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At least 1,423 records · Page 79Linked to original sources
PubMed2002

Five novel single nucleotide polymorphisms in the CYP2C8 gene, one of which induces a frame-shift.

Five novel single nucleotide polymorphisms (SNPs) were found in exon 3 and introns 1, 3, 7, and 8 in cytochrome P450 (CYP) 2C8 gene from 54 Japanese individuals, who were administered the anti-arrhythmic drug amiodarone. The detected SNPs were as follows: 1) SNP, MPJ6_2C8014; GENE NAME, CYP2C8; ACCESSION NUMBER, NT_008769; LENGTH, 25 bases; 5'-ATTCAGAAATATC/TGAATCTATGTGT-3' 2) SNP, MPJ6_2C8015; GENE NAME, CYP2C8; ACCESSION NUMBER, NM_000770 and NT_008769; LENGTH, 25 bases; 5'-GGAGGAGTTGAGA/-AAAACCAAGGGT-3'. 3) SNP, MPJ6_2C8016; GENE NAME, CYP2C8; ACCESSION NUMBER, NT_008769; LENGTH, 25 bases; 5'-ATTTGTAAGATAT/-TGTTTAAAATTT-3' 4) SNP, MPJ6_2C8017; GENE NAME, CYP2C8; ACCESSION NUMBER, NT_008769; LENGTH, 25 bases; 5'-TTGGTTCCAACCC/TTCTAACAACACA-3' 5) SNP, MPJ6_2C8018; GENE NAME, CYP2C8; ACCESSION NUMBER, NT_008769; LENGTH, 25 bases; 5'-GATAGCAAATATA/GTCTCTTTTTGTA-3' Among these SNPs, MPJ6_2C8015 was expected to cause a frame-shift due to the deletion of adenine 471, resulting in amino acid alterations from codon 159 and an early stop codon at residue 177. Therefore, the variant enzyme is most likely to be inactive since it lacks 64% of the protein structure, including the heme-binding site and 5 out of 6 substrate recognition sites.

Journal Article↗
PubMed2002

Twelve novel single nucleotide polymorphisms in ABCB1/MDR1 among Japanese patients with ventricular tachycardia who were administered amiodarone.

Twelve novel single nucleotide polymorphisms (SNPs) were found in the gene encoding the ATP-binding cassette transporter, P-glycoprotein, from 60 Japanese individuals who were administered the anti-antiarrythmic drug, amiodarone. The detected SNPs were as follows: 1) SNP, MPJ6_AB1017 (IVS6-109); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 2) SNP, MPJ6_AB1018 (IVS7+14); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 3) SNP, MPJ6_AB1021 (IVS9-44); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 4) SNP, MPJ6_AB1052 (IVS12+17); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 5) SNP, MPJ6_AB1029 (IVS15-69); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 6) SNP, MPJ6_AB1040 (IVS24+16); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 7) SNP, MPJ6_AB1053 (IVS27-189); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 8) SNP, MPJ6_AB1054 (IVS27-172); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 9) SNP, MPJ6_AB1048 (IVS27-167); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 10) SNP, MPJ6_AB1055 (IVS27-152); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 11) SNP, MPJ6_AB1049 (IVS27-119); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168; 12) SNP, MPJ6_AB1051 (at nucleotide 3751 (exon 28) from the A of the translation initiation codon); GENE NAME, ABCB1; ACCESSION NUMBER, NT_017168. Among these SNPs, only MPJ6_AB1051 resulted in an amino acid alteration, V1251I.

Journal Article↗
PubMed2004

beta2 Adrenoceptor gene single nucleotide polymorphisms are associated with rheumatoid arthritis in northern Sweden.

BACKGROUND: beta(2) Adrenoceptor (beta(2)-AR) represents a link between the sympathetic nervous system and the immune system, and may be involved in human rheumatoid arthritis (RA). The gene encoding beta(2)-AR contains three single nucleotide polymorphisms (SNPs) at amino acid positions 16, 27, and 164. OBJECTIVE: To examine the common variants at positions 16 and 27 and their association with RA. METHODS: An allele-specific polymerase chain reaction to determine the common variants at positions 16 and 27 was used in 154 patients with RA and 198 ethnically matched healthy subjects from northern Sweden. RESULTS: Carriage of Arg16 and of Gln27 was associated with RA. Carriage of Gln27 was associated with activity of the disease and in combination with non-carriage of Arg16 with higher levels of rheumatoid factor. CONCLUSION: The beta2-AR SNPs may thus constitute an additional non-major histocompatibility complex association in RA.

Arthritis, Rheumatoid↗
PubMed2006

Microsatellites, single nucleotide polymorphisms and a sequence tagged site in starch-synthesizing genes in relation to starch physicochemical properties in nonwaxy rice (Oryza sativa L.).

Starch characteristics determine the quality of various products of rice, e.g., eating, cooking and processing qualities. Our previous study indicated that molecular markers inside or close to starch synthesizing genes can differentiate the starch properties of 56 waxy rices. Here we report microsatellite (or simple sequence repeat, SSR) polymorphism in the Waxy (Wx) gene, soluble starch synthase I gene (SS1) and starch branching enzyme 1 gene (SBE1), single nucleotide polymorphism (SNP) in Wx and starch branching enzyme 3 gene (SBE3), and a sequence tagged site (STS) in starch branching enzyme 1 gene (SBE1) among 499 nonwaxy rice samples and their relationships with starch physicochemical properties. The nonwaxy rice samples consist of landraces (n = 172) obtained from germplasm centers and cultivars and breeding lines (n = 327) obtained from various breeding programs. Ten (CT)( n ) microsatellite alleles, (CT)(8), (CT)(10), (CT)(11), (CT)(12, )(CT)(17), (CT)(18), (CT)(19), (CT)(20), (CT)(21), and (CT)(22), were found at the Wx locus, of which (CT)(11) was the most frequent, and (CT)(12), (CT)(21) and (CT)(22) were identified for the first time. Four (CT)( n ) microsatellite alleles were found at the SBE1 locus, (CT)(8), (CT)(9), and (CT)(10 )together with an insertion sequence of CTCTCGGGCGA, and (CT)(8) alone without the insertion, of which (CT)(9) and the insertion was a new allele identified in only one rice, IR1552. Multiple microsatellites clustered at the SS1 locus, and in addition to the three alleles previously detected (SSS-A = (AC)(2)...TCC(TC)(11)...(TC)(5)C(ACC)(11), SSS-B = (AC)(3)...TCT(TC)(6)...(TC)(4)C(ACC)(9), and SSS-C = (AC)(3)...TCT(TC)(6)...(TC)(4)C(ACC)(8)), one new allele (SSS-D = (AC)(2)...TCC(TC)(10)...(TC)(4)C(ACC)(9)) was found. Analysis of the starch physicochemical properties of the samples with different microsatellites, SNPs and STS groups indicated that these molecular markers can differentiate almost all the physicochemical properties examined, e.g., apparent amylose content (AAC), pasting viscosity characteristics, and gel textural properties. Wx SSR and Wx SNP alone explained more variations for all physicochemical properties than the other molecular markers. The total six markers could explain 92.2, 81 and 86% of total variation of AAC, gel hardness (HD), and gel cohesiveness (COH), respectively, and they could explain more than 40% of the total variation of hot paste viscosity (HPV), cool paste viscosity (CPV), breakdown viscosity (BD), setback viscosity (SB) and gel adhesiveness (ADH). However, only 29% of the total variation of peak viscosity (PV) and 37% of pasting temperature (PT) could be explained by all the molecular markers. Some of these markers can differentiate the starch physicochemical properties among the rice samples with the same Wx allele, indicating that the variation within Wx allele classes can be explained by other starch synthesizing genes. These SSRs, SNPs and STS are useful in marker-assisted breeding for the improvement of starch quality of rice.

1,4-alpha-Glucan Branching Enzyme↗
PubMed2005

Comparison of single-nucleotide polymorphisms and microsatellite markers for linkage analysis in the COGA and simulated data sets for Genetic Analysis Workshop 14: Presentation Groups 1, 2, and 3.

The papers in presentation groups 1-3 of Genetic Analysis Workshop 14 (GAW14) compared microsatellite (MS) markers and single-nucleotide polymorphism (SNP) markers for a variety of factors, using multiple methods in both data sets provided to GAW participants. Group 1 focused on data provided from the Collaborative Study on the Genetics of Alcoholism (COGA). Group 2 focused on data simulated for the workshop. Group 3 contained analyses of both data sets. Issues examined included: information content, signal strength, localization of the signal, use of haplotype blocks, population structure, power, type I error, control of type I error, the effect of linkage disequilibrium, and computational challenges. There were several broad resulting observations. 1) Information content was higher for dense SNP marker panels than for MS panels, and dense SNP markers sets appeared to provide slightly higher linkage scores and slightly higher power to detect linkage than MS markers. 2) Dense SNP panels also gave higher type I errors, suggesting that increased test thresholds may be needed to maintain the correct error rate. 3) Dense SNP panels provided better trait localization, but only in the COGA data, in which the MS markers were relatively loosely spaced. 4) The strength of linkage signals did not vary with the density of SNP panels, once the marker density was approximately 1 SNP/cM. 5) Analyses with SNPs were computationally challenging, and identified areas where improvements in analysis tools will be necessary to make analysis practical for widespread use.

Alcoholism↗
PubMed2001

A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity.

CD14 is a pattern recognition receptor that plays a central role in innate immunity through recognition of bacterial lipoglycans, primarily LPS. Recently, our group has identified a common single nucleotide polymorphism, -159C-->T, in the CD14 proximal promoter. Homozygous carriers of the T allele have a significant increase in soluble CD14, but a decreased total serum IgE. This epidemiologic evidence led us to investigate the molecular basis for the effects of CD14/-159C-->T on CD14 regulation in monocytes and hepatocytes, the two major cell types known to express this gene in vivo. EMSA analysis showed that the T allele results in decreased affinity of DNA/protein interactions at a GC box that contains a binding site for Sp1, Sp2, and Sp3 transcription factors. In reporter assays, the transcriptional activity of the T allele was increased in monocytic Mono Mac 6 cells, which express low levels of Sp3, a member of the Sp family with inhibitory potential relative to activating Sp1 and Sp2. By contrast, both alleles were transcribed equivalently in Sp3-rich hepatocytic HepG2 cells. Our data indicate that the interplay between CD14 promoter affinity and the [Sp3]:[Sp1 + Sp2] ratio plays a critical mechanistic role in regulating transcription of the two CD14 alleles. Variation in a key gene of innate immunity may be important for the pathogenesis of allergy and inflammatory disease through gene-by-gene and/or gene-by-environment interactions.

Base Sequence↗
PubMed2003

Amino acid substitutions in the human genome: evolutionary implications of single nucleotide polymorphisms.

Functional differences between amino acids have long been of interest in understanding protein evolution. Several indices exist for comparing residues on the basis of their physicochemical properties and frequencies of occurrence in conserved protein alignments. Here we present a residue dissimilarity index based on coding single nucleotide polymorphisms (SNPs) in the human genome. The index represents an average, organism-wide set of differences between residues and provides important insight into evolutionary restraints on residue substitutions in the human genome. Unlike previous models, it is not restricted to highly conserved protein structures, nor confounded by evolutionary differences between species. Our results confirm earlier observations regarding residue mutabilities but also suggest that in addition to the established key properties, such as size and polarity, charge conservation may be an important and currently underestimated factor in protein evolution. We also estimate that less than 51% of amino acid substitutions occurring in the human genome are evolutionarily neutral.

Amino Acid Substitution↗
PubMed2006

Single nucleotide polymorphisms of the HNF4alpha gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial.

Hepatocyte nuclear factor 4alpha (HNF4alpha) is a transcription factor, which is necessary for normal function of human liver and pancreatic islets. We investigated whether single nucleotide polymorphisms (SNPs) of HNF4A, encoding HNF4alpha, influenced the conversion from impaired glucose tolerance (IGT) to type 2 diabetes mellitus in subjects of the STOP-NIDDM trial. This trial aimed at evaluating the effect of acarbose compared to placebo in the prevention of type 2 diabetes mellitus. Eight SNPs covering the intragenic and alternate P2 promoter regions of HNF4A were genotyped in study samples using the TaqMan Allelic Discrimination Assays. Three SNPs in the P2 promoter region (rs4810424, rs1884614, and rs2144908) were in almost complete association (D'>0.97, r (2)>0.95) and, therefore, only rs4810424 was included in further analyses. Female carriers of the less frequent C allele of rs4810424 had a 1.7-fold elevated risk [95% confidence interval (CI) 1.09-2.66; P=0.020] for the conversion to diabetes compared to women with the common genotype after the adjustment for age, treatment group (placebo or acarbose), smoking, weight at baseline, and weight change. No association was found in men. Haplotype analysis based on three SNPs (rs4810424, rs2071197, and rs3818247) representing the linkage disequilibrium blocks in our study population indicated that the conversion to type 2 diabetes mellitus was dependent on the number of risk alleles in different haplotypes in women. Our results suggest that SNPs of HNF4A and their haplotypes predispose to type 2 diabetes mellitus in female subjects of the STOP-NIDDM study population.

Acarbose↗
PubMed2004

Association of single nucleotide polymorphisms in the thrombopoietin-receptor gene, but not the thrombopoietin gene, with differences in platelet count.

Little is known about the mechanisms explaining the wide variation in platelet counts (PLT) and other hematologic parameters in humans. We previously showed that the sex-based difference in hematocrit was associated with nucleotide variation in the erythropoietin receptor gene (EPOR). We sought to identify new polymorphisms of the human thrombopoietin (TPO) and thrombopoietin receptor (TPOR) genes to determine any associations with blood PLT counts. We screened TPO and TPOR for polymorphisms using single-strand conformation polymorphism (SSCP) and DNA sequencing. Association of polymorphisms was studied in 304 normal subjects with low or high PLT counts. Distribution of allelic frequency was analyzed by the Chi-square statistic. Single nucleotide polymorphisms (SNPs) with two alleles were found in TPO and TPOR. The TPO SNP was a G to A transition at nucleotide 5753, and the TPOR SNP was a C to A transversion at position 550 in the 5'-promoter area. The allelic frequencies were 0.54 for G and 0.46 for A of TPO, and 0.62 for C and 0.38 for A of TPOR in a Caucasian population. The frequency of the TPOR allele "C" was significantly higher in subjects with high PLT count (>258 k/mm3) versus low PLT count (<224 k/mm3) and in males with high PLT count (>258 k/mm3) versus males with low PLT count (<212 k/mm3). In contrast, the frequency of the TPO alleles was not related to blood PLT counts. An association of TPO and TPOR allele distribution to red and white blood cell parameters was seen. These new SNPs found for the human TPO and TPOR genes help explain variations in blood PLT counts and may be useful in patient studies related to the roles of TPO and/or TPOR in disease.

Adolescent↗
PubMed2005

Association of single nucleotide polymorphisms in the promoter region of the pro-opiomelanocortin gene (POMC) with low bone mineral density in adult women.

Among multiple factors influencing osteoporosis, genetic variations involved in bone-mineral metabolism can affect risks predisposing to the disease onset. Here, we studied single-nucleotide polymorphisms (SNPs) in the pro-opiomelanocortin (POMC) gene for possible association with bone mineral density (BMD) among 384 adult Japanese women and observed significant correlation between adjusted BMD and three SNPs in the promoter region (r>0.14, p<0.01). The most significant correlation was observed for -2353G/A (r=-0.16, p=0.002); homozygous carriers of the major (G) allele had the highest BMD (0.405+/-0.054 g/cm2) while heterozygous carriers were intermediate (0.390+/-0.053 g/cm2) and homozygous A-allele carriers had the lowest BMDs (0.369+/-0.048 g/cm2). Although no association was detected between these SNPs and body weight or body mass index (BMI), significant association was detected between the -2313A/C genotype and plasma total cholesterol level (r=-0.12, p=0.019). We propose that POMC is among the likely susceptibility genes for osteoporosis and may also be involved in dyslipidemia.

Adult↗
PubMed2005

Single-nucleotide polymorphisms in the 17beta-hydroxysteroid dehydrogenase genes might predict the risk of side-effects of estramustine phosphate sodium in prostate cancer patients.

BACKGROUND: Estramustine phosphate sodium (EMP) frequently causes side-effects such as gastrointestinal discomfort, nausea, and edema in extremities. We analyzed single nucleotide polymorphisms (SNP) in the 17beta-hydroxysteroid dehydrogenase (HSD17B) genes, which are involved in the metabolism of EMP, to predict the risk of EMP side-effects in prostate cancer patients. METHODS: We performed genotyping of SNP in the HSD17B genes of 44 Japanese patients with newly diagnosed prostate cancer. The association of SNP and individual EMP side-effects was evaluated. RESULTS: Peripheral edema occurred more frequently in patients with C/C genotype of IMS-JST123219 than in those with C/G genotype (OR: 5.47, 95% CI: 1.27-23.64). Haplotype analysis showed that appetite loss was associated with the G allele of IMS-JST123219 and the T allele of IMS-JST123218 (OR: 9.13, 95% CI: 1.15-72.76). CONCLUSIONS: These preliminary data demonstrated that analyses of SNP in the HSD17B genes might predict the occurrence of side-effects from EMP.

17-Hydroxysteroid Dehydrogenases↗
PubMed2004

Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway.

Significant variability in the antitumor efficacy and systemic toxicity of gemcitabine has been observed in cancer patients. However, there are currently no tools for prospective identification of patients at risk for untoward events. This study has identified and validated single-nucleotide polymorphisms (SNP) in genes involved in gemcitabine metabolism and transport. Database mining was conducted to identify SNPs in 14 genes involved in gemcitabine metabolism. Pyrosequencing was utilized to determine the SNP allele frequencies in genomic DNA from European and African populations (n=190). A total of 14 genetic variants (including 12 SNPs) were identified in eight of the gemcitabine metabolic pathway genes. The majority of the database variants were observed in population samples. Nine of the 14 (64%) polymorphisms analyzed have allele frequencies that were found to be significantly different between the European and African populations (P<0.05). This study provides the first step to identify markers for predicting variability in gemcitabine response and toxicity.

Antimetabolites, Antineoplastic↗
PubMed2006

Mutational spectrum in the recent human genome inferred by single nucleotide polymorphisms.

So far, there is no genome-wide estimation of the mutational spectrum in humans. In this study, we systematically examined the directionality of the point mutations and maintenance of GC content in the human genome using approximately 1.8 million high-quality human single nucleotide polymorphisms and their ancestral sequences in chimpanzees. The frequency of C-->T (G-->A) changes was the highest among all mutation types and the frequency of each type of transition was approximately fourfold that of each type of transversion. In intergenic regions, when the GC content increased, the frequency of changes from G or C increased. In exons, the frequency of G:C-->A:T was the highest among the genomic categories and contributed mainly by the frequent mutations at the CpG sites. In contrast, mutations at the CpG sites, or CpG-->TpG/CpA mutations, occurred less frequently in the CpG islands relative to intergenic regions with similar GC content. Our results suggest that the GC content is overall not in equilibrium in the human genome, with a trend toward shifting the human genome to be AT rich and shifting the GC content of a region to approach the genome average. Our results, which differ from previous estimates based on limited loci or on the rodent lineage, provide the first representative and reliable mutational spectrum in the recent human genome and categorized genomic regions.

Animals↗
PubMed2004

Analytical validation of the tag-it high-throughput microsphere-based universal array genotyping platform: application to the multiplex detection of a panel of thrombophilia-associated single-nucleotide polymorphisms.

BACKGROUND: We have developed a novel, microsphere-based universal array platform referred to as the Tag-It platform. This platform is suitable for high-throughput clinical genotyping applications and was used for multiplex analysis of a panel of thrombophilia-associated single-nucleotide polymorphisms (SNPs). METHODS: Genomic DNA from 132 patients was amplified by multiplex PCR using 6 primer sets, followed by multiplex allele-specific primer extension using 12 universally tagged genotyping primers. The products were then sorted on the Tag-It array and detected by use of the Luminex xMAP system. Genotypes were also determined by sequencing. RESULTS: Empirical validation of the universal array showed that the highest nonspecific signal was 3.7% of the specific signal. Patient genotypes showed 100% concordance with direct DNA sequencing data for 736 SNP determinations. CONCLUSIONS: The Tag-It microsphere-based universal array platform is a highly accurate, multiplexed, high-throughput SNP-detection platform.

Genotype↗
PubMed2006

ENU administration causes genomic instability along with single nucleotide polymorphisms in p53 during gliomagenesis: T11TS administration demonstrated in vivo apoptosis of these genetically altered tumor cells.

Advancement of molecular analysis of neoplastic cells demonstrated that multiple genetic changes are associated with the development of tumors. Cancer cell must exhibit a mutator phenotype, which is likely to be responsible for the genomic instability found in cancer tissues. The mutator phenotype, such as defective mismatch repair, is known to cause microsatellite instability, which is associated with certain cases of sporadic cancer. Previously many studies have been carried out to determine the relationship between microsatellite instability and human brain tumors. However information on genomic instability in the animal model of brain tumor is still very limited. In the present course of investigations we genetically characterized our ENU induced brain tumor animal model by using PCR based randomly amplified polymorphic DNA (RAPD) analysis and restriction fragment length polymorphism (RFLP) with three microsatellite probes. ENU induced tumors demonstrated genetic instability, including some microsatellite instability. As single nucleotide polymorphisms of the tumor suppressor gene p53 were associated with diverse types of human cancer, we examined the p53 gene of the tumor cells isolated from ENU induced brain tumor animal model, by PCR based RFLP method in p53 exon-2, -3 and -4. In these studies we showed that the restriction site of p53 exon-3 and 4 were mutated in ENU induced brain tumor indicating a genetic defect associated with ENU induced tumorigenesis. In the therapeutic part, we confirmed the anti-tumor property of T11TS/S-LFA-3 in the ENU induced genetically altered cells. Histological evidences, cytotoxic study, PI-FACS cell-cycle analysis and TUNEL assay confirmed the apoptotic death of glioma cells by T11TS treatment in which p53 is mutated. From the present study we can conclude that ENU administration causes genomic instability along with mutations in p53 during the process of gliomagenesis. Whereas, T11TS/S-LFA3 demonstrated the potential to induce apoptosis of these tumor cells even when p53 is mutated and thus showed its immense potential to be an anti-neoplastic probe against p53 mutated diverse types of tumors.

Alkylating Agents↗
PubMed2005

Which strategy is better for linkage analysis: single-nucleotide polymorphisms or microsatellites? Evaluation by identity-by-state-identity-by-descent transformation affected sib-pair method on GAW14 data.

The central issue for Genetic Analysis Workshop 14 (GAW14) is the question, which is the better strategy for linkage analysis, the use of single-nucleotide polymorphisms (SNPs) or microsatellite markers? To answer this question we analyzed the simulated data using Duffy's SIB-PAIR program, which can incorporate parental genotypes, and our identity-by-state - identity-by-descent (IBS-IBD) transformation method of affected sib-pair linkage analysis which uses the matrix transformation between IBS and IBD. The advantages of our method are as follows: the assumption of Hardy-Weinberg equilibrium is not necessary; the parental genotype information maybe all unknown; both IBS and its related IBD transformation can be used in the linkage analysis; the determinant of the IBS-IBD transformation matrix provides a quantitative measure of the quality of the marker in linkage analysis. With the originally distributed simulated data, we found that 1) for microsatellite markers there are virtually no differences in types I and II error rates when parental genotypes were or were not used; 2) on average, a microsatellite marker has more power than a SNP marker does in linkage detection; 3) if parental genotype information is used, SNP markers show lower type I error rates than microsatellite markers; and 4) if parental genotypes are not available, SNP markers show considerable variation in type I error rates for different methods.

Chromosome Mapping↗
PubMed2002

A novel rapid single nucleotide polymorphism (SNP)-based method for assessment of hematopoietic chimerism after allogeneic stem cell transplantation.

A major end point of nonmyeloablative hematopoietic stem cell transplantation is the attainment of either mixed chimerism or full donor hematopoiesis. Because the majority of human genetic disparity is generated by single nucleotide polymorphisms (SNPs), direct measurement of SNPs should provide a robust tool for the detection and quantitation of chimerism. Using pyrosequencing, a rapid quantitative sequencing technology, we developed a SNP-based assay for hematopoietic chimerism. Based on 14 SNPs with high allele frequencies, we were able to identify at least 1 informative SNP locus in 55 patients with HLA-identical donors. The median number of informative SNPs in related pairs was 5 and in unrelated pairs was 8 (P <.0001). Assessment of hematopoietic chimerism in posttransplantation DNA was shown to be quantitative, accurate, and highly reproducible. The presence of 5% donor cells was reliably detected in replicate assays. Compared with current measures of engraftment based on identification of short tandem repeats (STRs), variable number of tandem repeats (VNTRs), or microsatellite polymorphisms, this SNP-based method provides a more rapid and quantitative assessment of chimerism. A large panel of SNPs enhances the ability to identify an informative marker in almost all patient/donor pairs and also facilitates the simultaneous use of multiple markers to improve the statistical validity of chimerism measurements. The inclusion of SNPs that encode minor histocompatibility antigens or other genetic polymorphisms that may influence graft-versus-host disease or other transplantation outcomes can provide additional clinically relevant data. SNP-based assessment of chimerism is a promising technique that will assist in the analysis of outcomes following transplantation.

Case-Control Studies↗
PubMed2006

The single nucleotide polymorphisms of I(Ks) potassium channel genes and their association with atrial fibrillation in a Chinese population.

Recent studies suggest that genetic mutation of the slow delayed rectifier potassium channel (I(Ks)) may underlie atrial fibrillation (AF). We investigated the association between AF and the single nucleotide polymorphisms (SNPs) of genes KCNQ1, KCNE1 and KCNE4 associated with this channel. Common non-synonymous SNPs in KCNQ1 and KCNE1 known to be frequent in Asian people were selected and direct sequencing of KCNE4 was performed to identify possible SNPs. The AF group consisted of 142 hospitalized patients with AF, the community control group consisted of 120 subjects, and a ward control group consisted of 118 hospitalized patients without AF. Restriction fragment length polymorphism analysis was performed to determine the genotypes. The minor allele frequencies of P448R, R519H, G643S for KCNQ1 and G38S and D85N for KCNE1 in the AF group, the community control group and the ward control group were 9.9, 7.9, 9.3%; 0, 0, -; 4.3, 4.2, 1.7%; 28.4, 31.7, 29.7%; 0.7, 0.4%, -, respectively. There was no significant association between these SNPs and AF phenotype. There were eight SNPs in the whole length of KCNE4 plus 1,000 bases upstream of this gene including the non-synonymous SNP E145D. Logistical regression analysis revealed a difference in the distribution of KCNE4 E145D in the AF and the community control group (minor allele frequency was 34.0 versus 27.1% respectively, OR = 1.66, p = 0.044). We provided the frequencies of non-synonymous SNPs of KCNQ1 and KCNE1 in Chinese population; none of these SNPs was associated with AF. But KCNE4 E145D may be associated with the AF phenotype.

Aged↗