Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “nucleotide polymorphism patterns”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 523 records · Page 29Linked to original sources
PubMed2006

Intergeneration CAG expansion and contraction in a Chinese HD family.

The prevalence of juvenile-onset Huntington's disease (HD) is about ten times lower than adult HD. Here we report a Chinese HD family showing both intergeneration CAG expansion and contraction. The expansion resulted from a paternal transmission which leads to juvenile-onset HD for a 17-year-old Chinese boy (III-5). More interestingly, a contraction was noticed in a maternal transmission (III-3), which changed the CAG repeat from an expanded, disease-causing allele (48 repeats) to a normal or intermediate allele (34 repeats). Of note, the contraction resulted in a deletion of 14 CAG repeats, which is much larger than previously reported contractions. Our results are consistent with previous observations in Western Caucasians that juvenile-onset HD is more likely inherited through the male germline.

Adolescent↗
PubMed2026

Shared genetic architecture and therapeutic targets across paediatric immune-mediated diseases.

OBJECTIVES: Paediatric-onset immune-mediated inflammatory diseases (IMIDs), including juvenile idiopathic arthritis and related rheumatic diseases, remain genetically undercharacterised. We aimed to define shared and category-specific genetic architecture across paediatric IMIDs, compare signals with adult IMIDs, and identify therapeutic opportunities. METHODS: We analysed 24 paediatric IMIDs classified as autoimmune, polygenic-autoinflammatory, mixed-pattern, or allergic. Genome-wide association analyses included 18,086 cases and 131,019 controls of European ancestry. We estimated single nucleotide polymorphism (SNP)-based heritability, genetic correlations, and polygenic overlap; performed subset-based meta-analysis; and conducted functional annotation, gene prioritisation, pathway and protein network analyses, adult-IMID comparison, and drug-target prioritisation. RESULTS: SNP-based heritability ranged from 28.9% for allergic IMIDs to 61.9% for autoimmune IMIDs. Genetic correlation and polygenic modelling supported partial sharing across categories with category-specific components. Meta-analysis identified 39 genome-wide significant loci outside the Major Histocompatibility Complex (MHC) region, including 15 previously unreported loci; 19 loci were shared between categories. Gene-prioritisation and protein interaction analyses identified a core MHC-centred antigen-presentation network, with category-enriched modules involving complement, innate/barrier pathways, epithelial biology, and type 2 immunity. Enriched pathways included nuclear factor κB signalling, T helper 17 related pathways, Janus kinase-signal transducer and activator of transcription signalling, programmed cell death protein 1/programmed death‑ligand 1, cytotoxic T‑lymphocyte associated protein 4 regulation, and osteoclast differentiation, several of which are relevant to rheumatic diseases. Paediatric IMIDs shared broad polygenic architecture with adult IMIDs, whereas top-ranked genes converged strongly with adult rheumatic diseases. Priority Index analysis identified 178 high-scoring genes, including 43 approved or investigational IMID drug targets. CONCLUSIONS: Paediatric-onset IMIDs share core pathways with adult forms but exhibit distinct genetic architecture shaped by age-specific immune and neurodevelopmental biology. These findings provide a genomic framework for paediatric precision medicine, guiding classification, risk prediction, and therapeutic development.

Humans↗
PubMed2005

Cloning and characterization of the canine receptor for advanced glycation end products.

Metastasis is one of the major problems when dealing with malignant neoplasias. Accordingly, the finding of molecular targets, which can be addressed to reduce tumour metastasising, will have significant impact on the development of new therapeutic approaches. Recently, the receptor for advanced glycation end products (RAGE)-high mobility group B1 (HMGB1) protein complex has been shown to have significant influence on invasiveness, growth and motility of tumour cells, which are essential characteristics required for metastatic behaviour. A set of in vitro and in vivo approaches showed that blocking of this complex resulted in drastic suppression of tumour cell growth. Due to the similarities of human and canine cancer the dog has joined the common rodent animal model for therapeutic and preclinical studies. However, complete characterisation of the protein complex is a precondition to a therapeutic approach based on the blocking of the RAGE-HMGB1 complex to spontaneously occurring tumours in dogs. We recently characterised the canine HMGB1 gene and protein completely. Here we present the complete characterisation of the canine RAGE gene including its 1384 bp mRNA, the 1215 bp protein coding sequence, the 2835 bp genomic structure, chromosomal localisation, gene expression pattern, and its 404 amino acid protein. Furthermore we compared the CDS of six different canine breeds and screened them for single nucleotide polymorphisms.

Amino Acid Sequence↗
PubMed2000

Cladistic structure within the human Lipoprotein lipase gene and its implications for phenotypic association studies.

Haplotype variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase (LPL) gene was scored in three populations: African-Americans from Jackson, Mississippi (24 individuals), Finns from North Karelia, Finland (24), and non-Hispanic whites from Rochester, Minnesota (23). Earlier analyses had indicated that recombination was common but concentrated into a hotspot and that recurrent mutations at multiple sites may have occurred. We show that much evolutionary structure exists in the haplotype variation on either side of the recombinational hotspot. By peeling off significant recombination events from a tree estimated under the null hypothesis of no recombination, we also reveal some cladistic structure not disrupted by recombination during the time to coalescence of this variation. Additional cladistic structure is estimated to have emerged after recombination. Many apparent multiple mutational events at sites still remain after removing the effects of the detected recombination/gene conversion events. These apparent multiple events are found primarily at sites identified as highly mutable by previous studies, strengthening the conclusion that they are true multiple events. This analysis portrays the complexity of the interplay among many recombinational and mutational events that would be needed to explain the patterns of haplotype diversity in this gene. The cladistic structure in this region is used to identify four to six single-nucleotide polymorphisms (SNPs) that would provide disequilibrium coverage over much of this region. These sites may be useful in identifying phenotypic associations with variable sites in this gene. Evolutionary considerations also imply that the SNPs in the 3' region should have general utility in most human populations, but the 5' SNPs may be more population specific. Choosing SNPs at random would generally not provide adequate disequilibrium coverage of the sequenced region.

Black or African American↗
PubMed2006

Association study of the dystrobrevin-binding gene with schizophrenia in Australian and Indian samples.

Numerous studies have reported association between variants in the dystrobrevin binding protein 1 (dysbindin) gene (DTNBP1) and schizophrenia. However, the pattern of results is complex and to date, no specific risk marker or haplotype has been consistently identified. The number of single nucleotide polymorphisms (SNPs) tested in these studies has ranged from 5 to 20. We attempted to replicate previous findings by testing 16 SNPs in samples of 41 Australian pedigrees, 194 Australian cases and 180 controls, and 197 Indian pedigrees. No globally significant evidence for association was observed in any sample, despite power calculations indicating sufficient power to replicate several previous findings. Possible explanations for our results include sample differences in background linkage disequilibrium and/or risk allele effect size, the presence of multiple risk alleles upon different haplotypes, or the presence of a single risk allele upon multiple haplotypes. Some previous associations may also represent false positives. Examination of Caucasian HapMap phase II genotype data spanning the DTNBP1 region indicates upwards of 40 SNPs are required to satisfactorily assess all nonredundant variation within DTNBP1 and its potential regulatory regions for association with schizophrenia. More comprehensive studies in multiple samples will be required to determine whether specific DTNBP1 variants function as risk factors for schizophrenia.

Alleles↗
PubMed2000

[Detection of core promoter mutations in chronic hepatitis B].

OBJECTIVE: To study the core promoter mutation in chronic hepatitis B and its effect on viral serology. METHODS: HBV core promoter gene fragments were amplified by using mismatched PCR combined with a restriction fragment length polymorphism assay. The PCR products were digested with Bcl I and subjected to electrophoresis on agarose gels. RESULTS: We investigated the core promoter mutation in 89 patients with HBV DNA positive. The patterns of restriction fragment length polymorphism (RFIP) of the core promoter gene were distinguished and verified by direct sequencing. The combined mutations of nucleotides (nt) 1762 and 1764 in the core promoter from A to T and G to A were detected in 47 individuals, 21 of 43 HBeAg positive patients and 26 of 46 anti- HBe positive cases were found infected with this combined mutant. These two groups showed no significant difference (P > 0.05). The combined mutation was found in 11 of the 15 patients with medium and severe chronic hepatitis. In 5 chronic hepatitis B patients with coexistence of wild-type and mutant a tendency of superior accumulation of mutant was found. CONCLUSIONS: This study suggests that the core promoter mutations commonly exist in Chinese chronic hepatitis B patients. The mutation can only reduce the pre-core mRNA transcribing efficiency, but cannot discontinue the synthesis of HBeAg. The effect on serology in this mutation is different from that in pre-core stop 28 mutation. The superior accumulation of mutations seems relating to the degree of chronic liver disease.

Adolescent↗
PubMed1999

Characterisation of the lpdA gene from Neisseria meningitidis by polymerase chain reaction, restriction fragment length polymorphism and sequencing.

P64k protein from Neisseria meningitidis is well recognised in sera from individuals convalescent from meningococcal disease or vaccinated with the Cuban antimeningococcal vaccine VA-MENGOC-BC. The presence of the protein in more than 80 meningococcal strains has also been verified. It is immunogenic in animal models and the antibodies elicited show bactericidal activity against meningococci. To further investigate at the molecular level whether lpdA, the gene coding for P64k protein, is conserved among different N. meningitidis strains, a total of 20 strains isolated from different geographic areas were differentiated on the basis of restriction fragment length polymorphism (RFLP) patterns after polymerase chain reaction (PCR) amplification of the lpdA gene and restriction endonuclease digestion with HpaII. Although a total of five different PCR-RFLP patterns were present, nucleotide sequence determination showed that identity levels were as high as 93-99% among the N. meningitidis strains analysed.

Amino Acid Sequence↗
PubMed1998

Definition and distribution analysis of glycoprotein B gene alleles of human herpesvirus 7.

As for other herpesviruses, glycoprotein B (gB) of human herpesvirus 7 (HHV-7) is believed to play a major role in virus infection and as a target of the host immunogenic response. Using nested PCR, we amplified the whole HHV-7 gB gene from 108 human peripheral blood mononuclear cell samples and studied its variability. By means of restriction fragment length polymorphism (RFLP) analysis, three distinct patterns, designated I, II, and III, were defined and detected at frequencies of 93, 5, and 2%, respectively. Determination of the nucleotide sequence allowed us to recognize five critical positions in the gB gene with six specific combinations of point changes at these positions. These combinations were gB alleles A, B, C, D, E, and F. Alleles D and E corresponded to RFLP patterns II and III, respectively, while the other four alleles corresponded to RFLP pattern I. Identical gB alleles were detected in serial samples as well as in paired samples of blood and saliva from the same individuals, except for one case. In contrast, the distribution of gB alleles differed according to the geographical origin of the human samples: C was the most frequent allele in both African and Caribbean samples, whereas F was the most frequent allele in European ones. Although none of the allele-specific nucleotide changes induced any modification at the protein level, the definition of gB alleles provided convenient viral markers for the study of both HHV-7 infections and human population genetics.

Africa↗
PubMed2001

Nucleotide polymorphism and natural selection at the pantophysin (Pan I) locus in the Atlantic cod, Gadus morhua (L.).

Molecular studies of nucleotide sequence variation have rarely attempted to test hypotheses related to geographically varying patterns of natural selection. The present study tested the role of spatially varying selection in producing significant linkage disequilibrium and large differences in the frequencies of two common alleles at the pantophysin (Pan I) locus among five populations of the Atlantic cod, Gadus morhua. Nucleotide sequences of 124 Pan I alleles showed strong evidence for an unusual mix of balancing and directional selection but no evidence of stable geographically varying selection. The alleles were highly divergent at both the nucleotide level (differing on average by 19 mutations) and at amino acid level (each having experienced three amino acid substitutions since diverging from a common ancestral allele). All six amino acid substitutions occurred in a 56-residue intravesicular loop (IV1 domain) of the vesicle protein and each involved a radical change. An analysis of molecular variation revealed significant heterogeneity in the frequencies of recently derived mutations segregating within both allelic classes, suggesting that two selective sweeps may be presently occurring among populations. The dynamic nature of the Pan I polymorphism in G. morhua and clear departure from equilibrium conditions invalidate a simple model of spatially varying selection.

Alleles↗
PubMed2002

Tumour necrosis factor-alpha polymorphism and the HLA-Cw*0602 allele in psoriatic arthritis.

OBJECTIVES: To investigate polymorphisms in the genes for tumour necrosis factor alpha (TNFA), interleukin 10 (IL10) and tumour necrosis factor receptor II (TNFRII) in patients with psoriatic arthritis (PsA) and their relationship to the HLA-Cw*0602 allele and to the ages at onset of psoriasis and arthritis and the pattern of joint involvement. METHODS: One hundred and twenty-four well-characterized patients with PsA were studied. Controls were 101 cadaveric organ donors. All were genotyped for single-nucleotide polymorphisms in TNFA (positions -308, -238, +488), IL10 (-1082, -819, -592) and in the 3'-untranslated region of TNFRII (+1663, +1668, +1690). The HLA-Cw*0602 allele was detected by polymerase chain reaction-based techniques. The frequencies of the respective variants were compared between patients and controls and in relation to the ages at onset of psoriasis and arthritis, to clinical subsets of the disease and to the presence of erosions. RESULTS: HLA-Cw*0602 was significantly increased in frequency in PsA (40 vs 26%; P<0.05) and was associated with younger age of onset of psoriasis (P<0.05). There was no significant increase in any of the polymorphisms studied within TNFA, IL10 or TNFRII in the total PsA group. Although the frequency of TNFA allele -238A was not increased in the total PsA group or in patients with a younger age of onset of psoriasis, TNFA allele -238A was absent in the spondyloarthritis group and increased in frequency in patients with peripheral polyarthritis. However, these latter findings could be explained by linkage disequilibrium as all TNFA -238A alleles (23/23) in patients with PsA were HLA-Cw*0602-positive (P<0.0001). CONCLUSIONS: An association between young age of onset of psoriasis and HLA-Cw*0602 is confirmed in patients with PsA. The uncommon TNFA -238A allele is strongly linked to HLA-Cw*0602 and as such is associated with the development of peripheral polyarthritis rather than spondylitis. Further investigation of possible HLA-Cw*0602 linked genes in PsA is warranted.

Adult↗
PubMed1995

Genotyping of ABO blood groups by PCR and RFLP analysis of 5 nucleotide positions.

The genotyping of ABO blood groups was performed using the polymerase chain reaction (PCR) method. The 4 DNA fragments containing the nucleotide position 261, 526, 703 and 796 of cDNA from A-transferase were amplified by PCR, and the amplified DNA subjected to restriction fragment length polymorphism (RFLP) analysis. The different nucleotide at position 803 was clearly distinguished by electrophoresis of the PCR products amplified with allele-specific primers. By analyzing the electrophoresis patterns, ABO genotyping was conclusively accomplished. The frequencies of ABO genotypes found in Japanese blood donors with A and B phenotypes were as follows: in the phenotype A group, AA = 19.8% and AO = 80.2%; and in the phenotype B group, BB = 12.8% and BO = 87.2%.

ABO Blood-Group System↗
PubMed2004

Genetic variability of arylalkylamine-N-acetyl-transferase (AA-NAT) gene and human sleep/wake pattern.

The cyclic production and secretion of melatonin has been associated with the sleep/wake cycle as well as other circadian rhythms. Since arylalkylamine-N-acetyl-transferase (AA-NAT) is the rate-limiting enzyme responsible for the production of melatonin, it has been postulated to determine the circadian oscillations of melatonin. Genetic variability of the AA-NAT gene may therefore potentially influence sleep patterns in the normal population. In this study, a sleep pattern survey was performed in 210 students. Five subjects with early sleep onset time and long sleep duration (early/long sleepers), and 5 subjects with late sleep onset time and short sleep duration (late/short sleepers) were identified for genetic studies. All 10 subjects had identical sequences throughout the coding regions of the AA-NAT gene. In the promoter region, a -263G/C (relative to the transcription start site) single nucleotide polymorphism (SNP) was observed in 4 of the 5 late/short sleepers, but in only 1 of 5 early/long sleepers. The -263G/C SNP may therefore be an important determinant of the late/short sleep pattern.

Adolescent↗
PubMed2006

Molecular evidence for infection by HTLV-2 among individuals with negative serological screening tests for HTLV antibodies.

Previous serological studies on the Arara do Laranjal Indian group revealed extensive HTLV-2 infections. A collection of 97 new samples from the Arara were found repeatedly negative using three different commercial enzyme immunoassays. Eight samples that exhibited optical density readings close to the cut-off value were re-evaluated using Western blot (GeneLab 2.4, Singapore) assay. One sample was found to be non-reactive, five exhibited indeterminate patterns, one was classified as HTLV, and one was confirmed as HTLV-2. Peripheral blood mononuclear cell DNA of the eight samples were subjected to nested PCR and restriction fragment length polymorphism (RFLP) analysis of the pX and env regions, and nucleotide sequencing of the 5'-LTR region. All produced amplification products of pX, but env could be amplified in only one sample with the commonly used primers. RFLP analysis of the pX region using TaqI confirmed HTLV-2 infection. Nucleotide sequencing of the 5'-LTR region was performed in three samples (HTLV-2, HTLV and indeterminate based on Western blot pattern). Phylogenetic analysis of a 449-nt fragment using the Neighbour-Joining method clearly demonstrated that the three samples clustered within the HTLV-2c molecular subtype. The present study confirms the wide dissemination of the HTLV-2c subtype among linguistically and culturally distinct Amazonian Indian groups, and emphasizes the unique occurrence of infection by this subtype in Brazil. Moreover, it emphasizes the limitation of employing the present serological screening assays in blood banks, epidemiological studies, and the importance of molecular assays in the confirmatory procedures for the primary detection of HTLV-2 infections.

Brazil↗
PubMed2005

SNP selection for association studies: maximizing power across SNP choice and study size.

Selection of single nucleotide polymorphisms (SNPs) is a problem of primary importance in association studies and several approaches have been proposed. However, none provides a satisfying answer to the problem of how many SNPs should be selected, and how this should depend on the pattern of linkage disequilibrium (LD) in the region under consideration. Moreover, SNP selection is usually considered as independent from deciding the sample size of the study. However, when resources are limited there is a tradeoff between the study size and the number of SNPs to genotype. We show that tuning the SNP density to the LD pattern can be achieved by looking for the best solution to this tradeoff. Our approach consists of formulating SNP selection as an optimization problem: the objective is to maximize the power of the final association study, whilst keeping the total costs below a given budget. We also propose two alternative algorithms for the solution of this optimization problem: a genetic algorithm and a hill climbing search. These standard techniques efficiently find good solutions, even when the number of possible SNPs to choose from is large. We compare the performance of these two algorithms on different chromosomal regions and show that, as expected, the selected SNPs reflect the LD pattern: the optimal SNP density varies dramatically between chromosomal regions.

Gene Frequency↗
PubMed1991

Genetic variation of putative core gene in hepatitis C virus.

Genetic variation of hepatitis C virus was assessed. We prepared RNA fractions from 21 patients' sera which were positive for hepatitis C virus RNA, synthesized their cDNAs, and amplified fragments, 406 base pairs, encoding a putative core protein, by polymerase chain reaction. One of them, N 15, was cloned and sequenced. N 15 showed 92.4% homology at the nucleotide level and 97.0% homology at the amino acid level compared with HC-J 1 which is the first isolated clone in Japan and similar to that isolated in USA. By restriction fragment length polymorphisms analysis, 14 out of 21 patients (66.7%) showed the same pattern as N 15. No patients showed the pattern of HC-J 1. We could not find a correlation between the genetic variation and clinical features of hepatitis C virus infection. These results indicate that the region, which encodes the core protein and is believed to be relatively conserved in hepatitis C virus genome, has several variations at the nucleotide level, and the major part of hepatitis C virus in Okayama district is different from HC-J 1 and the USA clone.

Adult↗
PubMed2004

Insulin gene profile cycles with season of birth of future diabetic children and their relatives.

BACKGROUND: HLA class II gene pattern and IA-2A antibody positivity, revealing selected risks for prediction of type 1 diabetes mellitus (DM1), were previously shown to be cycling roughly in parallel with seasonally fluctuating frequencies of births of future diabetic children. Is this also true for insulin genotyping? Is this also true for births of the healthy close relatives of children with DM1? PATIENTS AND METHODS: In 98 Slovak children with DM1 and in 60 healthy parents and siblings, two single nucleotide polymorphisms of the insulin gene (-23 Hph I; +1127 Pst I) were typed. Results were expressed as score 0 (maximal risk) up to 2 (minimal risk or protection), or 0-4 for the sum of both scores. Birth seasonality of these risk scores was tested by Halberg cosinor regression. RESULTS: Results were similar for the two alleles; therefore, the summed risk score was evaluated. The DM1 risk from the insulin gene pattern in births of future diabetics cycled significantly semi-annually, with maxima around the spring and autumn equinoxes. In the relatives, a significant annual and extremely pronounced quarterly peaking rhythm was found, with maximum risk in births around the autumn equinox and shortly after the winter solstice. Significant protection peaks are present in late winter, spring and summer. CONCLUSION: The highest frequency of Coxsackie infections in the Slovakian child population, and of 'diabetic' births and manifestations, found earlier together with maximal risks from HLA II and IA-2A antibodies in late summer and early autumn, is now confirmed also for the insulin gene pattern in diabetic children and even also for their healthy close relatives.

Adult↗
PubMed2006

Development of a multiplex PCR assay for polymorphism analysis of Brucella suis biovars causing brucellosis in swine.

Swine brucellosis is caused by the biovars 1, 2 and 3 of Brucella suis the identification of which up to now relies on microbiological tests lacking adequate specificity together with time consuming and expensive molecular procedures. Based on sequence variation of the omp2b gene, we have developed a four primer set multiplex PCR assay that was tested for polymorphism analysis of B. suis biovars causing brucellosis in swine. The assay exploits the single nucleotide polymorphisms found in omp2b gene of B. suis reference biovars which are conserved in 43 B. suis field isolates from different geographic origins and hosts. Three specific amplification patterns (S1, S2 and S3) were obtained for reference strains of B. suis biovars 1, 2 and 3, respectively. However, some B. suis field isolates identified as biovars 2 or 3 according AMOS-PCR, PCR-RFLP of omp31 and omp2 genes and classical bacteriological methods, resulted also in S1 patterns, limiting the typing usefulness of the method.

Amino Acid Sequence↗
PubMed2000

The impact of genomics on therapeutic drug development.

Genomics can be defined as a set of related technologies that are focused on the discovery of genes implicated in human disease. Although many of the estimated 100,000 genes in the human genome have been at least partially identified by nucleotide sequence, elucidation of biological function has been achieved for only a small percentage of these. An even smaller percentage of genes discovered by these methodologies have become valid drug targets. This review discusses the various genomics technologies and their likelihood of yielding therapeutic drugs. Emerging advances in microarray "chip" technology have allowed the parallel analysis of gene expression patterns for thousands of genes simultaneously. Sequence information derived from the genomes of many individuals is leading to the rapid discovery of single nucleotide polymorphisms or SNPs. Detection of these human polymorphisms will fuel the discipline of pharmacogenomics, resulting in an increase in the success of clinical trials, the rescue of drugs that have previously failed in clinical trials because of adverse reactions from patient subpopulations, and ultimately, in the development of more personalized drug therapies. The impending identification of all human genes will signal the end of the structural genomics phase and usher in the function genomics phase. Technologies have already begun to move toward high-throughput elucidation of gene relationships, interactions and, it is hoped, toward their functions.

Biotechnology↗