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Results for “intronic polymorphism”

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PubMed1997

The genotype 2/2 of the presenilin-1 polymorphism is decreased in Spanish early-onset Alzheimer's disease.

We have found a significantly lower frequency of the presenilin-1 (PS-1) intronic polymorphism 2/2 genotype in early-onset Alzheimer's disease (AD) patients without APOE epsilon4 alleles (2/2 = 0.054; P = 0.009) as compared to age matched non-epsilon4 controls (2/2 = 0.227). Moreover the average age of onset in AD patients with the PS-1 2/2 genotype is older than that in AD patients with a 1/2 genotype or with a 1/1 genotype. This data suggest a protective effect of the 2/2 genotype which would delay the age of onset in AD. Our results do not support an association between the 1/1 genotype and AD. However, a non-significant increase of the 1/1 genotype is found in non-epsilon4 AD patients (P = 0.20).

Age of Onset↗

PubMed2006

Interferon-gamma gene (T874A and G2109A) polymorphisms are associated with microscopy-positive tuberculosis.

Genetic susceptibility to tuberculosis includes several unknown yet different loci each contributing to a small extent. Intronic polymorphisms within the interferon-gamma (IFN-gamma) gene IFNG T+874A and IFNG G+2109A correlate with the IFN-gamma production in vitro, and the frequency of potential high IFN-gamma producers was previously reported by others to be lower in patients than in controls from Sicily. The aim of this study was to determine whether there is an association between polymorphisms in the IFN-gamma gene and predisposition to tuberculosis. We analysed two IFNG SNPs (T+874A and G+2109A) in patients (n = 253) hospitalized in Rijeka (Croatia) and controls (n = 519) from the same area. One-fifth of the controls were healthy contacts of the diseased, and the rest were blood donors. IFNG alleles, their predicted haplotypes or genotypes were not associated with disease susceptibility. Thus, we could not reproduce results from Sicilian case-control study. However, T/T+874 (possible high IFN-gamma producer) and +874A/A (putative low producer) genotypes were associated with microscopically positive-negative forms of disease. Haplotypes (T+874A and G+2109A) based on a prediction by software phase and subsequent genotype analysis corroborated these findings. Patients had significantly higher frequency of genotypes without T at +874 (AA/AA; AA/AG and AG/AG) in microscopy- or bacterial culture-positive groups compared with their negative counterparts. These data suggest an association with disease severity rather than susceptibility to tuberculosis in Croatian Caucasian population.

Alleles↗

PubMed2000

The decanucleotide insertion/deletion polymorphism in the promoter region of the coagulation factor VII gene and the risk of familial myocardial infarction.

Recently, an association has been found between factor VII polymorphisms and the risk of familial myocardial infarction. To obtain a thorough evaluation of the influence of factor VII gene on the risk of myocardial infarction, we extended our analysis to the role of a decanucleotide insertion/deletion functional polymorphism (-323 0/10-bp) in the promoter region of factor VII and to possible interactions with the HVR4 intron polymorphism. We performed a case-control study of 176 patients with myocardial infarction, over 45 years, who had a familial history of arterial thrombosis and 227 control subjects without a personal or family history of cardiovascular disease. The frequency of the rare allele of 10 bp was lower in cases (0.14 95% CI, 0.10-0.17) than in controls (0.19 95% CI, 0.16-0.23; chi(2)=4.7, p=0.03). Allowing for Hardy-Weinberg equilibrium in controls and testing for association under restricted maximisation, there was a significant difference in genotype frequency between cases and controls (p=0.02). Carriers of the 10-bp allele had an odds ratio for myocardial infarction of 0.65 (95% CI, 0.37-1.12), in multivariate logistic regression analysis. Combination analysis of -323 0/10-bp and HVR4 polymorphisms shows half reduction in the risk of myocardial infarction in comparison with the reference group for all the other groups, suggesting that there was no additivity between the effect of the 10-bp and the H7 alleles. Our findings suggest that the promoter polymorphism of factor VII gene may influence the risk of familial myocardial infarction.

Aged↗

PubMed2003

Genetic variation in genes associated with arsenic metabolism: glutathione S-transferase omega 1-1 and purine nucleoside phosphorylase polymorphisms in European and indigenous Americans.

Individual variability in human arsenic metabolism has been reported frequently in the literature. This variability could be an underlying determinant of individual susceptibility to arsenic-induced disease in humans. Recent analysis revealing familial aggregation of arsenic metabolic profiles suggests that genetic factors could underlie interindividual variation in arsenic metabolism. We screened two genes responsible for arsenic metabolism, human purine nucleoside phosphorylase (hNP), which functions as an arsenate reductase converting arsenate to arsenite, and human glutathione S-transferase omega 1-1 (hGSTO1-1), which functions as a monomethylarsonic acid (MMA) reductase, converting MMA(V) to MMA(III), to develop a comprehensive catalog of commonly occurring genetic polymorphisms in these genes. This catalog was generated by DNA sequencing of 22 individuals of European ancestry (EA) and 24 individuals of indigenous American (IA) ancestry. In (Italic)hNP(/Italic), 48 polymorphic sites were observed, including 6 that occurred in exons, of which 1 was nonsynonymous (G51S). One intronic polymorphism occurred in a known enhancer region. In hGSTO1-1, 33 polymorphisms were observed. Six polymorphisms occurred in exons, of which 4 were nonsynonymous. In contrast to hNP, in which the IA group was more polymorphic than the EA group, in hGSTO1-1 the EA group was more polymorphic than the IA group, which had only 1 polymorphism with a frequency > 10%. Populations representing genetic admixture between the EA and IA groups, such as Mexican Hispanics, could vary in the extent of polymorphism in these genes based upon the extent of admixture. These data provide a framework in which to conduct genetic association studies of these two genes in relevant populations, thereby allowing hNP and hGSTO1-1 to be evaluated as potential susceptibility genes in human arsenicism.

Arsenic↗

PubMed2003

DNA variants of DLC-1, a candidate tumor suppressor gene in human hepatocellular carcinoma.

The DLC-1 gene encoding a regulator of the Rho family of small GTPases is altered in breast, prostate, colon, and liver cancer and has several characteristics of a tumor suppressor gene. DLC-1 overexpression causes inhibition of in vitro growth of liver tumor cells and complete suppression of in vivo tumorigenicity of breast tumor cells. Inactivation and aberrant expression of DLC-1 in human hepatocellular carcinoma (HCC) is frequently associated with hemizygous and homozygous genomic deletion and promoter methylation. Since inactivation of tumor suppressor genes in cancer cells is also commonly associated with point mutation, we evaluated the incidence of mutation of the DLC-1 gene by PCR-SSCP in 17 primary HCC and 18 HCC cell lines. One missense mutation was detected at codon 991 of exon 12 (C-->T transition, Val-->Ile) in an HCC cell line. In addition, two types of polymorphisms were identified: a G-->T at codon 745 of exon 9, a T-->C at 17 bp downstream of exon 2. While the pathogenic relevance of the intronic polymorphism is not known, the low rate of mutation of the DLC-1 gene in HCC implies that genomic deletion and promoter methylation primarily account for the altered expression and tumor suppressive inactivation of the DLC-1 gene.

Carcinoma, Hepatocellular↗

PubMed1996

Failure to find associations of the CA repeat polymorphism in the first intron and the Gly-63/Glu-63 polymorphism of the neurotrophin-3 gene with schizophrenia.

This study aimed to replicate positive associations between polymorphisms of the neurotrophin-3 gene and schizophrenia. The reported associations, which were the results of searching for mutations in the locus in schizophrenics under the hypothesis of neurodevelopmental etiology of schizophrenia, are that the states carrying the (CA)23 allele of the CA repeat in the first intron have a 2.56-fold increased risk of schizophrenia and those carrying the allele Glu-63 instead of Gly-63 have a 2.6-fold increased risk of schizophrenia with onset before 25 years and with duration of the illness of more than 10 years. We analyzed these polymorphisms in 80 schizophrenics with onset before 25 years of age and with duration of illness of more than 10 years and 80 age-matched psychosis-free controls. With our sample size, there was a 90% chance of detecting odds ratios observed in initial positive reports. We found similar allele and genotype frequencies of both polymorphisms between the schizophrenic and control groups. We failed to support associations between the polymorphisms of the neurotrophin-3 gene analyzed and schizophrenia.

Adult↗

PubMed2003

TNF and TNF receptor polymorphisms in Korean Behcet's disease patients.

Behcet's disease (BD) is an autoimmune disease characterized by recurrent oral ulcers, genital ulcers, erythema nodosum, and uveitis. Genetic factors are considered important in its pathogenesis. The serum level of tumor necrosis factor (TNF) is elevated in patients with active BD, and its production is elevated in monocytes and in the gamma delta T cells of BD patients. A dramatic response to anti-TNF-alpha antibody treatment further supports the role of TNF in BD. In this study, we investigated genetic polymorphisms of TNF alpha -308 G/A, TNF beta +252 G/A, and TNFR2 196 R/M in 94 Korean BD patients and age- and sex-matched healthy controls to investigate the role of TNF and TNF receptor polymorphisms in BD. The polymerase chain reaction-restriction fragment length polymorphism was used to identify the TNF-alpha promoter (G = TNFA1, A = TNFA2) and TNF-beta intron polymorphisms (G = TNFB1, A = TNFB2), and polymerase chain reaction-singly-strand conformation polymorphism was used to identify TNFR2 196R/M polymorphism (T = TNFR2M, G = TNFR2R). No differences were found in the TNF-alpha, TNF-beta or TNFR2 polymorphisms of the patients and the healthy controls. The allele frequencies of TNFA1/A2 were 0.94/0.06 in patients and 0.96/0.04 in healthy controls (p = 0.36, OR = 0.65, 95% CI = 0.26-1.63), for TNFB1/TNFB2 these were 0.42/0.58 in patients and 0.44/0.56 in controls (p = 0.68, OR = 0.91, 95% CI = 0.61-1.38), and for TNFR2R/TNFR2M 0.23/0.77 in patients and 0.21/0.79 in controls (p = 0.62, OR = 1.13, 95% CI = 0.69-1.84). In conclusion, this study found no differences of TNF alpha -308 G/A, TNF beta +252 G/A or of the TNFR2 196R/M polymorphisms in Korean BD patients versus healthy controls. These findings suggest that the role of TNF in BD is not genetically determined, but can be functionally explained.

Adult↗

PubMed2000

Screening of thiopurine S-methyltransferase mutations by horizontal conformation-sensitive gel electrophoresis.

The genetic polymorphism of thiopurine S-methyltransferase (TPMT) has had a highly significant clinical impact due to its association with individual variation in the toxicity and therapeutic efficiency of thiopurine drugs, which are pharmaceutical agents widely used in the treatment of several kinds of diseases. Until now, ten mutant alleles responsible for TPMT deficiency and several silent and intronic mutations have been described. In this work we present an alternative molecular method for the detection of TPMT alleles. It is an adaptation for horizontal conditions of a conformation-sensitive gel electrophoresis technique. The method has proven to be very efficient as a rapid screening approach for the study of TPMT genetic variability. The method was applied to analyse eight TPMT exons and the corresponding flanking intronic regions in a sample of unrelated healthy individuals from North Portugal. Here we report the allelic frequencies concerning TPMT-deficient alleles and several silent and intronic mutations, including two newly detected intronic polymorphisms: an A (-101) T substitution in intron 3 and a variation involving the number of T nucleotides in a DNA stretch in intron 5. Additionally, we also present data from a sample of 43 children undergoing therapy for acute lymphoblastic leukemia. In this clinical sample we have registered a statistically significant higher frequency for the TPMT*3C allele. This finding raises the question whether the TPMT genotype can contribute to any genetic predisposition for development of the malignancy.

Alleles↗

PubMed2002

Relationship between adverse effects of antipsychotic treatment and dopamine D(2) receptor polymorphisms in patients with schizophrenia.

Extrapyramidal adverse symptoms (EPS) represent a major type of adverse events in treatment with typical antipsychotic drugs which share high affinity to the dopamine D(2) receptor (DRD2). Genetic variants of this receptor may modulate the therapeutic response and the severity of adverse symptoms of antipsychotics. We analyzed nine known polymorphisms of the DRD2 in 665 schizophrenic patients with European Caucasian ethnic background and compared the intensity of acute dystonia, extrapyramidal symptoms, akathisia, and tardive dyskinesia between carriers of different DRD2 genotypes. In a subgroup of 40 patients with most severe extrapyramidal symptoms we sequenced the coding region including the exon-intron junctions of the DRD2 gene. Functionally relevant DRD2 amino acid variants (Ser(310), Cys(311)) were rare or were not found at all (Ala(96)). Complete sequence analysis of sufferers from the most severe adverse effects revealed two new intronic polymorphisms and a silent polymorphism in exon 7, but no new amino acid variants beyond those which are already known. We found no significant association between these polymorphisms and the intensity of the different types of adverse neurologic effects of the antipsychotics. These results were obtained by correlating adverse events with each of the nine single nucleotide polymorphisms and by correlation with the estimated haplotypes. In conclusion, genetic variations in the DRD2 gene were no major predictors of the individually variable adverse effects from antipsychotic treatment in Caucasian schizophrenic patients.

Adolescent↗

PubMed2002

Cyclooxygenase 1 (COX1) polymorphisms in African-American and Caucasian populations.

Cyclooxygenases (COXs) are the primary targets of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), and thus enzymes of major interest to pharmacology, pharmacogenetics, and epidemiology. Genetic variants that affect enzyme function, or the interaction with NSAIDs, could alter drug response. We have screened the human COX1 gene coding regions of 48 African-American and 47 Caucasian individuals using DNA sequencing. We identified 13 coding-region variants, of which seven were amino-acid substitutions, and further five intronic polymorphisms within 60bp of an exon. All nonsynonymous variants were confirmed in an independent Caucasian population (n=94 unrelated individuals). Most of the discovered polymorphisms were rare, although some variants resulting in amino-acid changes occurred at appreciable frequency in at least one population (> or =4%: R8W, P17L, L237M). We used two sequence-homology-based software programs to predict the potential impact of these polymorphisms on COX1 function. The L237M substitution was predicted as most likely to alter protein function, whereas the glycine at position 230 may be specific to COX1 function. More detailed phenotypic characterizations of these COX1 polymorphisms remain to be undertaken.

Amino Acid Substitution↗

PubMed2004

[The distribution of gene polymorphisms in the intron 2 and exon 2 of interleukin-1 receptor antagonist and their correlation with the serum lipoprotein level].

OBJECTIVE: To study the distribution of variable numbers of tandem repeat (VNTR) polymorphism in the intron 2 and the single nucleotide polymorphism (SNP) at position +8006 in the exon 2 of IL-1RN in healthy Chinese Han Population of Wuhan province and to analyze their correlation with the serum lipoprotein level. METHODS: IL-1RN (VNTR) and IL-1RN (+8006) polymorphisms were detected by PCR and PCR-RFLP methods in 251 healthy Chinese Han Population of Wuhan, and the levels of serum lipoprotein, IL-1 and IL-1Ra were inspected simultaneously. RESULTS: In IL-1RN (VNTR), allele I appeared most common, then allele II, and allele IV was rare. At the position of IL-1RN (+8006), allele T was most commonly seen followed by allele C. Allele II of IL-1RN (VNTR) always existed with allele C of IL-1RN (+8006). The levels of serum lipoprotein, IL-1 and IL-1Ra were not different among the different genotypes of the two polymorphisms. CONCLUSION: There were two gene polymorphisms in the intron 2 and exon 2 of IL-1RN, which were not correlated with the levels of serum lipoprotein, IL-1 and IL-1Ra. However, there seemed to be a linkage disequilibrium between IL-1RN (VNTR) and IL-1RN (+8006).

Adolescent↗

PubMed1996

Genomic structure of the human OB receptor and identification of two novel intronic microsatellites.

Identification of the OB (leptin) receptor (OBR) as the gene that is defective in diabetes (Leprdb) mice and fatty (Leprfa) rats provides an important candidate gene for the study of the genetics of human obesity. We defined the boundaries of the 18 coding exons for the long form of OBR, and sequenced the immediately adjacent intronic regions. These sequences can be used to generate reagents for genetic analysis (e.g., direct sequencing, single-stranded conformational polymorphism analysis, etc.) of the possible role of OBR in the regulation of adiposity in humans. In addition, we have identified two highly polymorphic intronic microsatellites that can be scored with the polymerase chain reaction.

Animals↗

PubMed2001

Association studies using novel polymorphisms in BACE1 and BACE2.

The release of amyloid-beta peptide (Abeta) from beta-amyloid precursor protein (APP) requires cleavage by beta- and gamma-secretases. Several groups have identified a candidate for the beta-site APP-cleaving enzyme, BACE1, and its homologue BACE2. We sequenced the genes for BACE1 and BACE2 and found several polymorphisms in both genes. Genotyping a large cohort of AD cases and controls has shown no association between AD and the intronic polymorphism in BACE2 while there was a weak association between the BACE1 polymorphism in exon 5 and AD in those carrying the APOE epsilon4 allele.

Aged↗

PubMed2006

Ubiquilin 1 polymorphisms are not associated with late-onset Alzheimer's disease.

Several studies have reported evidence for linkage of late-onset Alzheimer's disease (LOAD) to chromosome 9. Recently, an intronic polymorphism affecting alternative splicing of exon 8 of ubiquilin 1 (UBQLN1) was reported to be associated with LOAD. We attempted to replicate this observation by genotyping this polymorphism, rs12344615 (also known as UBQ-8i), in a large sample of 1,544 LOAD cases and 1,642 nondemented controls. We did not find any evidence that this single nucleotide polymorphism, or any of six others tested in UBQLN1, increases risk for LOAD.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Genotypic determinants of phenotype in North American patients with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is characterized by excess accumulation of protoporphyrin, which is due to deficient activity of the enzyme ferrochelatase (FECH). This results in photosensitivity and in some patients liver disease which may necessitate liver transplantation. The aim of this study was to delineate the abnormalities in the FECH gene which cause phenotypic expression in EPP. We identified 43 individuals from 25 North American families with EPP who were heterozygous for various FECH mutations, but the mutations did not adequately explain the variable phenotype. We also examined the presence of an intron polymorphism (IVS3-48c) in the FECH gene which was shown to cause the formation of aberrantly spliced FECH mRNA. FECH DNA analysis demonstrated that 94% of 31 symptomatic individuals with FECH mutations were heterozygous for IVS3-48c, whereas 12 asymptomatic individuals with FECH mutations were homozygous for IVS3-48t. Haplotype analysis in four families showed that symptomatic members had the IVS3-48c polymorphism in the non-mutant FECH allele. Sequencing of the proximal FECH gene promoter showed no additional changes which might affect gene expression. The levels of normal FECH mRNA, measured by relative quantitative RT-PCR, and FECH enzyme activity were correspondingly lower in the cultured lymphoblasts of family members with the IVS3-48c polymorphism. These results indicate that symptomatic disease in most North American patients with EPP is explained by the inheritance of a mutation in one FECH allele which causes a structural alteration in the protein, together with a low expressing non-mutant FECH allele which is caused by the IVS3-48c polymorphism.

Adolescent↗

PubMed2002

Association of novel and established polymorphisms in neuronal nicotinic acetylcholine receptors with sporadic Alzheimer's disease.

Since the loss of cholinergic neurons in the Alzheimer's disease (AD) brain was first reported, considerable evidence in vivo and in vitro has accumulated in support of the cholinergic hypothesis of AD. The hypothesis is greatly supported by the fact that the most promising drugs against AD are inhibitors of acetylcholinesterase (AChE). To identify the possible mutations and/or polymorphisms of neuronal nicotinic acetylcholine receptor (nAChR) genes related to the pathogenesis of sporadic AD, we have performed mutational analyses of the major neuronal nAChR genes (CHRNA3, 4, 7 and CHRNB2) expressed in central nervous system. Allelic analysis showed association of specific silent or intronic polymorphisms of the CHRNA3 and CHRNA4 genes and AD. Two novel missense point mutations, Ser413Leu in the CHRNA4 gene and Gln397Pro in the CHRNB2 gene, were identified in two different AD cases but were not found in other AD cases and controls. These findings suggested that genetic polymorphisms of the neuronal nAChR genes might be related to the pathogenesis of sporadic AD.

Adult↗

PubMed1984

Polymorphisms of human albumin gene after DNA restriction by HaeIII endonuclease.

Hybridization of albumin clones cDNA with human DNAs digested by several restriction endonucleases reveals two HaeIII polymorphisms. The first polymorphism, H1, is of low frequency (f1 = 0.05); the second, which is validated by family analysis, occurs frequently (f2 = 0.21) and is an intronic polymorphism, probably of substitution--base type.

Albumins↗

PubMed2006

Association of TNF-alpha/LTA polymorphisms with Crohn's disease in Koreans.

Polymorphisms of the proinflammatory and immunoregulatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin-alpha (LTA), have been shown to affect their production and be associated with Crohn's disease. However, the actual alleles associated with the disease are variable among populations. The aim of this study was to test whether TNF-alpha and LTA polymorphisms were associated with Crohn's disease risk in Korean samples. Genotyping for five TNF-alpha promoter polymorphisms (-1031, -863, -857, -308, and -238) and two LTA polymorphisms (intron 1 and Thr60Asn) were performed on 289 Korean patients with Crohn's disease and 399 unrelated healthy controls. Carriers of an individual polymorphism of TNF-alpha at -857T, showed statistically significant association with Crohn's disease (adjusted OR=1.64, 95% CI=1.11-2.41, P=0.013). Following haplotype analysis, carriers of the haplotype consisted of the -1031C, -863A, and -857C alleles showed statistically significant association with Crohn's disease (adjusted OR=1.54, 95% CI=1.02-2.32, P=0.040). Significantly reduced frequencies were seen for the carriers of the LTA Thr60Asn polymorphism in patients (OR=0.62; 95% CI=0.42-0.93, P=0.019), suggesting a protective effect on Crohn's disease. Our data support the hypothesis that the TNF-alpha/LTA genotypes play an important role in the pathogenesis of Crohn's disease in Koreans.

Adult↗