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Biomedical subjects

E Coto

Publications and source records attributed to E Coto.

At least 37 records · Page 2Linked to original sources
PubMed2001

Variability of genetic alterations in different sites of head and neck cancer.

OBJECTIVE: Tumors arising from different sites of the head and neck area have different clinical behavior. However, most of the studies on genetic alterations in head and neck squamous cell carcinomas do not make a distinction between the sites within this area. The objective of this study is to compare the genetic alterations in three different sites of the head and neck (larynx, oropharynx, and hypopharynx). STUDY DESIGN: Prospective study. METHODS: Thirty-eight laryngeal, 29 oropharyngeal, and 37 hypopharyngeal carcinomas were studied. DNA from tumor and healthy tissue was evaluated for amplification of the oncogenes at 11q13 region (CCND1, FGF3, FGF4 and EMS1) and of the oncogenes MYC and ERBB1; for integration of the human papillomavirus (HPV) types 6b and 16; for loss of heterozygosity (LOH) at p53 and NAT2; and for the cellular DNA content. RESULTS: FGF3 and FGF4 showed a significantly higher frequency of amplification in hypopharyngeal tumors (P =.006 and P =.0002, respectively). CCND1 amplification had a nearly statistically significant (P =.072) higher frequency of amplification in hypopharyngeal tumors. Aneuploid tumors were found in a significantly lower proportion in the larynx (P =.03) compared with the other sites. For the other genetic alterations, no significant differences among the three sites were found. CONCLUSIONS: These results suggest that cancers originating from different sites in the head and neck may have different tumor biology. Therefore, they should be considered as different entities.

Aneuploidy↗
PubMed2000

Genetic variation in the renin-angiotensin system and athletic performance.

The D allele at the angiotensin-I-converting enzyme (ACE)-insertion/deletion polymorphism has been associated with an increased risk of developing several pathological processes, such as coronary heart disease and ventricular hypertrophy. Individuals with the DD genotype show a significantly increased left-ventricular mass in response to physical training, compared to the II genotype (which would be associated with the lowest plasma ACE levels) and the ID genotype. The II genotype has been linked to a greater anabolic response. In accordance with a role for ACE in the response to rigorous physical training, a higher frequency of the I allele has been reported to exist among elite rowers and high-altitude mountaineers. Sixty elite (professional) athletes (25 cyclists, 20 long-distance runners, and 15 handball players), and 400 healthy controls were genotyped for the DNA polymorphisms of the ACE, angiotensinogen (Ang) and angiotensin receptor type 1 (AT1) genes. Plasma ACE levels showed a strong correlation with the I/D genotype in our population. The I-allele occurred at a significantly higher frequency in athletes compared to controls (P = 0.0009). Gene and genotype frequencies for the Ang and AT1 polymorphisms did not differ between athletes and controls. Since the frequency of the ACE I allele was significantly increased among our elite athletes, we conclude that the ACE polymorphism represents a genetic factor that contributes to the development of an elite athlete.

Adult↗
PubMed2000

Analysis of chromosome 6p in Spanish families with recessive polycystic kidney disease.

Several previous reports have suggested that autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in a single gene (the PKDH1 gene). Linkage analysis showed a positive linkage for polymorphic markers at the short arm of chromosome 6 (6p) in all families. PKHD1 has not been cloned. Recombinants in the critical region would permit the narrowing of the 6p interval containing the PKHD1 gene, thus facilitating the final identification (cloning) of this gene. Our study included 30 Spanish families. Each family consisted of both parents and at least two children, with at least one diagnosed with ARPKD by clinical and pathological parameters. DNA was obtained and 6p microsatellite markers were used to establish haplotypes for each family. A positive linkage to chromosome 6p was found for all families. In 2 cases, recombinants in the region containing the PKHD1 gene were found. These families will help narrow the size of the 6p region, facilitating the efforts to position and clone the PKHD1 gene. In conclusion, our analysis of Spanish ARPKD families confirms the lack of linkage heterogeneity. This suggests that mutations at a single locus on chromosome 6p21.1-p12 are responsible for the broad clinical spectrum of variable phenotypes.

Adolescent↗
PubMed2000

CCR5 (chemokine receptor-5) DNA-polymorphism influences the severity of rheumatoid arthritis.

Chemokines are critical for the inflammatory process in autoimmune diseases such as rheumatoid arthritis (RA). The chemokine receptor-5 (CCR5) mediates chemotaxis by CC-chemokines and is expressed by lymphocytes with the Th1 phenotype and monocyte/macrophages. A 32 bp deletion in the CCR5 (CCR5-delta 32 allele) abolishes receptor expression in homozygotes, while CCR5-delta 32 carriers would express less receptor than wild-type homozygotes. This polymorphism is related to the resistance to HIV-1 infection and progression towards AIDS. We hypothesized that the CCR5-delta 32 allele may modulate the severity of disease in RA. A total of 160 RA-patients (71 and 89 with severe and non-severe phenotypes, respectively) and 500 healthy individuals from the same Caucasian population (Asturias, northern Spain) were genotyped. Carriers of the CCR5-delta 32 allele were at a significantly higher frequency (P = 0.012) in non-severe compared to severe patients (17% vs 4%). Our results suggest that the CCR5-delta 32 polymorphism is a genetic marker related to the severity of RA.

Arthritis, Rheumatoid↗
PubMed2000

Location of mutations within the PKD2 gene influences clinical outcome.

BACKGROUND: Since the cloning of the gene for autosomal dominant polycystic kidney disease type 2 (PKD2), approximately 40 different mutations of that gene have been reported to be associated with the disease. The relationship between the PKD2 genotype and phenotype, however, remains unclear. METHODS: Detailed clinical information was collected for PKD2 families in which the underlying mutation had been identified. Logistic regression analysis was employed to assess the influence of age and sex on hypertension, hematuria, renal calculi, and urinary tract infections, and a clinical phenotype score was computed. Patients were then grouped according to the relative location of their mutation within the cDNA sequence, and differences in the mean phenotypic score between groups were tested for statistical significance by means of a multiple pairwise t-test. RESULTS: While phenotypic scores for each mutational group revealed a considerable degree of intragroup variability, the variability in phenotypic scores was significantly higher between mutational groups than within groups. A group-wise comparison of the mean phenotypic scores confirmed the observation of significant nonlinear variation in disease severity, with high- and low-scoring mutational groups interspersed along the gene sequence. CONCLUSION: The identification of groups of mutations in the PKD2 gene, which differ significantly with respect to clinical outcome, is to our knowledge the first description of a genotype/phenotype correlation in autosomal dominant polycystic kidney disease. It also provides evidence against complete loss of function of the mutant PKD2 gene product.

Analysis of Variance↗
PubMed2000

Normal frequencies of the C677T genotypes on the methylenetetrahydrofolate reductase (MTHFR) gene among lymphoproliferative disorders but not in multiple myeloma.

The folate availability seems to be critical for the DNA integrity since it is required for the transfer of methyl groups in the biosynthesis of thymidilate. Although the excessive incorporation of uracils to the DNA can be efficiently removed, this mechanism of reparation produces many double-strand breaks from two opposing nicks. Several chromosomal abnormalities (mainly translocations and deletions perhaps not well understood) are involved in the origin of lymphoproliferative disorders. The TT homozygosity at nucleotide 677 in the gene of methylene tetrahydrofolatereductase (MTHFR), a key enzyme in folate metabolism, was recently linked to a significant protection against colon carcinoma and acute lymphoblastic leukaemia in adults. We analysed the genotype frequencies of C677T-MTHFR in a group of 143 patients with lymphoproliferative disorders (REAL classification) and 200 controls. Overally, the frequencies of the polymorphic allele were similar (35.3% and 32.0% respectively)(P=0.6). We did not find differences between patients and controls except for myeloma/plasmacytoma group (n=26) which showed a CC genotype less than expected (19% vs 46%) (p=0.01) with a frequency ratio of 0.28 (0.10-0.77). Even among the IgG myeloma cases only one patient showed a common genotype (CC) (1/15, 7%) (P=0.003). If these preliminary data are validated with prospective studies, the 677C allele of MTHFR gene could be confirmed as an effective multiple myeloma protective factor (specially for the IgG cases).

Adult↗
PubMed2000

A DNA polymorphism at the alpha2-macroglobulin gene is associated with the severity of rheumatoid arthritis.

OBJECTIVE: To determine if DNA polymorphisms at the alpha2-macroglobulin (alpha2m) and angiotensin converting enzyme (ACE) genes were associated with rheumatoid arthritis (RA). METHODS: A total of 160 patients (71 with early active severe RA, 89 with non-severe RA) were genotyped (polymerase chain reaction) for the alpha2m (5 bp deletion/insertion) and ACE (I/D) polymorphisms. We also genotyped 500 healthy controls from the same Caucasian population (Asturias, Northern Spain). RESULTS: Carriers of the alpha2m deletion allele were at a significantly higher frequency among patients with an early active severe form of the disease, compared to patients with non-severe RA (p = 0.037). The frequency of the alpha2m deletion allele was significantly higher in patients with severe compared to nonsevere RA (p = 0.017). In addition, the frequency of the deletion allele was significantly higher among patients with 5 or more episodes of acute exacerbation of disease activity per year (n = 39) compared to those with none (n = 46) (p = 0.002). Gene and genotype frequencies for the ACE-I/D polymorphism did not differ between those with early active severe and non-severe RA. CONCLUSION: The genetic variation at alpha2m is associated with the severity of RA. Carriers of the alpha2m deletion allele would have increased risk of developing an early active severe form of the disease. Our data suggest that alpha2m could be a valuable target in the treatment of RA.

Arthritis, Rheumatoid↗
PubMed2000

Synergistic effect between apolipoprotein E and angiotensinogen gene polymorphisms in the risk for early myocardial infarction.

BACKGROUND: Several studies based on different populations worldwide have described an association between cardiovascular diseases and genetic variations in the apolipoprotein E (A:POE), angiotensinogen (A:GT), angiotensin receptor type 1 (A:T1R), and angiotensin-converting enzyme (A:CE) genes. In addition, there is growing evidence of an interaction between hypercholesterolemia and the renin-angiotensin system in the risk for hypertension and atherosclerosis. METHODS: To determine whether the DNA polymorphisms in A:POE (epsilon2, epsilon3, and epsilon4 alleles), A:GT (M235T), A:T1R (1166 A:/C:), and ACE (I:/D:) are associated with early onset of myocardial infarction (MI), we genotyped 220 patients and 200 controls <55 years of age. Patients and controls were males from the same homogeneous Caucasian population. Data concerning hypertension, diabetes, and tobacco consumption were recorded. The lipid profiles of patients and controls were also determined. RESULTS: APOE, ACE, AGT, and AT1R allele and genotype frequencies did not differ between patients and controls. None of these polymorphisms was related to the biochemical values in patients or controls. The frequency of individuals who were both APOE epsilon4 allele carriers and AGT-TT homozygotes was significantly higher in patients than in controls (11% vs 3.5%; P: = 0.0037). In patients, the frequency of epsilon4 carriers was significantly higher (P: <0.00001) in those who were AGT-TT (46%) than those who were AGT-MT/MM (14%). Mean cholesterol was significantly higher in AGT-TT + APOE epsilon34/44 patients than in the TM/MM + epsilon34/44 or TT + epsilon23/33 genotypes (P: = 0. 029). CONCLUSIONS: Our data suggest a synergistic effect between the APOE and AGT polymorphisms and early MI. The increased risk could be mediated in part through higher cholesterol concentrations among individuals who are AGT-TT + APOE epsilon4 allele carriers.

Adult↗
PubMed1999

[Frequency of the APOE-4 allele in Alzheimer's disease and its variation with age in Asturias (Spain)].

BACKGROUND: Patients with late-onset Alzheimer's disease show a higher frequency of the APOE-4 than controls. The usefulness of the APOE genotyping in the diagnosis of the disease is controversial. Recently, an age dependent prevalence of APOE-4 in Alzheimer's disease has been described, with a maximum frequency for patients with an age at onset between 65 and 80 years. Additionally, the APOE-4 frequency in healthy controls is similar among the different age-groups, including healthy octogenarians. These data suggest that APOE-4 determines when and not who will develop the disease. PATIENTS AND METHODS: The APOE genotype was defined following a previously described PCR-protocol. We analysed 120 patients with clinically defined probable Alzheimer's disease and 250 controls from the same Caucasian population (Austrias, Northern Spain). RESULTS: We found a significantly higher frequency of the APOE-4 in patients, compared to controls (p = 0.00001). The prevalence of this allele was 65% among patients with an age at onset 66-70, falling to 36% and 18% in patients younger than 65 and older than 80 years, respectively. The average age (SD) at onset did not differ between the E-44 (69 years), E-34 (73 years) and E-33 (73 years). APOE-4 frequency was similar between the different age-groups of controls, including healthy octogenarians. CONCLUSIONS: In Asturias, APOE genotyping can not be used for the presimptomatic diagnosis of Alzheimer's disease. However, individuals carrying this allele would have a higher probability of developing the disease at an age between 65 and 80 years if they are predisposed (genetically and/or environmentally) to the disease.

Adult↗
PubMed1999

Association between an alpha(2) macroglobulin DNA polymorphism and late-onset Alzheimer's disease.

An association between a five-base-pair deletion/insertion DNA polymorphism at the alpha(2) macroglobulin gene (A2M) and late-onset Alzheimer's disease (LOAD) has been recently described. We developed a PCR assay to analyze this polymorphism in 190 LOAD patients (older than 65 years) and 400 controls from Spain. Controls were stratified into three groups: <65 years (n = 200), 65 to 80 years (n = 100), and 81 years or older (n = 100). We found a significantly higher frequency of carriers of the D allele in patients older than 81 years compared to controls older than 81 years (p = 0.0012). In addition, the frequency of the D allele was significantly lower in controls older than 81 years compared to controls younger than 65 (p = 0.048). Our work suggests that the D allele confers an age-dependent increased risk to develop late-onset Alzheimer's disease.

Age of Onset↗
PubMed1999

Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group.

BACKGROUND: Although autosomal dominant polycystic kidney disease type 2 (PKD2) is known to have a milder clinical phenotype than PKD1, neither disorder has been compared with an unaffected control population in terms of survival. We report the findings of a multicentre survey that aimed to define more precisely the survival and clinical expression of PKD1 and PKD2. METHODS: Clinical data from 333 people with PKD1 (31 families) were compared with data from 291 people with PKD2 (31 families) and 398 geographically matched controls. Survival analysis was used to compare age-at-event data. Differences in the prevalence of complications were assessed by logistic regression. FINDINGS: Median age at death or onset of end-stage renal disease was 53.0 years (95% CI 51.2-54.8) in individuals with PKD1, 69.1 years (66.9-71.3) in those with PKD2, and 78.0 years (73.8-82.2) in controls. Women with PKD2 had a significantly longer median survival than men (71.0 [67.4-74.8] vs 67.3 [64.9-69.7] years), but no sex influence was apparent in PKD1. Age at presentation with kidney failure was later in PKD2 than in PKD1 (median age 74.0 [67.2-80.8] vs 54.3 [52.7-55.9] years). PKD2 patients were less likely to have hypertension (odds ratio 0.25 [95% CI 0.15-0.42]), a history of urinary-tract infection (0.50 [0.31-0.83]), or haematuria (0.59 [0.35-0.98]). INTERPRETATION: Although PKD2 is clinically milder than PKD1, it has a deleterious impact on overall life expectancy and cannot be regarded as a benign disorder.

Adult↗
PubMed1999

Multiple endocrine neoplasia type 1 (MEN1): clinical heterogeneity in a large family with a nonsense mutation in the MEN1 gene (Trp471Stop).

OBJECTIVE: Familial multiple endocrine neoplasia type 1 (MEN1) is an hereditary dominant trait characterized by tumours of the parathyroids, anterior pituitary and endocrine pancreatic glands, among others. The MEN1 gene has recently been cloned, and MEN1-mutations have been identified in several families as well as in a number of sporadic cases. The aim of this study was to search for mutations in a large MEN1-family in order to define the clinical heterogeneity among mutation-carriers. We also analysed DNA from several tumour tissues in order to test the 'two hit' model for inactivation of the MEN1 gene. PATIENTS AND METHODS: We searched for mutations in the MEN1-gene in members of a large MEN1-family. A total of 11 affected and 4 healthy at risk individuals were analysed. DNA was obtained and exons 1 to 10 of the MEN1-gene were PCR-amplified and subjected to automated-direct sequencing. In addition, we isolated DNA from parathyroid tumours of two family members, and compared this DNA with that of the normal tissue counterpart to define if the normal copy of the MEN1-gene was deleted. RESULTS: G to A change at nucleotide 7640 (exon 10) that would convert Trp to Stop at codon 471 was found. This mutation was identified in eleven affected individuals, as well as in four healthy (asymptomatic) family members. These patients showed a wide spectrum of clinical symptoms and ages of presentation. Comparison of normal and tumour DNAs showed the loss of the normal (non-mutated) copy of MEN1 gene in the tumour tissue. CONCLUSION: The different ages of disease presentation and the heterogeneity of symptoms among carriers of the Trp471Stop mutation, which would lead to the synthesis of a truncated non-functional protein, suggest that clinical heterogeneity is a characteristic of MEN1 independent of the type of mutation. Finally, the lack of amplification of the normal MEN1-allele on DNA from parathyroid tumours of two family members indicates that MEN1 is a tumour suppressor gene, the second hit that inactivates the normal copy in mutation carriers being a deletion.

Adolescent↗
PubMed1999

N-acetyltransferase-2, glutathione S-transferase M1, alcohol dehydrogenase, and cytochrome P450IIE1 genotypes in alcoholic liver cirrhosis: a case-control study.

BACKGROUND: Only a small percentage of long-term alcoholics develop liver cirrhosis. Genetic and non-genetic factors have been implicated in the risk of developing this disease. Among the genetic factors, case-control studies suggest an association with some polymorphisms at the alcohol dehydrogenase and cytochrome P450IIE1 genes. N-Acetyltransferase-2 metabolizes multiple compounds, transforming some of them to organ-toxic compounds and others into non-toxic molecules. Slow- and rapid-acetylator individuals exist in most human populations, and the mutations responsible for the slow-acetylator genotype have been determined. Slow acetylators, who should be at higher risk of developing breast cancer, and fast acetylators, who have an increased risk of developing colon cancer, can be characterized by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) genotyping. GSTM1 is another detoxifying enzyme for which functional interindividual differences, on the basis of gene polymorphisms, have been described. METHODS: We conducted a case-control study in which 120 alcoholic cirrhotics, 30 long-term non-cirrhotic alcoholics, and 200 healthy controls were genotyped for polymorphisms (RFLPs) at the ADH2, P450IIE1, and NAT2 genes. PCR, followed by restriction enzyme digestion, was performed. The homozygous deletion of the GSTM1 gene was also PCR-analyzed. Genotype frequencies were statistically compared. RESULTS: Frequencies for the ADH2, P450IIE1, and GSTM1 polymorphisms did not differ between patients and controls. Individuals homozygous for the NAT2*5 allele, which is the most frequent slow-acetylator (SA) allele and shows the lowest acetylator activity, were at a significantly decreased frequency among the cirrhotic patients compared with controls (9% versus 16%; P = 0.042). The frequency of this SA genotype was significantly increased (40%) in long-term alcoholics who did not develop cirrhosis (P = 0.0041 compared with controls; P= 0.000017 compared with cirrhotics). CONCLUSIONS: According to our results, NAT2 activity may be a factor that determines the risk of developing alcoholic liver cirrhosis, and slow acetylators would be protected.

Acetylation↗