A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G).

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. More than 20 genes with autosomal recessive (LGMD2A to LGMD2Q) and autosomal dominant inheritance (LGMD1A to LGMD1H) have been mapped/identified to date. Mutations are known for six among the eight mapped autosomal dominant forms: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin-3), LGMD1D (desmin), LGMD1E (DNAJB6), and more recently for LGMD1F (transportin-3). Our group previously mapped the LGMD1G gene at 4q21 in a Caucasian-Brazilian family. We now mapped a Uruguayan family with patients displaying a similar LGMD1G phenotype at the same locus. Whole genome sequencing identified, in both families, mutations in the HNRPDL gene. HNRPDL is a heterogeneous ribonucleoprotein family member, which participates in mRNA biogenesis and metabolism. Functional studies performed in S. cerevisiae showed that the loss of HRP1 (yeast orthologue) had pronounced effects on both protein levels and cell localizations, and yeast proteome revealed dramatic reorganization of proteins involved in RNA-processing pathways. In vivo analysis showed that hnrpdl is important for muscle development in zebrafish, causing a myopathic phenotype when knocked down. The present study presents a novel association between a muscular disorder and a RNA-related gene and reinforces the importance of RNA binding/processing proteins in muscle development and muscle disease. Understanding the role of these proteins in muscle might open new therapeutic approaches for muscular dystrophies.

Amerindian mtDNA haplogroups and celiac disease risk HLA haplotypes in mixed-blood Latin American patients.

BACKGROUND AND OBJECTIVE: Risk haplotypes have been described in celiac disease (CD), but the influence of native genes on CD in Hispanic Americans is unknown. The aim of the study was to measure the frequency of Amerindian mitochondrial DNA (mtDNA) haplogroups (inherited by the maternal line) in mixed-blood patients with CD from Chile, Argentina, and Uruguay, and to assess the relation between these and human leukocyte antigen (HLA) alleles and haplotypes and clinical presentations. PATIENTS AND METHODS: Clinical history, histological data, and genetic studies were conducted following 2 protocols: a case-control study of 72 Chilean patients with CD and controls, and an assessment of 43 (additional) samples of celiac patients from Chile, 96 from Argentina, and 57 from Uruguay, compared with the mtDNA frequency in the corresponding country. HLA typing was performed by a commercial kit, and mtDNA was determined by means of polymerase chain reaction and restriction fragment length polymorphisms analysis. RESULTS: A total of 73.6% of cases had typical presentations. The most frequent HLA alleles were HLA-DQB*201 and 202. No-DQ2/DQ8 HLA haplotypes were found in 7% of cases. mtDNA frequencies for typical Amerindian haplogroups were found in 71% of cases and 64% of controls (P χ2 = 0.016); in the comparative analysis, mtDNA distribution was not different from the figures reported for the respective general country population. No relation was found between haplotypes or haplogroups and clinical presentations. CONCLUSIONS: mtDNA haplogroups A/B/C/D were frequently found in celiac patients and controls, but no relations appeared between haplogroups, haplotypes, and clinical presentations.

Association of TCF7L2 mutation and atypical diabetes in a Uruguayan population.

AIM: To investigate if mutations in TCF7L2 are associated with "atypical diabetes" in the Uruguayan population. METHODS: Healthy, nondiabetic controls (n = 133) and patients with type 2 diabetes (n = 177) were selected from among the presenting population at level-3 referral healthcare centers in Uruguay. Patients with type 2 diabetes were subgrouped according to "atypical diabetes" (n = 92) and "classical diabetes" (n = 85). Genotyping for the rs12255372 and rs7903146 single nucleotide polymorphisms (SNPs) in the TCFTL2 gene was carried out with TaqMan® probes. Random samples were sequenced by Macrogen Ltd. (South Korea). Statistical analysis of the SNP data was carried out with the SNPStats online tool (http://bioinfo.iconcologia.net/SNPstats). The best inheritance model was chosen according to the lowest values of Akaike's information criterion and Bayesian information criterion. Differences between groups were determined by unpaired t-tests after checking the normal distribution or were converted to normalize the data. The association of SNPs was tested for matched case-control samples by using χ2 analysis and calculation of odds ratios (ORs) with 95% confidence intervals (CIs). All statistical tests were performed using SPSS v10.0 and EpiInfo7 statistical packages. Significant statistical differences were assumed in all cases showing adjusted P < 0.05. RESULTS: We genotyped two TCF7L2 SNPs (rs7903146 and rs12255372) in a population-based sample of 310 Uruguayan subjects, including 133 healthy control subjects and 177 clinical diagnosed with type 2 diabetes. For both SNPs analyzed, the best model was the dominant type: rs12255372 = G/G vs G/T+T/T, OR = 0.63, 95%CI: 0.40-0.98, P < 0.05 and rs7903146 = C/C vs C/T+T/T, OR = 0.79, 95%CI: 0.41-1.55, P = 0.3. The rs12255372 SNP showed high association with the type 2 diabetes cases (OR = 1.60, 95%CI: 1.20-2.51, P < 0.05). However, when the type 2 diabetics group was analyzed according to the atypical and classical subgroupings, the association with diabetes existed only for rs12255372 and the classical subgroup (vs controls: OR = 2.1, 95%CI: 1.21-3.75, P < 0.05); no significant differences were found for either SNP or atypical diabetes. CONCLUSION: This is the first time SNPs_TCF7L2 were genotyped in a diabetic population stratified by genotype instead of phenotype. Classical and atypical patients showed statistical differences.

Loss of TP53-DNA interaction induced by p.C135R in lung cancer.

The p53 tumor suppressor gene (TP53; OMIM: 191170) plays an important role in tumorigenesis in lung epithelial cells. TP53 encodes a sequence-specific DNA-binding protein that regulates transcription of several genes in response to DNA damage promoting cell cycle arrest, DNA repair or apoptosis. A mutation does not necessarily alter the protein function and since not all altered tumor protein p53 (TP53) conformations lead to the same biological properties, we studied Cys135Arg TP53 gene mutation in squamous cell type of non-small cell lung cancers (NSCLCs), by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct sequencing. Cys135Arg TP53 mutation, rare in databases (11/23544 in R11, IARC TP53 database), was detected. We chose p.C135R in order to examine DNA-TP53 interaction. A comparison with the wild-type after 1 nano-second molecular dynamic simulation analysis revealed a significant structural change (over 4A displacement) in the contact loop Lys-Ser-Val which lies upstream and next to the mutated site in the TP53, that sterically prevents its DNA-binding activity. Additionally, the mutation produced a change in the electrostatic potential surface of the protein in the same loop where the structural modification took place. To demonstrate the degree of loss of function, functional assays in yeast and bacteria with oligonucleotides for competitive electrophoretic mobility shift assays (EMSAs) were done proving that this mutation decreases TP53 ability to bind DNA of the TP53 response element from the human p21 gene. These results demonstrate that the amino acid change C135R in the human TP53 generates the loss of TP53 DNA-binding activity directly affecting its role as a transcription factor and suggests that this observation can explain part of the phenotype described in patients affected by this type of tumor.

The Genetic Profile from HLA and Non-HLA Loci Allows Identification of Atypical Type 2 Diabetes Patients.

The complex diagnosis and treatment of diabetes highlight the need for markers to define how to monitor patients correctly during the course of their disease. Different studies demonstrate the existence of patients who cannot be clearly classified. We have previously shown that it is possible to differentiate "atypical diabetic patients" based on genotyping the HLA. In this work we show that the analysis of non-HLA related to type 1 diabetes in the INS-VNTR, SNP rs689, and rs3842753 improves the identification of these patients. We genotyped 913 individuals comprising controls from the general population and "classic" and "atypical" diabetic patients. We compared the distribution of these loci and analyzed linkage disequilibrium. The haplotype was in LD for all the SNPs that were evaluated. Regarding their association with the disease, the haplotype IAC was associated with type 1 (odds 2.60, 1.82-3.72, CI 95%) and "atypical diabetes" (odds 1.50, 1.01-2.23, CI 95%), whereas we did not observe an association with type 2 diabetes. Therefore, our results confirm that atypical diabetes is a different entity of the disease where the patient presents with a genetic background of T1D and a T2D phenotype, findings that are likely to be relevant for patient diagnosis and management in the clinic.

A low prevalence of cystic fibrosis in Uruguayans of mainly European descent.

Cystic fibrosis is the most common hereditary disease in populations of European descent, with its prevalence depending on the populations and ethnic groups studied. In contrast to Europe and North America, there is little information about this disease in Latin America. Uruguay currently has a human population of 3,000,000, with a low rate of miscegenation and no remaining isolated Amerindian groups. In the present study, we estimated the prevalence of cystic fibrosis in this country based on the detection of DeltaF508 mutation carriers in 500 unrelated individuals and on the frequency of individuals homozygous for this mutation within the affected population. The latter was calculated from the frequency of the different mutations and genotypes observed in a sample of 52 previously described patients with confirmed cystic fibrosis. A theoretical estimate of the prevalence of cystic fibrosis based on anthropological data suggested a frequency of 25 affected individuals/100,000 inhabitants. However, our data indicated that the true prevalence in the population was considerably lower (6.9 cases/100,000 inhabitants).

Cystic fibrosis in Uruguay.

We conducted clinical and genetic analyses of 52 cystic fibrosis (CF) patients in Uruguay, which is about half of the known affected individuals in the country. A relatively high proportion had a mild presentation, characterized by pancreatic sufficiency (28%), a strong pulmonary component (97%), and borderline sweat electrolyte measurements (25%). Mutational analysis of CF chromosomes demonstrated a relatively low incidence of the DeltaF508 allele (40%) and a large number of other cystic fibrosis conductance regulator mutations, with an overall detection rate of about 71%. Fifteen different mutations were detected in our patients: DeltaF508, G542X, R1162X, G85E, N1303K, R334W, R75Q, R74W, D1270N, W1282X, DeltaI507, 2789+5G-->A, R1066C, -816C/T, R553X, as well as RNA splicing variant IVS8-5T. This group of Uruguayan CF patients has some characteristics in common with other populations of similar origin (Hispanics), as well as some unique characteristics.

Association between diabetes type 1 and DQB1 alleles in a case-control study conducted in Montevideo, Uruguay.

We studied HLA DQB1 allele frequencies and the relative risk (RR) of various genotypes in 72 type 1 diabetic patients and 40 control individuals in Uruguay. This is a tri-racial (Caucasian, Black and Indo-American) mixed population. The products of the polymerase chain reaction amplifications were hybridized with oligonucleotides by allele-specific oligonucleotide reverse or dot blot methods. Significant differences between these two groups were observed only for allele DQB1*0302 (35%, RR = 7.34, P<0.001). The frequency of the alleles carrying a non-aspartic acid residue at position 57 was significantly higher in the diabetic patients (85 vs 53%, P<0.001). In contrast, the frequency of Asp alleles was negatively associated with type 1 diabetes (RR = 0.20, P<0.001). The genotype DQB1*0302/DQB1*0201 (33%, RR = 5.41, P<0.05) was positively associated with this disease. The genotype frequencies associated with type 1 diabetes in our population were significantly different from what is known for Caucasian and Black populations as well as compared with another admixed population, from Chile.

HLA alleles may serve as a tool to discriminate atypical type 2 diabetic patients.

AIM: To investigate whether the presence of human leukocyte antigen (HLA) marker could add new information to discriminated atypical diabetic type 2 patients. METHODS: We analyzed 199 patients initially diagnosed as type 2 diabetes who are treated in special care diabetes clinics (3(rd) level). This population was classified in "atypical" (sample A) and "classic" (sample B) according to HLA typing. We consider "classic patient" when has absence of type 1 diabetes associated HLA alleles and no difficulties in their diagnosis and treatments. By the other hand, we considered "atypical patient" when show type 1 diabetes associated HLA alleles and difficulties in their diagnosis and treatments. The standard protocol Asociacion Latinoamericana de Diabetes 2006 was used for patients follow up. To analyze differences between both populations in paraclinical parameters we used unpaired t tests and contingence tables. Bivariate and multivariate analyses were carried out using the SPSS software program. In all studies we assume differences statistically significant, with a P-value < 0.05 corrected and 95%CI. RESULTS: The typing HLA in the "atypical" populations show that 92.47% patients presented at list one type 1 diabetes associated HLA alleles (DQB1*0201-0302 and DR 3-4) and 7.53% had two of its. The results showed for categorical variables (family history, presence or absence of hypertension and/or dyslipidemia, reason for initial consultation) the only difference found was at dyslipidemia (OR = 0.45, 0.243 < OD < 0.822 (P < 0.001). In relation to continuous variables we found significant differences between atypical vs classic only in cholesterol (5.07 ± 1.1 vs 5.56 ± 1.5, P < 0.05), high density lipoproteins (1.23 ± 0.3 vs 1.33 ± 0.3, P < 0.05) and low density lipoproteins (2.86 ± 0.9 vs 3.38 ± 1.7, P < 0.01). None of the variables had discriminating power when logistic regression was done. CONCLUSION: We propose an algorithm including HLA genotyping as a tool to discriminate atypical patients, complementing international treatment guidelines for complex patients.

The phenotype masks the genotype: A possible new expression of diabetes.

The concept of a new form of diabetes, with signs of both types 1 and 2, has not been often considered, until recently. It is of immense interest to explore the role of the admixture that characterizes the Uruguayan population (higher and different from other Latin America countries) for the presence of such expression of that particular disease. We describe here a child who possibly presents with this expression. He had typical signs of both diabetic conditions: type 1 (young age, positive immunologic and genetic markers, ketoacidosis) and type 2 (obesity [body mass index = 36 kg/m(2)] and acanthosis nigricans). In spite of complying with the established guidelines, therapeutic and nutritional control, quality of life and good metabolic control, the patient's obesity had been continually increasing. Looking for a genetic explanation, we studied three single nucleotide polymorphisms involved in three different metabolic pathways (peroxisome proliferator-activated receptor gamma 2, insulin receptor substrate-1 and uncoupling protein-2) associated with insulin resistance. Our patient showed three mutations, GG, GA, GG, associated with insulin resistance that explains obesity associated with limited response to the commonly used drugs. According to the clinical presentation and the genetic and immunological background, we considered that this patient presents with a new form of diabetes. We have termed this particular disease "hybrid diabetes" because of the involvement of genes associated with both the classical type of diabetes. However, at least in an admixed population such as in Uruguay, clinical classification would not strictly dictate the choice of treatment.

Frequencies of the four major Amerindian mtDNA haplogroups in the population of Montevideo, Uruguay.

mtDNA Amerindian polymorphisms were studied in 108 inhabitants of Montevideo, Uruguay, using PCR RFLP analysis. Amerindian haplogroups were found in 20.4% of the sample. The frequency of Amerindian polymorphisms in Montevideo differed significantly from that observed in Tacuarembó, a city about 400 km away, indicating the high level of variation within Uruguay. Results for mitochondrial markers indicate that admixture occurred primarily as a result of Amerindian females mating with European males.

A recurrent chromosome 4 marker in primary squamous cell lung cancer.

A sample of eight primary lung tumors histologically identified as squamous cell type carcinomas (SQC) were cytogenetically analyzed after a short-term (7 days) culture. Several numerical and structural abnormalities were observed. As G-banding analysis is unable to fully characterize complex marker chromosomes, we applied the fluorescence chromosome painting technique to identify one as a marker derived from a chromosome 4 that has not been described until now. We found it in half of the analyzed cases.

The association between HLA DQ genetic polymorphism and type 1 diabetes in a case-parent study conducted in an admixed population.

Susceptibility to the type 1 diabetes is genetically controlled and there is an increased risk associated with the presence of some specific alleles of the human leukocyte antigens class II loci (DQA1 and DQB1 genes). The purpose of this study is to evaluate the association between type 1 diabetes and HLA DQ alleles using case-parents trios in the admixed population of Uruguay composed by a mixture of Caucasian, Amerindian and Negroid populations. DQA1 and DQB1 genotyping was performed by polimerase chain reaction followed by oligospecific probes hybridization in 51 case-parents trios. The transmission disequilibrium test was used for detecting differential transmission in the HLA DQ loci. DQB1*0302 was the only allele for which preferential transmission is suggested (probability of transmission = 67.56%; exact p-value TDT = 0.047 uncorrected for multiple comparisons). DQA1*0301 allele showed a trend for preferential transmission without achieving statistical significance. This result would confirm the hypothesis previously advanced in a case-control study. Therefore, DQB1*0302 allele could be considered as the most important susceptibility allele for developing type 1 diabetes in Uruguay population.

Estudio comparativo de prevalencia del gen de la ECA en muestras de diabéticos y población general / Comparative study on the prevalence of the Angiostatin-converting enzyme gene in diabetic patients and general population samples

Introducción: previamente se ha demostrado que los pacientes diabéticos poseen una incidencia aumentada de patologías micro y macrovasculares. En la exploración de posibles determinantesaparece como candidato atractivo el gen de la enzima convertidora de angiotensina (ECA) el cual presenta de acuerdo al polimorfismo InDel existente, un aumento de la concentración enzimática en sangre asociado a enfermedades vasculares. Objetivo: se plantearon como objetivos establecer la prevalencia del polimorfismo del gen de la ECA, en pacientes diabéticos y comparar las frecuencias con las halladas para la población general demanera de revelar si existe asociación del locus con la diabetes mellitus.Material y método: la población estudiada consistió en 131 individuos con diagnóstico certero de diabetes según criterios de la American Diabetes Association. Se hallaron las frecuencias génicas y genotípicas del polimorfismo InDel del gen de la ECA mediante la técnica de reacción en cadena dela polimerasa (PCR). Resultados: no se encontraron diferencias significativas en la prevalencia del marcador estudiadoentre diabéticos y la población general. Las frecuencias génicas halladas en diabéticos fueron 0,435 para alelo I y 0,565 para alelo D versus 0,440 alelo I y 0,560 alelo D en la población general.Discusión: en suma, este marcador es un factor de riesgo que no está asociado a la diabetes en sí misma, sino que la relación entre este gen y las complicaciones vasculares serían las mismas para diabéticos que para la población general.

Introduction: we have previously demonstrated that diabetic patients have an increased incidence of micro and macrovascular pathologies. Upon exploration of possible determining factors, the ACE gene appears as an attractive factor, since it presents, according to the existing InDelpolymorphism, an increase of the enzyme concentration in blood associated to vascular diseases.Objective: to establish the prevalence of polymorphism of the ACE gene in diabetic patients, and to compare thefrequencies with those found in the general population, in order to find out whether there is a relationship betweenlocus and diabetes mellitus. Method: the population studied consisted of 131 individuals with a certain diagnosis of diabetes, according to criteria of the American Diabetes Population. We determined InDel polymorhism´s genic and genotypic frequencies in the ACE gene through the polymerase chain reaction (PCR). Results: we failed to find meaningful differences in theprevalence of the marker studied between diabetic patients and the general population. Discussion: to sum up, the present marker is a risk factor that is not associated to diabetes itself; hence the relationship between this gene and vascular complications would be the same in diabetic patients and the general population.

Introdução: está demonstrado que os pacientes diabéticos apresentam uma maior incidência de patologias microy macrovasculares. Na pesquisa de possíveis determinantes aparece como candidato possível o gen da ECA queapresenta, de acordo ao polimorfismo Índio existente, um aumento da concentração enzimática no sangue associado a patologias vasculares.Objetivo: estabelecer a prevalência do polimorfismo do gen da enzima convertidora de angiotensina (ECA), empacientes diabéticos e comparar as freqüências encontradas com as determinadas para a população em geral para verificar a existência de uma associação do lócus com a diabetes mellitus. Material e método: a população estudada estava composta por 131 indivíduos com diagnóstico confirmadode diabetes de acordo com os critérios da American Diabetes Association. As freqüências gênicas e genotípicas do polimorfismo InDel do gen da ECA foramdeterminadas pela técnica de reação em cadeia da polimerase (PCR). Resultados: nao se encontraram diferenças significativas na prevalên-cia do marcador estudado entre diabéticose a população em geral. As freqüências gênicas encontradas em diabéticos foram 0,435 para alelo I e 0,565para alelo D e, 0,440 alelo I e 0,560 alelo D na população em geral.Discussão: este marcador é um fator de risco que não está associado à diabetes, porém a relação entre este gen e as complicações vasculares seria a mesma para diabéticos que para a população em geral.

Prevalencia del polimorfismo I/D del gen de la enzima convertidora de amgiotensina (ECA) en la población de Montevideo / Prevalence of I/D polymorphism of the angiotensin converting enzyme (ACE) gene in Montevideo

Las nuevas técnicas de biología molecular aplicadas al diagnóstico genético y el uso de marcadores moleculares posibilitan el estudio de los mecanismos que subyacen en la predisposición individual y familiar a padecer determinadas enfermedades. Para llevar a cabo estos estudios, es necesario en primera instancia establecer cuál es la prevalencia de dichos marcadores en la población general. El estudio se realizó empleando una muestra de 108 individuos seleccionados por muestreo simple del banco de ADN de 500 individuos representativos de nuestra población, que pertenece al Departamento de Citogenética del Instituto de Investigaciones Biológicas Clemente Estable (IIBCE). Para establecer el genotipo del gen de la enzima convertidora de angiotensina (ECA) en cada una de las muestras, se amplificó un fragmento de ADN perteneciente al intrón 16 de este gen mediante la técnica de reacción en cadena de la polimerasa (PCR). El genotipo predominante en esta población control es el heterocigota I/D (50,9 por ciento), encontrándose el genotipo homocigota para la delección (D/D) (30,6 por ciento) en mayoría con respecto al genotipo homocigota para la inserción (I/I) (18,5 por ciento). Los resultados sugieren que existe, por tanto, un predominio del alelo D con respecto al alelo I en la población montevideana, habiéndose hallado diferencias significativas con respecto a poblaciones de origen asiático y americano, pero no con poblaciones europeas.

A low prevalence of cystic fibrosis in Uruguayans of mainly European descent

Cystic fibrosis is the most common hereditary disease in populations of European descent, with its prevalence depending on the populations and ethnic groups studied. In contrast to Europe and North America, there is little information about this disease in Latin America. Uruguay currently has a human population of 3,000,000, with a low rate of miscegenation and no remaining isolated Amerindian groups. In the present study, we estimated the prevalence of cystic fibrosis in this country based on the detection of DeltaF508 mutation carriers in 500 unrelated individuals and on the frequency of individuals homozygous for this mutation within the affected population. The latter was calculated from the frequency of the different mutations and genotypes observed in a sample of 52 previously described patients with confirmed cystic fibrosis. A theoretical estimate of the prevalence of cystic fibrosis based on anthropological data suggested a frequency of 25 affected individuals/100,000 inhabitants. However, our data indicated that the true prevalence in the population was considerably lower (6.9 cases/100,000 inhabitants).

Alelos HLA-DQB1 y DRB1 asociados con la enfermedad celíaca en pacientes hospitalarios / Association between HLA-DQB1 and HLA-DRB1 alleles and coeliac disease in hospitalized patients

La enfermedad celíaca (EC) es una afección autoinmune que presenta asociación con determinados genes del sistema HLA. Se ha descrito que ciertas variantes (alelos) HLA de clase II DQ y DR están involucradas en la susceptibilidad primaria de esta enfermedad. La frecuencia de alelos HLA varía entre los diferentes grupos étnicos. La población actual de nuestro país presenta características étnicas particulares y, hasta el momento de realizado este trabajo, no se conocía la asociación de estos alelos con la enfermedad. Se presentan, por tanto, los datos obtenidos mediante determinación molecular de alelos HLA de clase II de cadena beta DQ y DR para una muestra total de 37 individuos (pacientes y controles). Se calculó el riesgo relativo (RR) y la fracción etiológica (FE) para cada alelo, genotipo y haplotipo DQB1-DRB1. Se determinó que los alelos DQB1*0201 y DRB1*03 están positivamente asociados a los pacientes (RR= 10,7, p<0,001 y RR=13, p<0,001 respectivamente). Cuando se analizaron los haplotipos, fue precisamente la combinación de estos alelos la que presentó una asociación positiva con la EC. Estos resultados permitieron establecer que, si bien existe mezcla étnica en nuestra población, los alelos involucrados en la susceptibilidad de la enfermedad celíaca son los mismos a los descritos en la literatura variando la frecuencia y, por lo tanto, el riesgo asociado a cada alelo

Asociación entre hiperhomocisteinemia, cardiopatía isquémica y diabetes tipo 2

La hiperhomocisteinemia es considerada como un factor de riesgo para las enfermedades vasculares en la población general. Sin embargo, su rol en el desarrollo de la cardiopatía isquémica (CI) no ha sido totalmente dilucidado. El objetivo fue determinar, si existe, en primera instancia una asociación entre la cardiopatía isquémica y los niveles elevados de homocisteína en plasma y posteriormente investigar la posible asociación entre la hiperhomocisteinemia y la diabetes mellitus tipo 2. Se analizó la información de 204 pacientes atendidos en consultorios dependientes del CASMU con una edad promedio de 61,2±10,8 años. Se siguieron los criterios de las guías de Task Force y ADA para el diagnóstico de cardiopatía isquémica y diabetes, respectivamente. Se tomaron valores entre 5-15 µmoles/lt de homocisteína plasmática como normales. Los pacientes fueron clasificados en dos grupos: con cardiopatía isquémica (CCI) y sin cardiopatía isquémica (SCI). En las comparaciones realizadas entre los grupos se observaron diferencias significativas en la distribución de los niveles de homocisteína plasmática entre los individuos CCI y SCI (p<0,001). A su vez, se observó una asociación entre los valores de hiperhomocisteinemia y la CI (OR=2,66). Por otra parte, la ausencia de diferencias significativas entre diabéticos y no diabéticos con CI estaría indicando que la diabetes y la hiperhomocisteinemia serían dos características genéticas independientes o -dicho de otra forma- el hecho de ser diabético no altera la asociación entre la hiperhomocisteinemia y la cardiopatía isquémica.

A high plasmatic level of homocysteine is considered as a risk factor to vascular disease in the general population. However, the role of hyperhomocysteinaemia in the ischaemic heart disease development is not totally elucidated. The aim of our study was to determine in fist place, if in our sample there is an association between homocysteine levels and ischaemic heart disease and subsequently to investigate a possible association of hyperhomocysteinaemia to the presence of diabetes mellitus type 2. We analyzed the information of 204 patients attending to private health centers (depending from CASMU). All patients (61,2 ± 10,8 year olds average) were diagnosed as diabetic type 2 and ischaemic heart disease according to the ADA and Task Force guides criteria respectively. We took 5-15 µmol/l homocysteine plasmatic value as normal. The patients were classified in two groups: with (CCI) and without ischaemic heart disease (SCI). We observed statistical significant differences in the distribution of homocysteine plasmatic levels between: CCI and SCI (p<0,001). We also observed an association between hyperhomocysteinaemia and CI (OR=2,66). In the other hand, non-significant statistical differences between diabetic and non diabetics patient with CI would be indicate that that hyperhomocysteinaemia and diabetes are two independent genetics factors; the diabetes condition do not alter the association between hyperhomocisteinaemia and CI.

Fibrosis quística: ¿Se presenta de la misma manera en Uruguay que en el Viejo Mundo? / Cystic fibrosis: same presentation in Uruguay than in Europe?

La fibrosis quística (FQ), es una enfermedad genética, caracterizada por presentar grados variables de compromiso pulmonar e insuficiencia pancreática. Desde el punto de vista etiopatogénico es una alteración de los canales de cloro a nivel de la membrana celular. Se han descrito más de trescientas mutaciones a nivel del gen regulador de la conductancia transmembranosa (CFTR) de la FQ, localizado en el cromosoma 7, cuyas frecuencias varían en las diversas poblaciones analizadas. La información existente en Uruguay con respecto al mestizaje y los datos primarios aportados en este trabajo sobre las mutaciones observadas, permiten considerar que las mismas, así como sus frecuencias, serían diferentes a las descritas para el viejo mundo. Nuestro laboratorio utiliza técnicas de biología molecular, en este caso, la reacción de la polimerasa en cadena (PCR) para establecer dos parámetros poblacionales que consideramos de interés determinar: a) cuál es la real frecuencia de FQ en el país y b) cuáles son las mutaciones que están en juego en la determinación de la FQ en el Uruguay