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.

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.

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.

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.

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).

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).

Substantial Native American female contribution to the population of Tacuarembó, Uruguay, reveals past episodes of sex-biased gene flow.

For many years it has been assumed that the population of Uruguay is almost exclusively European-derived and that the biological contribution of the native population as well as of individuals of African descent is negligible. Several recent studies based on a variety of genetic markers, mostly morphological and serological markers, have produced quite a different picture of the constitution of the Uruguayan population. The Native American contribution varies from 1-20%, while the African contribution ranges from 7-15%, in different regions of the country. In the present study we examine the way the admixture process took place in Uruguay by analyzing the ancestry of maternal lineages in a sample from the northern city of Tacuarembó. To accomplish this goal we typed mitochondrial DNA (mtDNA) markers of Native American, African, and European origin and estimated the proportions of each parental group in the admixed population. We found that 62% of all mtDNA haplogroups were of Native American descent, a surprising figure considering the "European roots" of the country. Consequently, this result assimilates Uruguay to the rest of Latin American populations where sex-biased gene flow between European men and Native American women has been the rule. We further analyzed the distribution of the four major founding mitochondrial lineages in Tacuarembó and compared it to other South American populations. We discuss our findings in the light of historical records and assess the need for additional genetic studies.

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.

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.

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