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PubMed2006

Enhanced VWF biosynthesis and elevated plasma VWF due to a natural variant in the murine Vwf gene.

Both genetic and environmental influences contribute to the wide variation in plasma von Willebrand factor (VWF) levels observed in humans. Inbred mouse strains also have highly variable plasma VWF levels, providing a convenient model in which to study genetic modifiers of VWF. Previously, we identified a major modifier of VWF levels in the mouse (Mvwf1) as a regulatory mutation in murine Galgt2. We now report the identification of an additional murine VWF modifier (Mvwf2). Mvwf2 accounts for approximately 16% of the 8-fold plasma VWF variation (or approximately 25% of the genetic variation) observed between the A/J and CASA/RkJ strains and maps to the murine Vwf gene itself. Twenty SNPs were identified within the coding regions of the A/J and CASA/RkJ Vwf alleles, and in vitro analysis of recombinant VWF demonstrated that a single SNP (+7970G>A) and the associated nonsynonymous amino acid change (R2657Q) confers a significant increase in VWF biosynthesis from the CASA/RkJ Vwf allele. This change appears to represent a unique gain of function that likely explains the mechanism of Mvwf2 in vivo. The identification of a natural Vwf gene variant among inbred mice affecting biosynthesis suggests that similar genetic variation may contribute to the wide range of VWF levels observed in humans.

Amino Acid Substitution↗
PubMed2001

Polymorphisms of the human prolactin gene--implications for production of lymphocyte prolactin and systemic lupus erythematosus.

Hyperprolactinaemia is associated with systemic lupus erythematosus (SLE) but the mechanism is unknown. Prolactin is expressed not only by pituitary lactotrophic cells but also by T-lymphocytes under the control of an alternative upstream promoter region. T-lymphocytes from SLE patients have been shown to secrete more prolactin than controls, thus implying a possible underlying difference in regulation. This may be due to genetic polymorphism that can be determined by scanning for mutations and using a variety of methods to determine their function. A polymorphism may also be used in disease association studies as it may be in linkage disequilibrium with a disease gene on the same haplotype. Single nucleotide polymorphisms (SNPs) have been found across the prolactin gene region including the extrapituitary and the pituitary promoter regions. These SNPs have been examined for genetic association with SLE and potential effects upon the function of the gene. One SNP in the lymphocyte specific upstream promoter affects prolactin transcription and disease association studies in a cohort of SLE cases demonstrated an increased frequency of the PRL-1149 G allele compared to control subjects. This indicates a possible mechanism for the association of prolactin with SLE. Although prolactin is likely to be one of several predisposing factors in the pathogenesis and progression of SLE, this suggests that manipulation of lymphocyte prolactin production (rather than pituitary production) might be a useful therapeutic approach.

Gene Expression Regulation↗
PubMed2006

ssSNPer: identifying statistically similar SNPs to aid interpretation of genetic association studies.

UNLABELLED: ssSNPer is a novel user-friendly web interface that provides easy determination of the number and location of untested HapMap SNPs, in the region surrounding a tested HapMap SNP, which are statistically similar and would thus produce comparable and perhaps more significant association results. Identification of ssSNPs can have crucial implications for the interpretation of the initial association results and the design of follow-up studies. AVAILABILITY: http://fraser.qimr.edu.au/general/daleN/ssSNPer/

Chromosome Mapping↗
PubMed2007

The alpha(1S) subunit of the L-type calcium channel is not a predisposition gene for thyrotoxic periodic paralysis.

OBJECTIVE: Thyrotoxic periodic paralysis (TTP) has been associated with genetic variations in the gene encoding the alpha 1 subunit of the L-type calcium channel (CACNA1S). Mutations in CACNA1S are known to account for the majority of cases of familial hypokalaemic periodic paralysis (HOKPP). In this study we have examined 48 genetic polymorphisms in the CACNA1S gene and genotyped a tagging set of representative polymorphisms to determine the role of this gene in TPP. DESIGN AND PATIENTS: A genetic association study was carried out with 98 TPP patients and 162 male thyrotoxic controls. Among 47 polymorphisms evaluated for linkage disequilibrium (LD) and the spectrum of haplotypes in the Chinese population, 31 were selected as tagging single-nucleotide polymorphisms (SNPs) for genotyping the whole sample. A new genotyping protocol was used to analyse an insertion/deletion (I/D) polymorphism. RESULTS: We studied the LD among 47 polymorphisms in the CACNA1S gene, which comprised a set of high-density markers with an average of one SNP every 2 kb. Subsequently, 31 tagSNPs were genotyped for all the samples. The gene is composed of three LD blocks. With this block structure, we were confident that variations of the gene were comprehensively covered by the tagSNPs. No significant association was found between the polymorphisms and TPP. CONCLUSION: We established the LD structure of this calcium channel subunit gene (CACNA1S) for the first time. However, its genetic variations are not associated with TPP in Chinese patients.

Adult↗
PubMed2004

Using the miraEST assembler for reliable and automated mRNA transcript assembly and SNP detection in sequenced ESTs.

We present an EST sequence assembler that specializes in reconstruction of pristine mRNA transcripts, while at the same time detecting and classifying single nucleotide polymorphisms (SNPs) occuring in different variations thereof. The assembler uses iterative multipass strategies centered on high-confidence regions within sequences and has a fallback strategy for using low-confidence regions when needed. It features special functions to assemble high numbers of highly similar sequences without prior masking, an automatic editor that edits and analyzes alignments by inspecting the underlying traces, and detection and classification of sequence properties like SNPs with a high specificity and a sensitivity down to one mutation per sequence. In addition, it includes possibilities to use incorrectly preprocessed sequences, routines to make use of additional sequencing information such as base-error probabilities, template insert sizes, strain information, etc., and functions to detect and resolve possible misassemblies. The assembler is routinely used for such various tasks as mutation detection in different cell types, similarity analysis of transcripts between organisms, and pristine assembly of sequences from various sources for oligo design in clinical microarray experiments.

Animals↗
PubMed2007

High-resolution analysis of allelic imbalance in neuroblastoma cell lines by single nucleotide polymorphism arrays.

Genomic copy number changes are detectable in many malignancies, including neuroblastoma, using techniques such as comparative genomic hybridization (CGH), microsatellite analysis, conventional karyotyping, and fluorescence in situ hybridization (FISH). We report the use of 10K single nucleotide polymorphism (SNP) microarrays to detect copy number changes and allelic imbalance in six neuroblastoma cell lines (IMR32, SHEP, NBL-S, SJNB-1, LS, and SKNBE2c). SNP data were generated using the GeneChip DNA Analysis and GeneChip chromosome copy number software (Affymetrix). SNP arrays confirmed the presence of all previously reported cytogenetic abnormalities in the cell lines, including chromosome 1p deletion, MYCN amplification, gain of 17q and 11q, and 14q deletions. In addition, the SNP arrays revealed several chromosome gains and losses not detected by CGH or karyotyping; these included gain of 8q21.1 approximately 24.3 and gain of chromosome 12 in IMR-32 cells; loss at 4p15.3 approximately 16.1 and loss at 16p12.3 approximately 13.2, 11q loss with loss of heterozygosity (LOH) at 11q14.3 approximately 23.3 in SJNB-1 cells; and loss at 8p21.2 approximately 23.3 and 9p21.3 approximately 22.1 with corresponding LOH in SHEP cells. The SNP arrays refined the mapping of the 2p amplicons in LS, BE2c, and IMR-32 cell lines, the 12q amplicon in LS cells, and also identified an 11q13 amplicon in LS cells. There was good concordance among SNP arrays, CGH, and karyotyping. SNP array analysis is a powerful tool for the detection of allelic imbalance in neuroblastoma and also allows identification of LOH without changes in copy number (uniparental disomy).

Allelic Imbalance↗
PubMed2003

Lack of a modulative factor in locus 8p23 in a Finnish family with nonsyndromic sensorineural hearing loss associated with the 1555A>G mitochondrial DNA mutation.

The chromosomal region around marker D8S277 is thought to contribute to susceptibility to hearing impairment in patients with the 1555A>G mutation in mtDNA. We have previously described a family with this mutation, in which some of the members had profound hearing loss, some had a hearing impairment for high-frequency tones and some had completely normal hearing. The phenotypes were thus compatible with a recessive inheritance pattern. We fine-mapped the region around marker D8S277 by sequencing single nucleotide polymorphisms (SNPs) along the 11 Mb region on 8p23, and also sequenced eight defensin genes in the vicinity of D8S277 and the genes GJB2, GJB3, MTO1 and TIMM8A. SNP haplotypes were constructed using the SimWalk2 program. The three persons with a profound hearing loss had identical genotypes in the 11 Mb region on 8p23, but this genotype was also present in a person with normal hearing. The persons with a hearing impairment for high-frequency tones did not share any common haplotype, but one of them shared a genotype with a healthy person. Thus, haplotype comparison excluded a contribution of the region concerned to the expression of hearing impairment in this family, nor could the susceptibility be assigned to the GJB2, GJB3, MTO1 or TIMM8A genes. Extended pedigrees with 1555A>G, such as the present one, provide a good opportunity to identify a modifying nuclear factor. The chromosomal region around 8p23 could be excluded here as the locus for susceptibility to hearing impairment.

Base Sequence↗
PubMed2004

Locked nucleic acid (LNA) single nucleotide polymorphism (SNP) genotype analysis and validation using real-time PCR.

With an increased emphasis on genotyping of single nucleotide polymorphisms (SNPs) in disease association studies, the genotyping platform of choice is constantly evolving. In addition, the development of more specific SNP assays and appropriate genotype validation applications is becoming increasingly critical to elucidate ambiguous genotypes. In this study, we have used SNP specific Locked Nucleic Acid (LNA) hybridization probes on a real-time PCR platform to genotype an association cohort and propose three criteria to address ambiguous genotypes. Based on the kinetic properties of PCR amplification, the three criteria address PCR amplification efficiency, the net fluorescent difference between maximal and minimal fluorescent signals and the beginning of the exponential growth phase of the reaction. Initially observed SNP allelic discrimination curves were confirmed by DNA sequencing (n = 50) and application of our three genotype criteria corroborated both sequencing and observed real-time PCR results. In addition, the tested Caucasian association cohort was in Hardy-Weinberg equilibrium and observed allele frequencies were very similar to two independently tested Caucasian association cohorts for the same tested SNP. We present here a novel approach to effectively determine ambiguous genotypes generated from a real-time PCR platform. Application of our three novel criteria provides an easy to use semi-automated genotype confirmation protocol.

Automation↗
PubMedDate not supplied

Pharmacogenetics approach to therapeutics.

1. Pharmacogenetics refers to the study of genetically controlled variations in drug response. Functional variants caused by single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolising enzymes, transporters, ion channels and drug receptors have been known to be associated with interindividual and interethnic variation in drug response. Genetic variations in these genes play a role in influencing the efficacy and toxicity of medications. 2. Rapid, precise and cost-effective high-throughput technological platforms are essential for performing large-scale mutational analysis of genetic markers involved in the aetiology of variable responses to drug therapy. 3. The application of a pharmacogenetics approach to therapeutics in general clinical practice is still far from being achieved today owing to various constraints, such as limited accessibility of technology, inadequate knowledge, ambiguity of the role of variants and ethical concerns. 4. Drug actions are determined by the interplay of several genes encoding different proteins involved in various biochemical pathways. With rapidly emerging SNP discovery technological platforms and widespread knowledge on the role of SNPs in disease susceptibility and variability in drug response, the pharmacogenetics approach to therapeutics is anticipated to take off in the not-too-distant future. This will present profound clinical, economic and social implications for health care.

ATP-Binding Cassette Transporters↗
PubMed2005

Development of an automation system for single nucleotide polymorphisms genotyping using bio-strand, a new three-dimensional microarray.

Previously, we developed a novel three-dimensional microarray system called Bio-Strand, which may be used in various applications including single nucleotide polymorphisms genotyping. In Bio-Strand, samples for detection are immobilized on a one-dimensional thread, which is wound around a cylinder-shaped core to form a three-dimensional thread-and-core structure. The thread-and-core structure is then inserted into a plastic pipette tip, where hybridization and detection are performed. In this study, we have developed an automation system, NIAGALA Bio-Station SDx, which enables automated hybridization and detection during the genotyping procedure using Bio-Strand. Using this system, we have performed the single nucleotide polymorphism (SNP) genotyping of CYP2C, one of the important human cytochrome P450 genes and the results were completely consistent with the genotyping results determined by the TaqMan method.

Algorithms↗
PubMed2004

Fine mapping a gene for pediatric gastroesophageal reflux on human chromosome 13q14.

We previously mapped a gene for severe pediatric gastroesophageal reflux disease ( GERD1) to a 9-cM interval on chromosome 13q14. In this report, we present the results of DNA sequencing and allelic association analyses that were done in an attempt to clone the GERD1 gene. Using a candidate transcript approach, we screened affected individuals for mutations in all transcribed regions of all genes, putative genes, and ESTs identified within the 6.2-Mb GERD1 locus based on alignments with the GenBank cDNA databases. From a total of 50 identifiable genes and 99 EST clusters in the GERD1 locus, we identified 163 polymorphisms (143 SNPs and 20 INDELs) in 21 genes and 37 ESTs. The patterns of inheritance and/or the high population frequencies of all polymorphic alleles identified in this study argued against causative relationships between any of the alleles and the GERD phenotype. Using a subset of 51 SNPs distributed throughout the GERD1 locus, we performed case-control and family (TDT) allelic association analyses on two sets of samples. The case-control study was performed with 73 GERD cases and 93 controls, and the family study was performed using 22 small families. SNP 160 (position 38,925,329 Mb, UCSChg15 map) gave a significant P value prior to multiple test correction in both the case control and family studies, while SNP168 (at 40,442,903 Mb) showed significant association after multiple test correction in the case-control sample, but was uninformative in the family sample. The results suggest that the GERD1 gene might be located near SNP160 or SNP168.

Adult↗
PubMed2002

ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels.

The authors have previously shown that individuals heterozygous for ABCA1 mutations have decreased high density lipoprotein cholesterol, increased triglycerides and an increased frequency of coronary artery disease (CAD), and that single nucleotide polymorphisms (SNPs) in the coding region of the ABCA1 gene significantly impact plasma lipid levels and the severity of CAD in the general population. They have now identified several SNPs in non-coding regions of ABCA1 which may be important for the appropriate regulation of ABCA1 expression (i.e. in the promoter, intron 1 and the 5' untranslated region), and have examined the phenotypic effects of these SNPs in the REGRESS population. Out of 12 SNPs, four were associated with a clinical outcome. A threefold increase in coronary events with an increased family history of CAD was evident for the G-191C variant. Similarly, the C69T SNP was associated with a twofold increase in events. In contrast, the C-17G was associated with a decrease in coronary events and the InsG319 was associated with less atherosclerosis. For all these SNPs, the changes in atherosclerosis and CAD occurred without detectable changes in plasma lipid levels. These data suggest that common variation in non-coding regions of ABCA1 may significantly alter the severity of atherosclerosis, without necessarily influencing plasma lipid levels.

5' Untranslated Regions↗
PubMed2002

Allele-specific PCR amplification due to sequence identity between a PCR primer and an amplicon: is direct sequencing so reliable?

PCR-direct sequencing (DS) is thought to be a very reliable method of determining DNA sequence and genotyping. Under certain conditions, however, DS can generate inaccurate results. Here we report a case of erroneous DS, in which a single nucleotide polymorphism (SNP) in the human PAX9 gene was mistyped due to allele-dependent PCR amplification. Examination of the amplified region showed that the 5' eight bases of one of the PCR primers were identical to the eight bases of the reverse strand downstream of the SNP, and the ninth base matched one of the alleles. Altering the primer so that it matched the other allele reversed the allele-specific inhibition. Reducing the base-pairing abolished the inhibition. Thus, the SNP was responsible for the difference in annealing efficacy of the primer and was therefore critical for the allele dependency. The allele-specific inhibition presented here can occur with any PCR primer sequence that encompasses a site that is polymorphic in the gene sequence. This phenomenon needs to be considered as a possibility when interpreting results from all PCR-based experiments. Sequence similarity between PCR primers and internal amplified regions should be considered for all methods for mutation detection and genotyping using PCR.

Alleles↗
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↗
PubMedDate not supplied

Cytokine genes single nucleotide polymorphism (SNP) screening analyses in canine malignant histiocytosis.

In humans, malignant histiocytosis is a tumour-like disease characterised by increasing proliferation of macrophages and reinforced degradation of erythrocytes. High progression of this disease leads to an unfavourable prognosis for the patients, most of them children up to the age of three years. Histological and cytological findings have proposed an important role of aberrant expression of cytokines in histiocytosis. Due to the fact that Bernese Mountain Dogs (BMD) show a predisposition for spontaneously developing malignant histiocytosis, these dogs could possibly be used as a genetic model organism to elucidate the mechanisms of human malignant histiocytosis. Canine cytokine cDNA transcripts of TNFalpha, Interleukin-1-alpha (IL-1alpha) and Interleukin-1-beta (IL-1beta) were screened for single nucleotide polymorphisms (SNPs). SNP screening in canine cytokine transcripts for malignant histiocytosis has not been carried out before. Total RNA was isolated from tissue samples from lung, spleen, testis and skin of 17 different dogs (fifteen BMDs, one Collie and one West Highland Terrier). The corresponding cytokine cDNAs were amplified, sequenced and then screened for SNPs. The resulting effects on the protein sequence were analysed. Several BMDs and the West Highland Terrier showed SNPs in the coding sequences which led to missense mutations within the protein sequences of TNFalpha, IL1alpha and IL1beta.

Animals↗
PubMed2004

A highly informative SNP linkage panel for human genetic studies.

We have developed a highly informative set of single-nucleotide polymorphism (SNP) assays designed for linkage mapping of the human genome. These assays were developed on a robust multiplexed assay system to provide a combination of very high accuracy and data completeness with high throughput for linkage studies. The linkage panel is comprised of approximately 4,700 SNPs with 0.39 average minor allele frequency and 624-kb average spacing. Based on almost 2 million genotypes, data quality was shown to be extremely high, with a 99.94% call rate, >99.99% reproducibility and 99.995% genotypes consistent with mendelian inheritance. We constructed a genetic map with an average 1.5-cM resolution using series of 28 CEPH pedigrees. The relative information content of this panel was higher than those of commonly used STR marker panels. The potent combination of this SNP linkage panel with the multiplexed assay system provides a previously unattainable level of performance for linkage studies.

Algorithms↗
PubMed2006

CYP2C9 polymorphism and warfarin sensitivity in Taiwan Chinese.

BACKGROUND: Warfarin prevents thromboembolism in patients with prosthetic heart valvular replacement. Cytochrome P4502C9 (CYP2C9) is polymorphic in human and is principally responsible for the metabolism of warfarin. However, known CYP2C9 polymorphisms cannot entirely account for the low dose requirement of warfarin in Chinese-Taiwanese receiving mitral valve replacement. We screened a new polymorphism of CYP2C9 and investigated its role in warfarin sensitivity. METHODS: We examined warfarin dose requirements in 239 Chinese-Taiwanese patients who had attended a cardiac surgery clinic in National Taiwan University Hospital. DNA samples were obtained from 106 Chinese-Taiwanese (37 patients and 69 unrelated healthy controls), and healthy control subjects of Caucasians (n=28) and African-Americans (n=28). Four out of those 37 patients were poor metabolizers of warfarin, and their DNA were subjected to sequencing analysis. Moreover, CYP2C9 genotyping analyses were performed using PCR-RFLP analysis. The chi2 test and Fisher's exact test were used to compare the differences of the allelic frequency and genotype. The association between warfarin dose requirement and genetic polymorphism of CYP2C9 was also analysed. RESULTS: The mean daily warfarin dose was 3.11+/-1.62 mg for the maintenance of the international normalized ratio of 2 to 3 in 239 patients. A single nucleotide substitution from G to C was found in this study. This SNP, G-65/C, is in intron 3, 65 base pairs upstream of exon 4. The allelic frequencies of C-65 in healthy controls were 0.125, 0.058 and approximately 0 with respect to African-American, Chinese-Taiwanese and Caucasian, implying inter-ethnic variations of the C-65 allele. In addition, patients who were carrier of either the heterozygous or homozygous C-65 variant received half of the usual warfarin dose. CONCLUSION: The novel intronic G-65/C mutation appears to be inter-racially different in allelic frequency, and that the anticoagulation was affected in response to warfarin sensitivity in Chinese-Taiwanese patients receiving mitral valve replacement.

Adult↗