisms frequencies among the study groups. RESULTS: A significantly higher frequency of a heterozygous genotype was found in the TIMP2 promoter region at position -418 in FMMD; that is, the G/C heterozygous genotype at position -418 was observed in nine of 11 patients with FMMD, in 16 out of 50 nonfamilial MMD control participants, and in 14 out of 50 non-MMD control participants (FMMD versus nonfamilial MMD: odds ratio, 9.56; 95% confidence interval, 1.85-49.48; P = 0.005; and FMMD versus non-MMD: odds ratio, 10.50; 95% confidence interval, 2.02-54.55; P = 0.001). This base at position -418 corresponds to the third base of the GAGGCTGGG sequence, an Sp1 binding site. Thus, changes in this position may influence Sp1 binding and subsequent transcription of the gene. CONCLUSION: Our findings suggest that the presence of a G/C heterozygous genotype at position -418 in TIMP2 promoter could be a genetic predisposing factor for FMMD.

Base Sequence↗
PubMed2005

Single nucleotide polymorphisms within the promoter region of the rhesus monkey tumor necrosis factor-alpha gene.

The human TNF-alpha gene is characterized by several single nucleotide polymorphisms (SNPs) in its promoter region, in part having been shown to influence TNF-alpha expression and susceptibility to various diseases. The rhesus macaque is widely used as an animal model for a variety of TNF-alpha associated pathological conditions, but little is known about genetic variation within the TNF-alpha promoter region. In order to check for such polymorphisms, primers based on rhesus sequence within 5' UTR were designed and used to amplify a approximately 1 kb product from genomic DNA of 29 animals. Sequencing and cloning revealed a total of 11 polymorphisms leading to five different haplotypes.

5' Untranslated Regions↗
PubMed1999

The human caspase-activated DNase gene (hCAD): genomic structure, exonic single-nucleotide polymorphisms, and a highly polymorphic dinucleotide repeat at the hCAD locus.

Caspase-activated DNase (CAD) cleaves chromosomal DNA during apoptosis. We determined its genomic structure and identified single-nucleotide polymorphisms (SNPs) within exons 5 and 7, as well as a highly polymorphic dinucleotide repeat of (CT)m(CA)n within the 5' region of the human CAD gene (hCAD). The genomic structure of hCAD presented here, together with information concerning SNPs within the gene, as well as a highly polymorphic (CT)m(CA)n repeat fragment at the hCAD locus, may assist in the construction of genetic maps for exploring gene(s) that play pivotal roles in carcinogenesis.

Deoxyribonucleases↗
PubMed2006

Functional impacts of non-synonymous single nucleotide polymorphisms: selective constraint and structural environments.

In this work, we studied the correlations between selective constraint, structural environments and functional impacts of non-synonymous single nucleotide polymorphisms (nsSNPs). We found that the relation between solvent accessibility and functional impacts of nsSNPs is not as simple as generally thought. Finer structural classifications need to be taken into account to reveal the complex relations between the characteristics of a structure environment and its influence on the functional impacts of nsSNPs. We introduced two parameters for each structural environment, consensus residue percentage and residue distribution distance, to characterize the selective constraint imposed by the environment. Both parameters significantly correlate with the functional bias of nsSNPs across the structural environments. This result shows that selective constraint underlies the bias of a structural environment towards a certain type of nsSNPs (disease-associated or benign).

Genetic Diseases, Inborn↗
PubMed2004

Single nucleotide polymorphism analysis in the human phosphatase PTPrj gene using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry.

Data derived from analysis of single nucleotide polymorphisms (SNPs) are being applied in many diverse fields, from medical studies of disease mechanisms and individual drug response, to population genetics for tracking migration and mixing of ancestral groups and also in forensic science for the identification of human remains and identification of individuals from bodily samples. All these applications have in common the need to generate data for multiple loci from large numbers of samples. Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOFMS) is a promising platform for the generation of such data and we present a simple, flexible and robust technique for SNP determination. We demonstrate these features by typing two SNPs (Q276P and R326Q) in the human phosphatase gene PTPrj, which has been implicated in the aetiology of colon, lung, breast and thyroid cancers. A nucleotide depletion primer extension assay using no commercial kits or dideoxyNTPs was used to genotype a panel of DNAs derived from thyroid cancer patients and normal volunteers. The results obtained were in perfect agreement with those generated via restriction fragment length polymorphism analysis. No significant association was noted between possession of either allelic variant and a disease state, but the technique was validated as simple, flexible and appropriate for application in this context. Furthermore, it was highly cost-effective and required minimal optimisation, rendering it ideal for this type of pilot study.

Adolescent↗
PubMedDate not supplied

Diversity of mutations and distribution of single nucleotide polymorphic alleles in the human alpha-L-iduronidase (IDUA) gene.

PURPOSE: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder resulting from a deficiency of the lysosomal glycosidase, alpha-L-iduronidase (IDUA). Patients with MPS I present with variable clinical manifestations ranging from severe to mild. To facilitate studies of phenotype-genotype correlation, the authors performed molecular studies to detect mutations in MPS I patients and characterize single nucleotide polymorphism (SNP) in the gene. METHODS: Twenty-two unrelated MPS I patients were subjects for mutation detection using reverse transcriptional polymerase chain reaction (RT-PCR) and genomic PCR sequencing. Polymorphism analyses were performed on controls by restriction enzyme assays of PCR amplicons flanking nine intragenic single nucleotide polymorphic alleles. RESULTS: Eleven different mutations including two common mutations (Q70X, W402X), five recurrent mutations (D315Y, P533R, R621X, R628X, S633L), and four novel mutations (R162I, G208D, 1352delG, 1952del25bp) were identified from MPS I patients. Multiple SNP alleles coexisting with the disease-causing mutations were detected. Allelic frequencies for nine SNP alleles including A8, A20, Q33H, L118, N181, A314, A361T, T388, and T410 were determined. CONCLUSIONS: The results provide further evidence for the mutational heterogeneity among MPS I patients and point out possible common haplotype structures in the gene.

Black People↗
PubMed2002

Quantification of single nucleotide polymorphisms: a novel method that combines primer extension assay and capillary electrophoresis.

We present a novel method for accurate quantification of single nucleotide polymorphism (SNP) variants in transcripts and pooled DNAs in a one-tube reaction. Our approach is based on single- nucleotide primer extension (SNuPE) and laser-induced fluorescence capillary electrophoresis (LIF-CE), and takes advantage of distinct mobilities of SNuPE products with different nucleotides incorporated at their 3' ends. The method, called SNuPE-ONCE, was tested on two polymorphisms and five mutations that comprised the three most frequent ( approximately 70%) nucleotide changes in the human genome (C/T, A/G, and A/T). The usefulness of the method was demonstrated by analyzing nonsense-mediated mRNA instability in fibroblasts. Our data show 1) that the method provides highly reproducible relative allele frequencies (SD<0.017) with a good accuracy (e.g. for heterozygotes 0.500 +/- 0.036, P = 0.01), depending on the sequence and the proportion of the SNP variants in the sample, and 2) that relative allele frequencies as low as 1% can be detected quantitatively and unambiguously. Our assay relies on a CE instrument available in many laboratories and offers a useful method for quantitative SNP genotyping as well as for a variety of expression studies.

Alleles↗
PubMed2006

Joint linkage and association of six single-nucleotide polymorphisms in the factor XIII-A subunit gene point to V34L as the main functional locus.

OBJECTIVE: Activated factor XIII (FXIII) crosslinks fibrin to enhance the mechanical strength of a blood clot and increase its resistance to fibrinolysis. The prevalence of a common variant in the FXIII-A gene (V34L) has been reported to be lower in patients with myocardial infarction and ischemic stroke than in controls, suggesting a protective role for this polymorphism in vascular diseases. The current study investigated 6 single-nucleotide polymorphisms (SNPs) within the FXIII A-subunit gene to locate functional polymorphism(s) responsible for variation in FXIII activation. METHODS AND RESULTS: A total of 201 dizygotic twin pairs were genotyped for 1 promoter and all common nonsynonymous coding polymorphisms in the FXIII A-subunit gene: -246G>A, V34L, Y204F, P564L, V650I, and E651Q. Tests of linkage, association, and combined linkage and association were performed using QTDT software. Significant linkage to the V34L polymorphism (P=5 x 10(-12)) as well as association (P=3 x 10(-49)) was observed. Adjusting for association while performing linkage made the linkage signal disappear for the V34L polymorphism (from chi2=47.55, P=5x10(-12) to chi2=1.30, P=0.25). Only haplotypes containing the 34L allele showed association with FXIII activation. CONCLUSIONS: Testing multiple SNPs in the FXIII A-subunit gene indicates that V34L is the main functional polymorphism influencing FXIII activation.

Adult↗
PubMed2003

Single-nucleotide polymorphism in the CD14 promoter and periodontal disease expression in a Japanese population.

It has been reported that there is a relationship between a single-nucleotide polymorphism (SNP) in the promoter region of the CD14 gene at position -159 (C-->T) and infectious diseases. The aim of the present study was to test the hypthesis that expression of this SNP correlates with periodontal disease in a Japanese population. The CD14 genotype was determined in 163 subjects with periodontitis and in 104 age- and gender-matched control subjects without periodontitis. The genotype distribution and allele frequency within the periodontitis patients were not significantly different from those of control subjects. There was, however, a significant difference in the genotype distribution between young patients (< 35 yrs) and older patients (>/==" BORDER="0"> 35 yrs). These findings suggest that CD14 -159C/T polymorphism is not related to the development of periodontitis in a Japanese population, but that, within the periodontitis subjects, expression of the SNP may be related to early disease activity.

Adult↗
PubMed2006

IMP PCR primers detect single nucleotide polymorphisms for Anopheles gambiae species identification, Mopti and Savanna rDNA types, and resistance to dieldrin in Anopheles arabiensis.

BACKGROUND: Polymerase chain reactions to distinguish single-nucleotide polymorphisms are commonly used for mosquito identification and identifying insecticide resistance alleles. However, the existing methods used for primer design often result in analyses that are not robust or require additional steps. METHODS: Utilizing oligonucleotides that are unique in having an intentional mismatch to both templates three bases from the SNP at the 3-prime end, three new PCR assays that distinguish SNP targets using standard gel electrophoresis of undigested DNA fragments were developed and tested. These were applied to: (1) an alternative ribosomal DNA PCR assay to distinguish five members of the Anopheles gambiae complex; (2) detection of the Mopti and Savanna rDNA types; and (3) an assay to distinguish resistance to dieldrin (Rdl) alleles in Anopheles arabiensis. RESULTS: Reproducible specific amplification of the target alleles was observed in all three assays. The results were consistent with existing analyses but proved simpler and the results more distinct in our hands. CONCLUSION: The simplicity and effectiveness of the method should be utilized in these and other PCR analyses to increase their specificity and simplicity. These results have the potential to be extended not only to mosquito analyses but also to parasite and human polymorphisms.

Animals↗
PubMed2003

Genotyping single nucleotide polymorphisms directly from genomic DNA by invasive cleavage reaction on microspheres.

Here we report proof-of-principle for a microsphere-based genotyping assay that detects single nucleotide polymorphisms (SNPs) directly from human genomic DNA samples. This assay is based on a structure-specific cleavage reaction that achieves single base discrimination with a 5'-nuclease which recognizes a tripartite substrate formed upon hybridization of target DNA with probe and upstream oligonucleotides. The assay is simple with two easy steps: a cleavage reaction, which generates fluorescent signal on microsphere surfaces, followed by flow cytometry analysis of the microspheres. Genomic DNA samples were genotyped for the SNP in the Apolipoprotein E gene at amino acid position 158. The assay successfully scored wild type, heterozygous and homozygous mutants. To our knowledge, this is the first report of a solid-support assay for detection of SNPs directly from genomic DNA without PCR amplification of the target.

Apolipoproteins E↗