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At least 397 records · Page 22Linked to original sources
PubMed2004

Whole-genome scan, in a complex disease, using 11,245 single-nucleotide polymorphisms: comparison with microsatellites.

Despite the theoretical evidence of the utility of single-nucleotide polymorphisms (SNPs) for linkage analysis, no whole-genome scans of a complex disease have yet been published to directly compare SNPs with microsatellites. Here, we describe a whole-genome screen of 157 families with multiple cases of rheumatoid arthritis (RA), performed using 11,245 genomewide SNPs. The results were compared with those from a 10-cM microsatellite scan in the same cohort. The SNP analysis detected HLA*DRB1, the major RA susceptibility locus (P=.00004), with a linkage interval of 31 cM, compared with a 50-cM linkage interval detected by the microsatellite scan. In addition, four loci were detected at a nominal significance level (P<.05) in the SNP linkage analysis; these were not observed in the microsatellite scan. We demonstrate that variation in information content was the main factor contributing to observed differences in the two scans, with the SNPs providing significantly higher information content than the microsatellites. Reducing the number of SNPs in the marker set to 3,300 (1-cM spacing) caused several loci to drop below nominal significance levels, suggesting that decreases in information content can have significant effects on linkage results. In contrast, differences in maps employed in the analysis, the low detectable rate of genotyping error, and the presence of moderate linkage disequilibrium between markers did not significantly affect the results. We have demonstrated the utility of a dense SNP map for performing linkage analysis in a late-age-at-onset disease, where DNA from parents is not always available. The high SNP density allows loci to be defined more precisely and provides a partial scaffold for association studies, substantially reducing the resource requirement for gene-mapping studies.

Arthritis, Rheumatoid↗
PubMed2005

Specific triplex binding capacity of mixed base sequence duplex nucleic acids used for single-nucleotide polymorphism detection.

Specific base recognition and binding between native double-stranded DNA (dsDNA) and complementary single-stranded DNA (ssDNA) of mixed base sequence is presented. Third-strand binding, facilitated and stabilized by a DNA intercalator, YOYO-1, occurs within 5 min at room temperature. This triplex binding capability has been used to develop a homogeneous assay that accurately detects 1-, 2-, or 3-bp mutations or deletions in the dsDNA target. Every type of 1-bp mismatch can be identified. The assay can reliably distinguish homozygous from heterozygous polymerase chain reaction (PCR)-amplified genomic dsDNA, thus providing a highly sensitive clinical diagnostic assay.

Base Pairing↗
PubMed2006

[Single nucleotide polymorphisms of three candidate genes in essential hypertension].

OBJECTIVE: To explore the association of single nucleotide polymorphisms (SNPs) of three candidate genes, including T869C of transforming growth factor beta1 (TGF-beta1), -344T/C of aldosterone synthase (CYP11B2) and Gly460Trp of alpha-Adducin with essential hypertension in Chinese Han population. METHODS: Three hundred ninety six hypertensive patients and 214 normotensive subjects were genotyped for T869C, -344T/C and Gly460Trp polymorphisms with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and mutagenically separated PCR (MS-PCR), respectively. RESULTS: In single-gene analysis, no association was observed between either CYP11B2 -344T/C or alpha-Adducin Gly460Trp polymorphism and essential hypertension. For female, there were significant difference in genotype distribution and allele frequency of T869C polymorphism (P < 0.02), as compared with subjects with T allele. CC homozygosity had a higher relative risk of hypertension (OR = 2.97, 95% CI, 1.38 to 6.32, P = 0.004), whereas we failed to detect any association between T869C polymorphism and essential hypertension in male. In multiple-gene analysis, the incidence of hypertension was higher in CYP11B2 TT homozygosity than in other CYP11B2 genotypes (OR = 1.99, 95% CI, 1.01 to 3.74, P = 0.03) in the presence of TGF-beta1 CC genotype. CONCLUSIONS: Our results indicated that T869C polymorphism of TGF-beta1 gene might be associated with essential hypertension in female, furthermore, the TGF-beta1 T869C and CYP11B2-344T/C polymorphisms appeared to interact in hypertensive population.

Alleles↗
PubMed2001

Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects.

BACKGROUND: P-glycoprotein, the gene product of MDR1, confers multidrug resistance against antineoplastic agents but also plays an important role in the bioavailability of common drugs in medical treatment. Various polymorphisms in the MDR1 gene were recently identified. A silent mutation in exon 26 (C3435T) was correlated with intestinal P-glycoprotein expression and oral bioavailability of digoxin. OBJECTIVE: We wanted to establish easy-to-use and cost-effective genotyping assays for the major known MDR1 single nucleotide polymorphisms and study the allelic frequency distribution of the single nucleotide polymorphisms in a large sample of volunteers. METHODS: In this study, the distribution of the major MDR1 alleles was determined in 461 white volunteers with the use of polymerase chain reaction and restriction fragment length polymorphism. RESULTS: Five amino acid exchanges were found with allelic frequencies of 11.2% for Asn21Asp and 5.5% for Ser400Asn. Strikingly, in exon 21 three variants were discovered at the same locus: 2677G (56.4%), 2677T (41.6%), and 2677A (1.9%), coding for 893Ala, Ser, or Thr. A novel missense Gln1107Pro mutation was found in two cases (0.2%). The highest frequencies were observed for intronic and silent polymorphisms; C3435T occurred in 53.9% of the subjects heterozygously, and 28.6% of individuals were homozygous carriers of 3435T/T with functionally restrained P-glycoprotein. CONCLUSION: This study provides the first analysis of MDR1 variant genotype distribution in a large sample of white subjects. It gives a basis for large-scale clinical investigations on the functional role of MDR1 allelic variants for bioavailability of a substantial number of drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Testing for candidate gene linkage disequilibrium using a dense array of single nucleotide polymorphisms in case-parents studies.

The future of genetic studies of complex human diseases will rely more and more on the epidemiologic association paradigm, in particular the use of the transmission/disequilibrium test to detect linkage disequilibrium in a case-parents study. With the rapid progress in genomic studies, many single nucleotide polymorphisms will be identified and genotyped within a very short physical distance. Analyzing multiple single nucleotide polymorphisms within a candidate gene/region with Bonferroni correction for multiple transmission/disequilibrium tests will lead to a conservative test, and hence a power loss. I propose a new method, the "Adaptive PRIncipal COmponent Test" (APRICOT). The method has the following properties: (1) it does not need haplotype information; (2) it is nonparametric-it does not make specific assumptions about the population history or population structure; and (3) the calculation of the test statistic and the determination of its significance level are simple and straightforward. Monte-Carlo simulation reveals that adaptive principal component test maintains the nominal significance level under the null hypothesis of no linkage disequilibrium, even under complex situations of multiple ancestral haplotypes and structured populations. It provides a substantial power advantage over the conventional Bonferroni approach. The adaptive principal component test is a promising method for candidate gene testing using single nucleotide polymorphisms.

Genetic Markers↗
PubMed2003

Single nucleotide polymorphism discrimination assisted by improved base stacking hybridization using oligonucleotide microarrays.

Efficiencies of mismatch discrimination using size-varied capture probes were examined at various hybridization temperatures. The probes were 17, 15, 13, 11, 9, and 7 nucleotides long and contained single-base mismatches at their 3' ends. The optimal signal intensity and efficiency of base stacking hybridization on mismatch discrimination were observed for capture probes with a melting temperature (Tm) value of 36 degrees C, in the detection of DNA sequence variations at 40 degrees C. We employed asymmetric PCR to prepare single-stranded target DNA labeled with a fluorescent dye, and the PCR product was hybridized on the DNA microarray with no further purification. Our efforts have enhanced the sensitivity and simplified the procedures of base stacking hybridization on mismatch discrimination. As a model experiment, this improved technology was used to identify plasmid templates of human leukocyte antigen (HLA)-A alleles 2601, 2902, and 0206 on oligonucleotide microarrays. It is now possible to apply this simple, rapid, sensitive, and reliable base stacking hybridization technology to detect DNA sequence variations on microarrays in clinical diagnosis and other applications.

Alleles↗
PubMed2003

Combination of DNA repair gene single nucleotide polymorphisms and increased levels of DNA adducts in a population-based study.

Inherited single nucleotide polymorphisms (SNPs) of DNA repair genes may contribute to variations in DNA repair capacity and susceptibility to cancer. We investigated the role of SNPs in three DNA repair genes (X-ray repair cross-complementing group 1-Arg399Gln, exon 10; X-ray repair cross-complementing group 3-Thr241Met, exon 7; and xeroderma pigmentosum-D-Lys751Gln, exon 23) and their combination, in modulating the levels of "bulky" DNA adducts in a population sample of 628 Italian healthy individuals belonging to the prospective European project "European Prospective Investigation into Cancer and Nutrition." DNA-adduct levels were measured as relative adduct level per 10(9) nucleotides by (32)P-post DNA labeling assay in WBCs from peripheral blood. Genotyping was performed by PCR-RFLP analysis or primer extension/denaturing high-performance liquid chromatography technique. We found a dose-response relationship between the number of at-risk alleles and levels of adducts (P = 0.0046). Individuals with at least three variant alleles had a statistically significant odds ratio (OR) for being in the highest tertile of adducts compared with those with undetectable adducts [three alleles, adjusted OR = 5.07, 95% confidence interval (CI) = 1.29-19.9; four alleles, adjusted OR = 5.03, 95% CI = 1.18-21.45; five alleles, adjusted OR = 7.65, 95% CI = 0.94-62.2]. Our study suggests that the combined effect of multiple variant alleles may be more important than the investigation of single SNP in modulating DNA repair capacity.

Alleles↗
PubMed2005

Properties of human and rabbit cytosolic serine hydroxymethyltransferase are changed by single nucleotide polymorphic mutations.

Serine hydroxymethyltransferase (SHMT) is a key enzyme in the formation and regulation of the folate one-carbon pool. Recent studies on human subjects have shown the existence of two single nucleotide polymorphisms that may be associated with several disease states. One of these mutations results in Ser394 being converted to an Asn (S394N) and the other in the change of Leu474 to a Phe (L474F). These mutations were introduced into the cDNA for both human and rabbit cytosolic SHMT and the mutant enzymes expressed and purified from an Escherichia coli expression system. The mutant enzymes show normal values for kcat and Km for serine. However, the S394N mutant enzyme has increased dissociation constant values for both glycine and tetrahydrofolate (tetrahydropteroylglutamate) and its pentaglutamate form compared to wild-type enzyme. The L474F mutant shows lowered affinity (increased dissociation constant) for only the pentaglutamate form of the folate ligand. Both mutations result in decreased rates of pyridoxal phosphate addition to the mutant apo enzymes to form the active holo enzymes. Neither mutation significantly affects the stability of SHMT or the rate at which it converts 5,10-methenyl tetrahydropteroyl pentaglutamate to 5-formyl tetrahydropteroyl pentaglutamate. Analysis of the structures of rabbit and human SHMT show how mutations at these two sites can result in the observed functional differences.

Animals↗
PubMed2002

Twenty single-nucleotide polymorphisms in four genes encoding cardiac ion channels.

We here report 20 novel single-nucleotide polymorphisms in four genes that are potentially involved in the excitement of cardiomyocytes: 1 in KCNA5 (encoding Kv1.5), 5 in KCNAB1 (encoding Kvbeta1.3), 5 in KCNIP2 (encoding KChIP2), and 9 in CACNA1C (encoding a cardiac L-type voltage-dependent calcium ion channel, dihydropyridine receptor). We also examined their allelic frequencies in Japanese individuals. These data will be useful for genetic association studies designed to investigate secondary long QT syndrome or other circulatory disorders.

Gene Frequency↗
PubMed2005

Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin.

PURPOSE: We investigated single-nucleotide polymorphisms of the cytidine deaminase gene (CDA), which encodes an enzyme that metabolizes gemcitabine, to clarify the relationship between the single-nucleotide polymorphism 208G>A and the pharmacokinetics and toxicity of gemcitabine in cancer patients treated with gemcitabine plus cisplatin. EXPERIMENTAL DESIGN: Six Japanese cancer patients treated with gemcitabine plus cisplatin were examined. Plasma gemcitabine and its metabolite 2',2'-difluorodeoxyuridine were measured using an high-performance liquid chromatography method, and the CDA genotypes were determined with DNA sequencing. RESULTS: One patient, a 45-year-old man with pancreatic carcinoma, showed severe hematologic and nonhematologic toxicities during the first course of chemotherapy with gemcitabine and cisplatin. The area under the concentration-time curve value of gemcitabine in this patient (54.54 microg hour/mL) was five times higher than the average value for five other patients (10.88 microg hour/mL) treated with gemcitabine plus cisplatin. The area under the concentration-time curve of 2',2'-difluorodeoxyuridine in this patient (41.58 microg hour/mL) was less than the half of the average value of the five patients (106.13 microg hour/mL). This patient was found to be homozygous for 208A (Thr70) in the CDA gene, whereas the other patients were homozygous for 208G (Ala70). CONCLUSION: Homozygous 208G>A alteration in CDA might have caused the severe drug toxicity experienced by a Japanese cancer patient treated with gemcitabine plus cisplatin.

Aged↗
PubMed2003

Association of single nucleotide polymorphisms in the growth hormone and growth hormone receptor genes with blood serum insulin-like growth factor I concentration and growth traits in Angus cattle.

This study was conducted to identify polymorphisms in the promoter and coding regions of the bovine growth hormone and growth hormone receptor genes and to study association of polymorphisms identified in these genes with growth traits and serum insulin-like growth factor-I (IGF-I) concentration. The denaturing gradient gel electrophoresis method and sequencing were utilized to identify three new single nucleotide polymorphisms in the promoter region of the growth hormone gene in Angus cattle. Polymerase chain reaction-based restriction fragment length polymorphism procedures were developed for rapid determination of the single nucleotide polymorphism genotypes in the growth hormone and the growth hormone receptor genes among Angus calves from lines divergently selected for high or low blood serum IGF-I concentration. The IGF-I concentration and growth traits were analyzed using animal models. The single nucleotide polymorphism in the promoter region of the growth hormone receptor gene was associated with serum IGF-I concentration on d 42 of the postweaning test and with mean IGF-I concentration. The associated effects of the markers need to be verified in other populations.

Animals↗
PubMed2003

Genome-wide loss of heterozygosity analysis from laser capture microdissected prostate cancer using single nucleotide polymorphic allele (SNP) arrays and a novel bioinformatics platform dChipSNP.

Oligonucleotide arrays that detect single nucleotide polymorphisms were used to generate genome-wide loss of heterozygosity (LOH) maps from laser capture microdissected paraffin-embedded samples using as little as 5 ng of DNA. The allele detection rate from such samples was comparable with that obtained with standard amounts of DNA prepared from frozen tissues. A novel informatics platform, dChipSNP, was used to automate the definition of statistically valid regions of LOH, assign LOH genotypes to prostate cancer samples, and organize by hierarchical clustering prostate cancers based on the pattern of LOH. This organizational strategy revealed apparently distinct genetic subsets of prostate cancer.

Alleles↗
PubMed2004

[Relationship between six single nucleotide polymorphisms of angiotensinogen gene and essential hypertension].

OBJECTIVE: To evaluate the relationship of six single nucleotide polymorphisms(SNPs) and their haplotypes of angiotensinogen(AGT) gene to essential hypertension(EH) in Chinese Han population. METHODS: The genotypes in 185 patients with EH and 185 healthy controls were determined by the method of ABI PRISM SNaPshot Multiplex Kit using six AGT gene polymorphisms at position -217(G/A), -152(G/A), -20(A/C) and -6(G/A) in the promoter region and T174M, M235T in exon 2. RESULTS: The distribution of AGT genotypes and alleles frequencies showed no significant difference between the group of EH and group of controls (P>0.05). However, haplotype analysis revealed that H4 haplotype frequency, which included -152A, -20C, -6A and 235T alleles, was significantly increased in the group of EH (P<0.05). CONCLUSION: G-152A, A-20C, G-6A and M235T polymorphisms of AGT gene might play an important role in the occurrence of EH in Chinese Han population.

Adult↗
PubMed2005

Quantitative genotyping of single-nucleotide polymorphisms by allele-specific oligonucleotide hybridization on DNA microarrays.

Genotyping of SNPs (single-nucleotide polymorphisms) has challenged the development of several novel techniques. Most of these methods have been introduced to discriminate binary SNPs in diploid species. In the present study, the quantitative genotyping of SNPs in natural DNA pools of a polyploid organism via DNA microarrays was analysed. Three randomly selected SNP loci were genotyped in the tetraploid species potato (Solanum tuberosum). For each SNP, 24 oligomers were designed, 12 with forward and 12 with reverse orientation. They contained the polymorphic site at one of the positions 11, 14 and 17. Several steps of optimizations were performed, including the 'materials' used and the establishment of hybridization conditions. Glass surfaces were either epoxy- or aldehyde-modified, and allele-specific oligonucleotides contained either SH or NH2 groups. Hybridization stringency conditions were established by varying the concentration of formamide in the hybridization buffer. For SNP BA213c14t7/403, the quantitative discrimination between all four different naturally occurring genotypes could be demonstrated.

Chromosome Mapping↗
PubMed2004

Single nucleotide polymorphism map of five long-QT genes.

We screened a white population for single nucleotide polymorphisms (SNPs) in five long QT syndrome genes, namely, KCNQ1 (LQT1), HERG (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6). We found 35 SNPs, 10 of which have not been previously described. Ten SNPs were in KCNE1, six in HERG, eight in KCNQ1, four in KCNE2, and seven in SCN5A. Four SNPs were associated with QTc interval in our 141 subjects, one in KCNE1, one in KCNE2, and two in SCN5A. Two of these SNPs have not been described. We conclude that these five long QT syndrome genes contain common variants, some of which are associated with QTc interval in normal persons. We suggest that analysis of these SNPs in a much larger cohort would enable establishment of common haplotypes that are associated with QTc. These haplotypes could facilitate prediction of arrhythmia risk in the general population.

Cohort Studies↗
PubMed2002

A C/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor gene is associated with polycystic ovary syndrome.

OBJECTIVE: To examine whether the insulin receptor (INSR) gene contributes to genetic susceptibility to the polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: Academic endocrinology clinic. PATIENT(S): Ninety-nine women with PCOS as defined by the National Institutes of Health consensus and polycystic ovaries on ultrasonography, and 136 healthy controls. MAIN OUTCOME MEASURE: Frequency of genotypes of a single nucleotide polymorphism of the INSR gene in patients and controls. RESULT(S): After stratification of participants by body mass index, the frequency of the uncommon T allele of the INSR single nucleotide polymorphism was significantly increased in lean patients with PCOS (body mass index < or =27 kg/m2) compared with lean controls (relative risk, 2.1). CONCLUSION(S): The INSR gene is a susceptibility gene for PCOS among lean patients with PCOS. It remains to be determined whether the exon 17 C/T single nucleotide polymorphism is the susceptibility single nucleotide polymorphism for PCOS or whether it is in linkage disequilibrium with another INSR gene polymorphism.

Adolescent↗
PubMed2004

Oligonucleotide ligation assay-based DNA chip for multiplex detection of single nucleotide polymorphism.

An oligonucleotide ligation assay-based DNA chip has been developed to detect single nucleotide polymorphism. Synthesized nonamers, complementary to the flanking sequences of the mutation sites in target DNA, were immobilized onto glass slides through disulfide bonds on their 5' terminus. Allele-specific pentamers annealed adjacent to the nonamers on the complementary target DNA, containing 5'-phosphate groups and biotin labeled 3'-ends, were mixed with the target DNA in tube. Ligation reactions between nonamers and pentamers were carried out on chips in the presence of T4 DNA ligase. Ligation products were directly visualized on chips through enzyme-linked assay. The effect of G:T mismatch at different positions of pentamers on the ligation were evaluated. The results showed that any mismatch between pentamer and the target DNA could lead to the decrease of ligation, which can be detected easily. The established approach was further used for multiplex detection of mutations in rpoB gene of rifampin-resistant Mycobacterium tuberculosis clinical isolates.

DNA↗