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E Coto

Publications and source records attributed to E Coto.

At least 55 records · Page 3Linked to original sources
PubMed1999

The prothrombin 20210A allele and the factor V Leiden are associated with venous thrombosis but not with early coronary artery disease.

This study was performed in order to establish the role of the prothrombin 20210 G/A and factor V Leiden (R506Q) polymorphisms in the susceptibility to develop venous thromboembolism and early coronary artery disease (CAD). These polymorphisms were determined in 82 consecutive patients with venous thromboembolism, 175 male patients with early CAD, and 200 healthy controls from the same Caucasian population (Asturias, Northern Spain). DNA was amplified using polymerase chain reactions and digested with the appropriate restriction enzymes in order to define the prothrombin and factor V genotypes. The prevalence of the heterozygous for the prothrombin A allele was 3.5% in the general population and 15.8% in patients with venous thrombosis (P = 0.0007); the frequency was 4% in patients with early CAD. No sex-related differences in the prevalence of the A allele were observed, and the average age at the first venous thromboembolic event was similar between GG and AG patients. The frequency of carriers of the factor V Leiden polymorphism was 9.75% among patients with venous thromboembolism, compared with 3.5% among controls, and 3.4% in the patients with CAD. Our data showed an association between venous thromboembolism and the AG genotype at the prothrombin 20210 G/A polymorphism. This polymorphism was not related to an increased risk for early CAD in our population of male patients.

Adult↗
PubMed1999

The O blood group protects against venous thromboembolism in individuals with the factor V Leiden but not the prothrombin (factor II G20210A) mutation.

We investigated the influence of the ABO blood group in the observed prevalences of the recently described factor V R506Q and factor II G20210A mutations in a thrombotic population. We determined the ABO blood group in a sample of 178 unselected patients (aged 17-83 years), diagnosed at our center with deep vein thrombosis or pulmonary embolism. The results of this study show a high prevalence of thrombosis in the non-O blood group. In the general population, the prevalence as a fraction of the O blood group was 2.69 (confidence interval 1.90-3.82). Of the factor V R506Q carriers (n = 28), only one had O group blood and 27 of 28 were non-O (24 A, one B and two AB). However, within the group of factor II G20210A carriers (n = 17), seven had O, nine A and one B type blood. The prevalence of the factor V R506Q mutation within the O blood group was 2.4% (one of 42), significantly lower than in the A group (23.3%, 24 of 103; P = 0.002), or in the overall non-O group (19.9%, 27 of 136; P = 0.006). This prevalence was similar to that observed previously in the non-thrombotic population in our area (3.5%; P = 0.9). We analyzed the clotting activity of factor VIII and we found higher levels in the non-O group (1.78+/-0.61 U/ml) than in the O blood group (1.30+/-0.51 U/ ml; P < 0.0001). We speculate that factor Va in individuals with the factor V Leiden mutation could interact with the high levels of factor VIII clotting activity as a necessary cofactor.

ABO Blood-Group System↗
PubMed1999

Angiotensin converting enzyme and endothelial nitric oxide synthase DNA polymorphisms and late onset Alzheimer's disease.

OBJECTIVES: Several lines of evidence suggest that the endothelial constitutive nitric oxide synthase (ecNOS) and angiotensin converting enzyme (ACE) may have a role in Alzheimer's disease. ACE is widely expressed in the brain, and a DNA polymorphism at the ACE gene has been linked to the risk for late onset Alzheimer's disease. Nitric oxide (NO) production by microglial cells, astrocytes, and brain microvessels is enhanced in patients with Alzheimer's disease. There is a growing evidence that NO is involved in neuronal death in Alzheimer's disease, and the oxidative stress caused by NO in the brain could be a pathogenic mechanism in Alzheimer's disease. The objective was to determine if two DNA polymorphisms at the ecNOS and ACE genes that have been linked with different levels of enzyme expression, have some effect on the risk of developing late onset Alzheimer disease. METHODS: A total of 400 healthy controls younger than 65 years and 350 patients with Alzheimer's disease (average age 72 years) were genotyped for the ACE and ecNOS polymorphisms. To define a possible role for these polymorphisms in longevity 117 healthy controls older than 85 years were also analysed. Genomic DNA was obtained and amplified by polymerase chain reaction, and genotypes were defined following a previously described procedure. Gene and genotype frequencies between patients and controls were compared statistically. RESULTS: Gene and genotype frequencies for the ecNOS and ACE polymorphisms did not differ between both groups of healthy controls (<65 years and >85 years). EcNOS gene and genotype frequencies were similar between patients and controls. There was a slight but significantly increased frequency of the ACE-I allele among patients with Alzheimer's disease compared with controls (p=0.03; OR=1.28, 95%CI= 1.04;1.58). CONCLUSIONS: The ACE-I allele was associated with a slightly increased risk of developing late onset Alzheimer's disease.

Age Factors↗
PubMed1999

Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease.

It is estimated that approximately 15% of families with autosomal dominant polycystic kidney disease (ADPKD) have mutations in PKD2. Identification of these mutations is central to identifying functionally important regions of gene and to understanding the mechanisms underlying the pathogenesis of the disorder. The current study describes mutations in six type 2 ADPKD families. Two single base substitution mutations discovered in the ORF in exon 14 constitute the most COOH-terminal pathogenic variants described to date. One of these mutations is a nonsense change and the other encodes an apparent missense variant. Reverse transcription-PCR from patient lymphoblast RNA showed that, in addition, both mutations resulted in out-of-frame splice variants by activating cryptic splice sites via different mechanisms. The apparent missense variant produced such a strong splicing signal that the processed transcript from the mutant chromosome did not contain any of the normally spliced, missense product. A third mutation, a nonconservative missense change effecting a negatively charged residue in the third transmembrane span, is likely pathogenic and defines a highly conserved residue consistent with a potential channel subunit function for polycystin-2. The remaining three mutations included two frame shifts resulting from deletion of one or two bases in exons 6 and 10, respectively, and a nonsense mutation due to a single base substitution in exon 4. The study also defined a novel intragenic polymorphism in exon 1 that will be useful in analyzing "second hits" in PKD2. Finally, the study demonstrates that there are reduced levels of normal polycystin-2 protein in lymphoblast lines from PKD2-affected individuals and that truncated mutant polycystin-2 cannot be detected in patient lymphoblasts, suggesting that the latter may be unstable in at least some tissues. The mutations described will serve as critical reagents for future functional studies in PKD2.

Humans↗
PubMed1999

[Huntington chorea: clniical and molecular analysis in Asturian patients].

UNLABELLED: AIM AND PATIENTS: To analyse 38 patients with Huntington's disease from 27 families. RESULTS: The CAG repeat at the huntingtin gene was expanded between 40 and 72 times. The size in normal chromosomes varied from 12 to 30 repeats. We found a significantly negative correlation between the number of CAG-repeats and the age of clinical manifestations. However, age and clinical characteristics of the first symptoms were highly variable between patients with a similar size of the expanded allele. Patients who inherited the disease from their fathers showed a higher number of repeats than those who received the disease from their mothers. However, in one case of father to son transmission we observed a reduction of the number of CAG repeats. CONCLUSIONS: These data make it difficult to use the molecular analysis for the presymptomatic diagnosis of clinical course in individuals carrying the expansion.

Adolescent↗
PubMed1998

Mutational analysis of the CCR5 and CXCR4 genes (HIV-1 co-receptors) in resistance to HIV-1 infection and AIDS development among intravenous drug users.

We analysed a group of Spanish intravenous drug users and controls to determine the role of mutations at the chemokine receptor-5/HIV-1 cofactor (CCR5), previously implicated in resistance to HIV-1 infection, and CXCR4 genes in susceptibility to HIV-1 infection. The complete coding sequence of both genes was amplified by the polymerase chain reaction from genomic DNA of 50 seropositive slow progressors and 10 long-term non-progressors, and analysed by the single-strand conformation polymorphism technique in a search for mutations. No mutation in CXCR4 was found, and delta ccr5 was the only mutation identified at the CCR5 gene. We genotyped (delta ccr5 allele) 150 HIV-1+ intravenous drug users and 250 healthy controls from the same population (Asturias, Northern Spain). Patients were divided into rapid progressors, presenting an event indicating progression to the acquired immunodeficiency syndrome (AIDS) in the 2 years after infection (100 patients), and slow progressors, remaining asymptomatic for 2-10 years (50 patients). The frequencies of the delta ccr5 allele were 0.105 and 0.040 in controls and HIV-1+ patients, respectively. Eighteen per cent of the controls (45/250) and 8% (12/150) of the patients carried the delta ccr-5 allele (P=0.013). The frequency of delta ccr5 carriers among rapid and slow disease progressors was 3 and 15%, respectively. A highly significant difference was found between rapid progressors and controls (P=0.0014). No patient (0/150) was delta ccr5 homozygous compared with 1% among controls. Thus, the delta ccr5 allele (the only CCR5 mutation found in our HIV-1 patients) was rare among seropositive intravenous drug users, suggesting that the absence of this mutation confers an advantage to the virus when infecting cells in vivo. In addition, patients carrying the delta ccr5 allele tend to show a slow progression towards HIV-1-related disease, remaining asymptomatic for longer periods of time.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphisms: association with early coronary disease.

OBJECTIVE: To examine the association between coronary artery disease and polymorphisms at the angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) genes. METHODS: A total of 181 patients younger than 50 years and 240 controls from the same homogeneous Caucasian population (Asturias, Northern Spain) were genotyped (using polymerase chain reaction) for the ACE insertion/deletion (ACE-I/D) and the AT1R A/C transversion (AT1R-A/C) (3-untranslated region) polymorphisms. RESULTS: The DD-genotype was at a non-significant higher frequency among patients (50%) than in controls (41%). No difference between the two groups was found for the AT1R-genotypes. Distribution of ACE-genotypes according to AT1R-genotypes showed a significant association between ACE-DD and AT1R-CC and early coronary disease. Among the CC patients 58% were DD, compared to 21% among the controls (p = 0.02; OR = 5.32, 95% CI = 1.45, 19.51). We determined the distribution of these genotypes among the hypertensive and non-hypertensive patients. Frequencies of ACE- or AT1R-genotypes did not differ between the two groups. However, we found an interaction between the DD- and CC-genotypes in the group of normotensives. Among the CC patients, 13% of the hypertensives and 75% of the normotensives were DD (p = 0.014). CONCLUSIONS: Our results indicate a synergistic contribution of ACE and AT1R polymorphisms to the risk of coronary artery disease. This gene-gene interaction could have clinical implications. Approximately 2% of individuals in our population are CC + DD, and the genotyping of both polymorphisms could identify those with a high relative risk for coronary artery disease.

Adult↗
PubMed1998

Genetic polymorphism of N-acetyltransferase-2, glutathione S-transferase-M1, and cytochromes P450IIE1 and P450IID6 in the susceptibility to head and neck cancer.

AIMS: To analyse the allele frequencies of DNA polymorphisms at the genes for cytochromes P450IIE1 and P450IID6, N-acetyltransferase-2, and glutathione S-transferase-M1 in patients with head and neck squamous cell carcinoma, in an attempt to define genetic factors involved in the susceptibility to this cancer, which is strongly associated with tobacco consumption. METHODS: Determination of restriction fragment length polymorphism (RFLP) at cytochromes P450IIE1/P450IID6 and NAT2 genes, and the presence of homozygous deletion of the GSTM1 gene, in 200 controls and 75 head and neck cancer patients. Allelic frequencies between the two groups were compared using a chi 2 test, and odds ratio with 95% confidence intervals were calculated. RESULTS: There was no evidence of an association between alleles of CYP2D6 and CYP2E1 and head and neck cancer in our population. Similarly, frequencies of individuals lacking the GSTM1 gene did not differ between controls and patients. However, individuals with the NAT2-SA phenotype were at higher risk of developing head and neck cancer. The frequencies of the most common SA genotype (homozygous for the NAT2*5 allele) were higher in patients than in controls (27% v 15%, respectively). Slow acetylators homozygous for the NAT2*6 allele, the second most common SA allele, were also more common in patients than in controls (11% v 5%, respectively). CONCLUSIONS: Slow NAT2 activity is a risk factor possibly leading to the development of head and neck cancer in response to tobacco carcinogens.

Acetyltransferases↗
PubMed1998

Chromosome 3p loss of heterozygosity and mutation analysis of the FHIT and beta-cat genes in squamous cell carcinoma of the head and neck.

AIMS: To study the loss of heterozygosity at the short arm of chromosome 3 in primary tumours from patients with squamous cell carcinoma of the head and neck; to determine whether the FHIT gene, mapped to 3p14.2 and the CTNNB1 (beta-cat) gene, mapped to 3p21, are deleted or mutated in these tumours. METHODS: DNA was extracted from fresh tumours. Loss of heterozygosity was assessed by microsatellite analysis of the following markers: D3S1283 and D3S1286 (3p24), D3S966 (3p21), and D3S1300 (3P14.2). Homozygous deletion was determined by radioactive multiplex polymerase chain reaction of exons 5 and 6 of the FHIT gene. The presence of mutations in FHIT exon 5 and beta-cat exon 3 was studied by single strand conformation polymorphism. RESULTS: 50% of informative cases (25/50) showed loss of heterozygosity for at least one of the 3p markers. 3p21 was the region with the highest rate of allelic deletion (63%). No point mutation was found in FHIT exon 5 or beta-cat exon 3. No case showed homozygous deletion for the FHIT (exons 5 and 6) or the beta-cat exon 3. CONCLUSIONS: The short arm of chromosome 3 is often deleted in the head and neck squamous cell carcinomas. In the remaining alleles of the FHIT or beta-cat genes, no evidence was found for point mutations or deletions, documented in other common carcinomas. Inactivation could occur by different mechanisms such as methylation, or other genes (not studied here) could be target of allelic losses in squamous cell carcinoma of the head and neck.

Carcinoma, Squamous Cell↗
PubMed1998

Apolipoprotein A1 gene polymorphisms and risk of early coronary disease.

Genetic studies have identified polymorphisms at the apolipoprotein (Apo) A1 gene associated with HDL cholesterol and apolipoprotein levels, and a relationship between the severity of coronary artery disease and polymorphisms at the 5'-end of Apo A1 has been also reported. This study was designed to examine the relationship between polymorphism at the Apo A1 gene and the risk of early coronary artery disease. Furthermore, the association of the polymorphism with the classical risk factors was analyzed. A total of 176 male patients (mean age 43 +/- 5 years) diagnosed as having unstable angina (53 cases) or myocardial infarction (123 cases) were prospectively evaluated. Data referring to hypertension, diabetes and tobacco consumption were recorded. The levels of total cholesterol, HDL cholesterol, Apo A1 and B and triglycerides were determined. DNA was obtained from the 176 patients and from 200 controls. In order to determine the Apo A1 genotypes at two polymorphic sites (G/A at -75 bp, and C/T at +83 bp), DNA was PCR amplified and digested with MspI. The frequency of carriers of the rare allele at the -75 bp site (M1-) was 0.34 in cases and 0.24 in controls (p < 0.05). The frequencies of the M1- allele among patients with angina and myocardial infarction were 0.43 (p = 0.009, angina vs. controls) and 0.30, respectively. No significant association between this polymorphism and other cardiovascular risk factors was found. No difference in the frequencies for carriers of the rare allele at the +83-bp polymorphism (M2) was observed among patients with angina (0.08 vs. 0.07) or myocardial infarction (0.04 vs. 0.07), and no association between this polymorphism and tobacco, hypertension and diabetes was noted. Patients carrying the rare M2- allele had a lower concentration of total cholesterol compared to those without this allele (183 +/- 29 vs. 223 +/- 54, p < 0.04) and HDL cholesterol was also lower among patients carrying the M2- (26 +/- 4 vs. 33 +/- 9, p < 0.02). In our community male patients with a diagnosis of coronary artery disease and age less than 50 years showed a higher frequency of the M1- allele at the -75-bp site of the Apo A1 gene. There was a significant increase in the frequency of the M1- allele in patients with unstable angina and no association with risk factors. In the +83-bp polymorphism there was no difference in the allelelic frequencies or the risk factors, except for the HDL cholesterol and total cholesterol where the patients with the allele M2- had lower levels than those homozygous for the M2+.

Adult↗
PubMed1998

[Familial episodic ataxia type 2. Clinical and genetic study of one family].

INTRODUCTION: Episodic familial ataxia type 2 is caused by mutations in the gene CACNA1A, in chromosome 19p, that codifies part of a calcium channel. We report a family affected by this disease. PATIENTS AND METHODS: Nine members of this pedigree, all of them symptomatic, were seen and followed by us, including a magnetic resonance scan in all the cases but one. We performed linkage analysis to markers close or included in the gene CACNA1A. RESULTS: All of the patients had brief, self-limiting attacks of ataxia, that usually started between the ages of 8 and 12. Other symptoms frequently associated were dysarthria, headache, nausea and somnolence. Only one patient, with severe alcoholic intake, developed progressive ataxia after several years with self-limiting attacks. The remaining cases had nystagmus in lateral gaze as the only abnormality on examination. Acetazolamide decreased or eliminated the attacks in those patients treated. Magnetic resonance scans always showed cerebellar vermian atrophy. Genetic study confirmed linkage to gene CACNA1A. CONCLUSIONS: We emphasize the importance in knowing about this disease, with an easily identifiable clinical and neuroimaging pattern, and an efficient symptomatic treatment.

Acetazolamide↗
PubMed1997

A spectrum of mutations in the second gene for autosomal dominant polycystic kidney disease (PKD2).

Recently the second gene for autosomal dominant polycystic kidney disease (ADPKD), located on chromosome 4q21-q22, has been cloned and characterized. The gene encodes an integral membrane protein, polycystin-2, that shows amino acid similarity to the PKD1 gene product and to the family of voltage-activated calcium (and sodium) channels. We have systematically screened the gene for mutations by single-strand conformation-polymorphism analysis in 35 families with the second type of ADPKD and have identified 20 mutations. So far, most mutations found seem to be unique and occur throughout the gene, without any evidence of clustering. In addition to small deletions, insertions, and substitutions leading to premature translation stops, one amino acid substitution and five possible splice-site mutations have been found. These findings suggest that the first step toward cyst formation in PKD2 patients is the loss of one functional copy of polycystin-2.

Adult↗
PubMed1997

Factor V Leiden (R506Q) and risk of venous thromboembolism: a case-control study based on the Spanish population.

Resistance to activated protein C (APC) is a frequent cause of thrombophilia. Most patients showing APC-resistance have a G to A mutation at codon 506 of the factor V that converts arginine to glutamine. This mutation is present in populations worldwide with frequencies ranging from 0.01 to 0.05. Genotyping of 150 control individuals from the Spanish population showed that 3.33% of them carried the mutation. Several studies have measured resistance to APC (following a classical functional assay) and have determined the factor V genotype in a number of thrombophilic patients, in an attempt to compare the predictive value of both laboratory methods. To assess the incidence of the factor V mutation among Spanish thrombophilic patients, we genotyped 51 of these. The frequency of mutation carriers rose from 3.33% in the controls to 53% in the patients. We found significant differences for the thrombosis-free survival curves and for the age at the first thrombotic event between patients who carried or did not carry the mutation. Analysis of relatives of 16 patients who carried the factor V mutation suggests the existence of additional genes that modulate the effect of the factor V gene in the development of venous thrombosis among carriers of the G to A mutation.

Adult↗
PubMed1997

HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis.

HLA-B27 is strongly associated to ankylosing spondylitis (AS) and represents a family of eleven B27 alleles (B*2701-11). Our aim was to analyze the distribution of B27 subtypes by PCR/SSOP and genomic sequencing in a large group of populations (n = 17). 711 B27-positive samples from Caucasoid, Asian, African, Amerindian and Polynesian populations were selected to ascertain transracial gene mapping of the B27 subtypes. 476 of these were AS patients, chosen to investigate the contribution of B27 alleles to AS susceptibility. Some significant new findings have arisen from this study: 1) B*2705 was the predominant subtype in circumpolar and subarctic areas. B*2702 was found to be practically restricted to Caucasian populations, showing a higher frequency in Middle-East (Jews) and North Africa (Arabs/Berbers) groups. 2) B*2703 appears associated with AS in Western Africans. This is of remarkable interest since it was suggested that B*2703 would be negatively disease-associated. 3) Although B*2706 appears negatively associated with AS in Thais, we identified two patients from northern China carrying it. This may be a reflection of a disease heterogeneity and could indicate that more than one pathogenic agent can be involved in AS. B*2709 has been recently described as negatively associated with AS in Sardinians. The molecular changes His114Asp (B*2706) and Asp116His (B*2709) could modify the genetic susceptibility to AS.

Alleles↗
PubMed1997

Mutation analysis of the p53, APC, and p16 genes in the Barrett's oesophagus, dysplasia, and adenocarcinoma.

AIMS: To study the loss of heterozygosity and the presence of mutations at the p53, p16/CDKN2, and APC genes in Barrett's oesophagus, low grade dysplastic oesophageal epithelium, and adenocarcinoma of the oesophagus; to relate the presence of alterations at these genes with the progression from Barrett's oesophagus to adenocarcinoma. METHODS: DNA was extracted from paraffin blocks containing tissue from Barrett's oesophagus (12 samples), low grade dysplasia (15 cases), and adenocarcinoma (14 cases). Loss of heterozygosity (LOH) at the p53, p16, and APC genes was determined by comparing the autoradiographic patterns of several microsatellite markers between the normal tissue and the malignant tissue counterpart. SSCP was used to determine the presence of mutations at p53 (exons 5 to 8), p16 (exon 2), and APC. Homozygous deletion of the p16 gene was defined through polymerase chain reaction followed by Southern blot. RESULTS: LOH at the p53, p16, and APC genes was not observed in Barrett's oesophagus without dysplasia, and increased to 90% (p53), 89% (p16), and 60% (APC) in the adenocarcinomas. The p53 gene was mutated in only two adenocarcinomas (codons 175 and 245). In one case a mutation at the APC gene (codon 1297) was found. No patient had mutation at the second exon of p16. However, this gene was homozygously deleted in three of the 12 adenocarcinomas. CONCLUSIONS: The tumour suppressor genes p53, p16, and APC are often deleted in adenocarcinomas derived from Barrett's oesophagus. Mutations at these genes are also found in the adenocarcinomas, including the homozygous deletion of the p16 gene. However, the absence of genetic alterations in the Barrett's oesophagus and the low grade dysplastic epithelia suggest that mutations at these genes develop later in the progression from Barrett's oesophagus to adenocarcinoma.

Adenocarcinoma↗
PubMed1997

Deletion and methylation of the tumour suppressor gene p16/CDKN2 in primary head and neck squamous cell carcinoma.

AIMS: To study the homozygous deletion and methylation status of the 5' CpG island of the p16 and p15 genes (9p21) in a set of primary advanced head and neck squamous cell carcinomas (SCC) and to test whether inactivation of these genes by these mechanisms contributes to head and neck SCC development. METHODS: DNA was extracted from fresh tumours. Homozygous deletion was determined by the polymerase chain reaction (PCR) followed by hybridisation with the corresponding probe, radioactively labelled by the random priming method. Methylation status of the CpG island of the 5' region of these genes was assessed by digestion with the appropriate restriction enzymes followed by PCR and subsequent hybridisation with the corresponding probe. The presence of point mutations was determined by PCR-SSCP (single strand conformation polymorphism). RESULTS: The p16 and p15 genes were homozygously deleted in 20% and 10% of the tumours, respectively. No point mutations were found at p16 and p15. The 5' CpG island at the p16 gene was methylated in 20% of the cases. CONCLUSIONS: The tumour suppressor gene p16 is inactivated through homozygous deletion or methylation in a significant proportion of cases of head and neck SCC.

Carcinoma, Squamous Cell↗