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At least 685 records · Page 38Linked to original sources
PubMed2005

Lipoprotein lipase gene is linked and associated with hypertension in Taiwan young-onset hypertension genetic study.

Hypertriglyceridemia has been extensively associated with hypertension. However, the mechanism behind it is poorly understood. A positive linkage signal between Lipoprotein lipase (LPL) and young-onset hypertension has been identified by us as the strongest among 18 candidate genes. Here we report our fine mapping works with seven microsatellite markers flanking LPL, sequencing results for its promoter and exons, and an extended association study with the identified single nucleotide polymorphisms(SNP). First, using data from 213 individuals in 59 nuclear families of young-onset hypertension, multipoint analysis revealed a NPL score of 3.02 for the LPL (GZ-14/GZ-15) marker in intron 6. LPL marker (p < 10(-12)) and the haplotypes containing its allele 1 (p < 0.0001) were also significantly associated with young hypertension by transmission disequilibrium test. In-depth sequencing revealed no mutation in promoter and exon regions, except two cSNP: 7754C--> A (C/A: 0.91/0.09), a silent mutation in exon 8 and S447X (C/G: 0.92/0.08), a stop codon mutation in exon 9. Other 11 cSNPs documented in NCBI GenBank are absent in our sample. Constructed from the above 2 cSNPs, haplotype AC showed a moderate TDT association with elevated triglyceride (p = 0.02) and with hypertension and elevated triglyceride combined (p = 0.06). Again, in an extended case-control study, a significant association was found between S447X and patients with persistent hypertension and elevated triglyceride (p = 0.02). We conclude that LPL variants may play a causal role in the development of hypertension in Taiwan Han Chinese. The moderate association with SNP haplotype suggests that other regulatory LPL variant may exist.

Adult↗
PubMed2001

Single nucleotide polymorphism (D68D, T to C) in the syntaxin 1A gene correlates to age at onset and insulin requirement in Type II diabetic patients.

AIM/HYPOTHESIS: Syntaxin 1A is a candidate gene for Type II (non-insulin-dependent) diabetes mellitus, because it plays an important role in insulin secretion from the islet beta cells. We aimed to scan this gene for mutations or genetic markers that correlate with Type II diabetes. METHODS: We identified and characterized coding exons of the syntaxin 1A gene and scanned the newly identified 10 exons using direct sequencing. RESULTS: In the single nucleotide polymorphism (SNP) of exon 3 (D68D, T to C) among three newly identified SNPs, genotype frequency of the homozygote of C allele (CC) occurred more frequently in a Type II diabetic group than in a non-diabetic group (16.48 %, n = 182, vs 11.05 %, n = 181, p = 0.0499). Among the diabetic patients, age of onset in patients with CC genotype was lower than that in patients with the TT and TC genotypes [40.10 +/- 1.50 years old (means +/- SEM) vs 44.20 +/- 0.58, p = 0.005]. Patients with the CC genotype had a higher frequency of insulin treatment (78.30 % vs 46.80 %, p = 0.006) with a duration equal to, or longer than, 10 years. Multiple regression analysis confirmed that the genotype was significantly and independently associated with age at onset and mode of treatment, respectively. CONCLUSION/INTERPRETATION: These data indicate that the SNP in the syntaxin 1A gene (D68D, T to C) correlates to the age of onset and insulin requirements of Type II diabetic Japanese patients.

Age of Onset↗
PubMed2004

Assessing function and pathology in familial dysautonomia: assessment of temperature perception, sweating and cutaneous innervation.

This study was performed to assess cutaneous nerve fibre loss in conjunction with temperature and sweating dysfunction in familial dysautonomia (FD). In ten FD patients, we determined warm and cold thresholds at the calf and shoulder, and sweating in response to acetylcholine iontophoresis over the calf and forearm. Punch skin biopsies from calf and back were immunostained and imaged to assess nerve fibre density and neuropeptide content. Mean temperature thresholds and baseline sweat rate were elevated in the patients, while total sweat volume and response time did not differ from controls. The average density of epidermal nerve fibres was greatly diminished in the calf and back. There was also severe nerve loss from the subepidermal neural plexus (SNP) and deep dermis. The few sweat glands present within the biopsies had had reduced innervation density. Substance P immunoreactive (-ir) and calcitonin gene related peptide-ir (CGRP-ir) were virtually absent, but vasoactive intestinal peptide-ir (VIP-ir) nerves were present in the SNP. Empty Schwann cell sheaths were observed. Temperature perception was more impaired than sweating. Epidermal nerve fibre density was found to be profoundly reduced in FD. Decreased SP and CGRP-ir nerves suggest that the FD gene mutation causes secondary neurotransmitter depletions. Empty Schwann cell sheaths and VIP-ir nerves suggest active denervation and regeneration.

Adolescent↗
PubMed2005

UDP-glucuronosyltransferase 1A4 polymorphisms in a Japanese population and kinetics of clozapine glucuronidation.

The UDP-glucuronosyltransferase (UGT) family plays a major role in the excretion of endobiotics and xenobiotics and their metabolites. Human UGT1A4 catalyzes the glucuronidation of primary, secondary, and tertiary amines, sapogenins, androgens, and progestins. We directly sequenced polymerase chain reaction-amplified fragments of the UGT1A4 gene from 100 healthy adult Japanese volunteers and calculated their mutation frequency. We identified four single nucleotide polymorphisms (SNPs): three in exon 1 (142T > G: L48V, 448T > C: L150L, 804G > A: P268P), and one in intron 1 (867 + 43C > T). We found three types of alleles with distinct SNP combinations that coded for different amino acid sequences: L48V-L150L-P268P-867 + 43C > T (frequency, 0.155), L48V (0.01), and P268P (0.01) (wild-type frequency was 0.825). The L48V mutant gave twice the efficiency (V(max)/K(m)) for the antipsychotic drug clozapine as the wild-type. Efficiencies of L48V for trans-androsterone, imipramine, and cyproheptadine were increased, but the efficiency for tigogenin was reduced. L48V therefore increased or decreased the glucuronidation activity, depending upon the substrates. This study shows the importance of identifying patients with the L48V polymorphism when calculating dosage, and when considering the potential adverse effects of drugs that are substrates of UGT1A4.

Alleles↗
PubMed2006

Genetic association of the antiviral restriction factor TRIM5alpha with human immunodeficiency virus type 1 infection.

The innate antiviral factor TRIM5alpha restricts the replication of some retroviruses through its interaction with the viral capsid protein, leading to abortive infection. While overexpression of human TRIM5alpha results in modest restriction of human immunodeficiency virus type 1 (HIV-1), this inhibition is insufficient to block productive infection of human cells. We hypothesized that polymorphisms within TRIM5 may result in increased restriction of HIV-1 infection. We sequenced the TRIM5 gene (excluding exon 5) and the 4.8-kb 5' putative regulatory region in genomic DNA from 110 HIV-1-infected subjects and 96 exposed seronegative persons, along with targeted gene sequencing in a further 30 HIV-1-infected individuals. Forty-eight single nucleotide polymorphisms (SNPs), including 20 with allele frequencies of >1.0%, were identified. Among these were two synonymous and eight nonsynonymous coding polymorphisms. We observed no association between TRIM5 polymorphism in HIV-1-infected subjects and their set-point viral load after acute infection, although one TRIM5 haplotype was weakly associated with more rapid CD4(+) T-cell loss. Importantly, a TRIM5 haplotype containing the nonsynonymous SNP R136Q showed increased frequency among HIV-1-infected subjects relative to exposed seronegative persons, with an odds ratio of 5.49 (95% confidence interval = 1.83 to 16.45; P = 0.002). Nonetheless, we observed no effect of individual TRIM5alpha nonsynonymous mutations on the in vitro HIV-1 susceptibility of CD4(+) T cells. Therefore, any effect of TRIM5alpha polymorphism on HIV-1 infection in primary lymphocytes may depend on combinations of SNPs or on DNA sequences in linkage disequilibrium with the TRIM5alpha coding sequence.

Adult↗
PubMed2005

Alu-associated enhancement of single nucleotide polymorphisms in the human genome.

Identifying features shaping the architecture of sequence variations is important for understanding genome evolution and mapping disease loci. In this study, high-resolution scanning of Alu-centered alignments of the human genome sequences has revealed a striking elevation of the frequency of single nucleotide polymorphisms (SNP) in the body and tail of Alu sequences compared to flanking regions. This enhancement in SNP density is evident for all twenty-four chromosomes, and in both the Alu-body and Alu-tail, which together may be referred to as the Alu-SNPs. Reduced levels of Alu-SNPs in the sex chromosomes, especially in the non-recombining NRY region of the Y chromosome, are consistent with recombination events playing an important role in the enhancement. The Alu elements are unstable recombination-mutation hotspots in the human genome, and it is suggested that the Alu-SNPs represent a key manifestation of this instability. Variations in Alu-SNPs among the HapMap populations of northern and western European ancestry (CEU), Han Chinese from Beijing (CHB), Japanese from Tokyo (JPT), and Yoruba from Ibadan, Nigeria (YRI) indicate that the Alu-SNPs provide useful sequence markers, in addition to the Alu-insertion polymorphisms themselves, for the delineation of human genome evolution. That Alu-SNP levels are highest in the youngest Alu-Y, intermediate in the Alu-S of intermediate age, and lowest in the oldest Alu-J is consistent with the occurrence of not only genetic drift but also natural selection on the Alu-SNPs. Such evolutionary selection in turn suggests that Alu-SNPs might include potential sites of disease association, and therefore deserve detailed investigation.

Alu Elements↗
PubMed2002

[Analysis of mutation sites of BRCA1 gene in Chinese patients with breast cancer].

OBJECTIVE: To detect the mutation sites of exons 2, 20, 11A and 11B in Chinese patients with breast cancer. METHODS: A total of 86 patients with breast cancer without blood relationship were randomly selected. Polymerase chain reaction (PCR) and double-strand DNA direct sequencing were applied. RESULTS: No mutations, especially deletions were found in exons 2, 20 and 11 with carefully checking the sequencing results, although they were reported frequently in Europe populations with breast cancer. We found one polymorphism in exon 11, with high frequency, and in the test of chi-square, the frequencies of two alleles had no significant difference between the patients and controls. CONCLUSION: The above results suggest this SNP may not be associated with the breast cancer in Chinese population, and indicates that the gene sequence of what we have studied doesn't account much for occurrence of the breast cancer in the population of China.

Asian People↗
PubMed2006

Anthracene based base-discriminating fluorescent oligonucleotide probes for SNPs typing: synthesis and photophysical properties.

2- and 9-Anthracenecarboxamide labeled 2'-deoxyuridines were synthesized and their photophysical properties were examined. These oligonucleonucleotide probes are capable of detecting adenine base on a target DNA sequence. It was also found that 2-anthracene based oligonucleotide probe is more efficient than the corresponding 9-anthracene based oligonucleotide in the application for DNA chip based SNP detection, due to its longer emission wavelength and high fluorescence intensity.

Adenine↗
PubMed2005

An SNP in protamine 1: a possible genetic cause of male infertility?

Gene targeting of the sperm nuclear proteins, the protamines, in mice leads to haploinsufficiency, abnormal chromatin compaction, sperm DNA damage, and male infertility. In order to investigate whether changes in amount or structure of the protamines could be a cause of human infertility, we sequenced the protamine genes of infertile men whose sperm appeared phenotypically similar to those of protamine deficient mice. We identified a heterozygous single nucleotide polymorphism (SNP) in the protamine (PRM1) gene in three infertile men (10% of the total infertile men analysed). This SNP disrupts one of the highly conserved arginine clusters needed for normal DNA binding. To rapidly screen for this SNP in infertile patients, we developed a simple PCR restriction fragment length polymorphism assay. This is the first report of a SNP in the PRM1 gene that appears associated with human male infertility.

Amino Acid Sequence↗
PubMed2006

[Cloning to rule out 10 candidate genes located in chromosome 12q24 for Charcot-Marie-Tooth disease type 2L].

OBJECTIVE: To clone the disease-causing genes possibly existing in 6.8 cM distance between microsatellite markers D12S1720 and D12S1611 in chromosome 12q24 for Charcot-Marie-Tooth disease type 2L (CMT2L). METHODS: Ten positional and functional candidate genes were chosen among all known genes in this locus region by bioinformatics inqury. Mutation detection was performed by sequencing the exons and intron-exon junctions of the candidate genes. RESULTS: Eleven sequence variations, that included 5 heterozygous and 6 homozygous variations, were detected in the exons and flanking areas of the 10 candidate genes. All the variations showed no co-segregation with disease phenotype. CONCLUSION: Ten candidate genes(TAOK3, RAB35, RPLP0, PXN, RNF10, RHOF, VPS33A, RSN, DENR, RNP24) were ruled out as the disease-causing gene for CMT2L. Ten single nucleotide polymorphisms (SNP) were reported for the first time.

Base Sequence↗
PubMed2006

Complete maternal uniparental isodisomy of chromosome 4 in a subject with major depressive disorder detected by high density SNP genotyping arrays.

Uniparental isodisomy (iUPD) is a rare genetic condition caused by non-disjunction during meiosis that ultimately leads to a duplication of either the maternal or paternal chromosome in the affected individual. Two types of disorders can result, those due to imprinted genes and those due to homozygosity of recessive disease-causing mutations. Here, we describe the third known case of complete chromosome 4 iUPD of maternal origin. This condition became apparent during whole genome linkage studies of psychiatric disorders in the Portuguese population. The proband is an adult female with normal fertility and no major medical complaints, but a history of major depressive disorder and multiple suicide attempts. The proband's siblings and parents had normal chromosome 4 genotypes and no history of mood disturbance. A brief review of other studies lends support for the possibility that genes on chromosome 4 might confer risk for mood disorders. We conclude that chromosome 4 maternal uniparental disomy (UPD) is a rare disorder that may present with a major depressive phenotype. The lack of a common disease phenotype between this and two other cases of chromosome 4 iUPD [Lindenbaum et al. [1991] Am J Med Genet 49(Suppl 285):1582; Spena et al. [2004] Eur J Hum Genet 12:891-898) would suggest that there is no vital maternal gene imprinting on chromosome 4. However, since there is no reported case of paternal chromosome 4 UPD, paternal gene imprinting on chromosome 4 cannot be excluded.

Adult↗
PubMed2002

Mutation screening of the macrophage migration inhibitory factor gene: positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis.

OBJECTIVE: To determine if polymorphisms of the macrophage migration inhibitory factor (MIF) gene are associated with juvenile idiopathic arthritis (JIA). METHODS: Denaturing high-performance liquid chromatography was used to screen the MIF gene in 32 UK Caucasian controls and 88 UK Caucasian JIA patients. Ninety-two healthy UK Caucasian controls were then genotyped for each of the polymorphic positions identified. A panel of 526 UK Caucasian JIA patients and 259 UK Caucasian controls were subsequently genotyped for a single-nucleotide polymorphism (SNP) identified in the 5'-flanking region of the gene, using SNaPshot ddNTP primer extension and capillary electrophoresis. The functional significance of this polymorphism was also studied using luciferase-based reporter gene assays in human T lymphoblast and epithelial cell lines. RESULTS: A tetranucleotide repeat CATT((5-7)) beginning at nucleotide position -794 and 3 SNPs at positions -173 (G to C), +254 (T to C), and +656 (C to G) of the MIF gene were identified. No JIA-specific mutations were found. Allele and genotype frequencies differed significantly between the controls and the JIA patients for the MIF-173 polymorphism. Individuals possessing a MIF-173*C allele had an increased risk of JIA (34.8% versus 21.6%) (odds ratio 1.9, 95% confidence interval 1.4-2.7; P = 0.0002). Furthermore, the MIF-173* G and C variants resulted in altered expression of MIF in a cell type-specific manner. Serum levels of MIF were also significantly higher in individuals who carried a MIF-173*C allele (P = 0.04). CONCLUSION: The -173-MIF*C allele confers increased risk of susceptibility to JIA. Our data suggest a cell type-specific regulation of MIF, which may be central to understanding its role in inflammation.

Alleles↗
PubMed2006

ATM haplotypes and breast cancer risk in Jewish high-risk women.

While genetic factors clearly play a role in conferring breast cancer risk, the contribution of ATM gene mutations to breast cancer is still unsettled. To shed light on this issue, ATM haplotypes were constructed using eight SNPs spanning the ATM gene region (142 kb) in ethnically diverse non-Ashkenazi Jewish controls (n=118) and high-risk (n=142) women. Of the 28 haplotypes noted, four were encountered in frequencies of 5% or more and accounted for 85% of all haplotypes. Subsequently, ATM haplotyping of high-risk, non-Ashkenazi Jews was performed on 66 women with breast cancer and 76 asymptomatic. One SNP (rs228589) was significantly more prevalent among breast cancer cases compared with controls (P=4 x 10(-9)), and one discriminative ATM haplotype was significantly more prevalent among breast cancer cases (33.3%) compared with controls (3.8%), (P< or =10(-10)). There was no significant difference in the SNP and haplotype distribution between asymptomatic high-risk and symptomatic women as a function of disease status. We conclude that a specific ATM SNP and a specific haplotype are associated with increased breast cancer risk in high-risk non-Ashkenazi Jews.

Adult↗
PubMed1998

Generation of co-dominant PCR-based markers by duplex analysis on high resolution gels.

Rapid and efficient procedures for the detection of sequence polymorphisms are essential for chromosomal walking and mutation detection analyses. While DNA chip technology and denaturing high-performance liquid chromatography (DHPLC) are the methods of choice for large scale facilities, small laboratories are dependent on simple ready-to-use techniques. We show that heteroduplex analysis on high resolution gel matrices efficiently detects sequence polymorphism differing as little as a single base pair (e.g. single-nucleotide polymorphism, SNP) with standard laboratory equipment. Furthermore, the matrices also discerned differences between homoduplexes, a prerequisite for co-dominant markers. The markers thus generated are referred to as duplex analysis markers. We designed PCR primers for 36 Arabidopsis thaliana loci ranging in length from 230 bp to 1000 bp. Among three ecotypes, more than half (n = 19) of the loci examined were polymorphic; five of which contained three different alleles. This simple, high resolution technique can be used to rapidly convert sequence tagged sites into co-dominant PCR-based molecular markers for fine-scale mapping studies and chromosomal walking strategies as well as for the detection of mutations in particular genes.

Alleles↗
PubMed1999

A local, high-density, single-nucleotide polymorphism map used to clone Caenorhabditis elegans cdf-1.

Ras-mediated signaling is required for induction of vulval cell fates during Caenorhabditis elegans development. By screening for suppressors of the multivulva phenotype caused by constitutively active let-60 ras, we identified the mutation n2527. To clone the gene affected by n2527, we developed a method for high-resolution mapping. We took advantage of the genomic DNA sequence of the N2 strain by using DNA sequencing to scan for single-nucleotide polymorphisms (SNPs) at defined genomic positions of the RC301 strain. An average of one polymorphism per 1.4 kb was detected in predicted intergenic regions. Because of this high frequency, DNA sequencing is an efficient method to scan for SNPs. By alternating between identifying SNPs and mapping n2527 using selected recombinants, we generated an SNP map of progressively higher density. An intensive search for SNPs resulted in a local map with an average marker spacing of approximately 4 kb. This was used to map n2527 to a 9.6-kb interval. The small size of this interval made it feasible to use DNA sequencing to identify the molecular lesion. In principle, this approach can be used for high-resolution mapping of any C. elegans mutation. Furthermore, this approach can be applied to other species as the genomic sequence becomes available. The n2527 mutation affects a previously uncharacterized gene that we named cdf-1, as it encodes a predicted protein with significant similarity to members of the cation diffusion facilitator family.

Animals↗
PubMed2004

MCP-1 in Alzheimer's disease patients: A-2518G polymorphism and serum levels.

MCP-1 levels are increased in CSF of patients with Alzheimer's disease (AD) compared with controls, suggesting a role in the development of dementia. Recently, a biallelic A/G polymorphism in the MCP-1 promoter at position -2518 has been found, influencing the level of MCP-1 expression in response to an inflammatory stimulus. The distribution of the A-2518G SNP was determined in 269 AD patients and in 203 healthy age matched controls, showing no differences between the two groups. On the contrary, a significant increase of MCP-1 serum levels in AD patients carrying at least one G mutated allele was observed. Moreover, the highest peaks of MCP-1 serum levels were present in patients carrying two G alleles. Stratifying by ApoE genotype, gender or age at onset, no differences in both allele frequency and MCP-1 serum concentration were observed. The A-2518G polymorphism in MCP-1 gene does not seem to be a risk factor for the development of AD, but its presence correlates with higher levels of serum MCP-1, which can contribute to increase the inflammatory process occurring in AD.

Age of Onset↗
PubMed2006

Risk of radiation-induced subcutaneous fibrosis in relation to single nucleotide polymorphisms in TGFB1, SOD2, XRCC1, XRCC3, APEX and ATM--a study based on DNA from formalin fixed paraffin embedded tissue samples.

PURPOSE: In two previously published studies, associations with risk of radiation-induced subcutaneous fibrosis were found for single nucleotide polymorphisms (SNP) in TGFB1 (transforming growth factor beta 1 gene), XRCC1 (X-ray repair cross-complementing 1 gene), XRCC3 (X-ray repair cross-complementing 3 gene), SOD2 (manganese superoxide dismutase gene) and ATM (gene of ataxia telangiectasia mutated). The present study was conducted to seek a confirmation of these findings. MATERIALS AND METHODS: Like the 41 patients previously investigated, the 120 subjects included in the present study were accrued from a historical cohort of 319 post-mastectomy radiotherapy patients. All patients received hypo-fractionated radiotherapy. The TGFB1 position--509, codons 10 and 25, XRCC1 codons 194, 280 and 399, XRCC3 codon 241, SOD2 codon 16, ATM codon 1853 and APEX (apurinic/apyrimidinic exonuclease gene) codon 148 polymorphisms were assessed based on archival histological material. Differences in fibrosis risk were quantified from dose-response assessments. RESULTS: For none of the investigated polymorphisms, significant associations with risk of subcutaneous fibrosis were observed. A detailed analysis did not reveal any obvious explanation for the discrepancy between the previous and the present study. CONCLUSION: The previously observed associations with risk of radiation-induced subcutaneous fibrosis could not be replicated in the present study. Further studies are needed to elucidate the influence of genetic variation upon normal tissue radiosensitivity.

Adult↗
PubMed2005

BRAF polymorphisms and risk of melanocytic neoplasia.

Somatic mutations of the BRAF gene are common in melanomas and nevi but the contribution of polymorphisms in this gene to melanoma or nevus susceptibility remains unclear. An Australian melanoma case-control sample was typed for 16 single nucleotide polymorphisms (SNP) within the BRAF gene, and five SNP in three neighboring genes. The sample comprised 755 melanoma cases from 740 families stratified by family history of melanoma and controls from 635 unselected twin families (2,239 individuals). Ancestry of the cases and controls was recorded, and the twins had undergone skin examination to assess total body nevus count, degree of freckling, and pigmentation phenotype. Genotyping was carried out via primer extension followed by matrix-assisted laser desorption ionization-time of flight mass spectrometry. SNP in the BRAF gene were found to be weakly associated with melanoma status but not with development of nevi or freckles. The estimated proportion of attributable risk of melanoma due to variants in BRAF is 1.6%. This study shows that BRAF polymorphisms predispose to melanoma but the causal variant has yet to be determined. The burden of disease associated with this variant is greater than that associated with the major melanoma susceptibility locus CDKN2A, which has an estimated attributable risk of 0.2%.

Diseases in Twins↗