Diet and Leukocyte Telomere Length in a Population with Extended Longevity: The Costa Rican Longevity and Healthy Aging Study (CRELES).

Elderly Costa Ricans have lower mortality rates compared to their counterparts from developed countries. Reasons for this survival advantage are not completely known. In the present study, we aimed to identify dietary factors associated with leukocyte telomere length (LTL), a marker of biologic aging, in the elderly population of Costa Rica. We conducted prospective analysis in 909 participants aged 60+ years from the Costa Rican Longevity and Healthy Aging Study (CRELES). We used a food frequency questionnaire to assess usual diet. We calculated dietary patterns using Principal Component Analysis (PCA). We used generalized linear models to examine the association of dietary patterns and food groups with leukocyte telomere length. We found two major dietary patterns explaining 9.15% and 7.18% of the total variation of food intake, respectively. The first dietary pattern, which represents a traditional Costa Rican rice and beans pattern, was more frequent in rural parts of the country and was positively associated with baseline LTL: ß (95% CI) = 42.0 base-pairs (bp) (9.9 bp, 74.1 bp) per one-unit increase of the traditional dietary pattern. In analysis of individual food groups, intake of grains was positively associated with baseline LTL: ß (95% CI) = 43.6 bp (13.9 bp, 73.3 bp) per one-serving/day increase of consumption of grains. Our results suggest that dietary factors, in particular a traditional food pattern, are associated with telomere length and may contribute to the extended longevity of elderly Costa Ricans.

Correlates of longitudinal leukocyte telomere length in the Costa Rican Longevity Study of Healthy Aging (CRELES): On the importance of DNA collection and storage procedures.

The objective is to identify cofactors of leukocyte telomere length (LTL) in a Latin American population, specifically the association of LTL with 36 socio-demographic, early childhood, and health characteristics, as well as with DNA sample collection and storage procedures. The analysis is based on longitudinal information from a subsample of 1,261 individuals aged 60+ years at baseline from the Costa Rican Study of Longevity and Healthy Aging (CRELES): a nationally representative sample of elderly population. Random effects regression models for panel data were used to estimate the associations with LTL and its longitudinal changes. Sample collection procedures and DNA refrigerator storage time were strongly associated with LTL: telomeres are longer in blood collected in October-December, in DNA extracted from <1-year-old blood cells, and in DNA stored at 4°C for longer periods of time up to five years. The data confirmed that telomeres are shorter at older ages, as well as among males, and diabetic individuals, whereas telomeres are longer in the high-longevity Nicoya region. Most health, biomarkers, and early childhood indicators did not show significant associations with LTL. Longitudinal LTL variation over approximately two years was mainly associated with baseline LTL levels, as found in other studies. Our findings suggest that if there is unavoidable variability in season of sample collection and DNA storage time, these factors should be controlled for in all demographic and epidemiologic studies of LTL. However, due to unobserved components of measurement variation, statistical control may be inadequate as compared to standardization of data collection procedures.

Amerindian ancestry and extended longevity in Nicoya, Costa Rica.

OBJECTIVES: The aim of this study was to address the hypothesis that Amerindian ancestry is associated with extended longevity in the admixed population of Nicoya, Costa Rica. The Nicoya Peninsula of Costa Rica has been considered a "longevity island," particularly for males. METHODS: We estimated Amerindian ancestry using 464 ancestral informative markers in 20 old Nicoyans aged ≥99 years, and 20 younger Nicoyans (60-65 years). We used logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) of the association of Amerindian ancestry and longevity. RESULTS: Older Nicoyans had higher Amerindian ancestry compared to younger Nicoyans (43.3% vs 36.0%, P = .04). Each 10% increase of Amerindian ancestry was associated with more than twice the odds of being long-lived (OR = 2.32, 95% CI = 1.03-5.25). CONCLUSIONS AND IMPLICATIONS: To our knowledge, this is the first time that ancestry is implicated as a likely determinant of extended longevity. Amerindian-specific alleles may protect against early mortality. The identification of these protective alleles should be the focus of future studies.

Genetic variation of the Y chromosome in Chibcha-speaking Amerindians of Costa Rica and Panama.

Genetic variation of the Y chromosome in five Chibchan tribes (Bribri, Cabecar, Guaymi, Huetar, and Teribe) of Costa Rica and Panama was analyzed using six microsatellite loci (DYS19, DYS389A, DYS389B, DYS390, DYS391, and DYS393), the Y-chromosome-specific alphoid system (alphah), the Y-chromosome Alu polymorphism (YAP), and a specific pre-Columbian transition (C-->T) (M3 marker) in the DYS 199 locus that defines the Q-M3 haplogroup. Thirty-nine haplotypes were found, resulting in a haplotype diversity of 0.937. The Huetar were the most diverse tribe, probably because of their high levels of interethnic admixture. A candidate founder Y-chromosome haplotype was identified (15.1% of Chibchan chromosomes), with the following constitution: YAP-, DYS199*T, alphah-II, DYS19*13, DYS389A*17, DYS389B*10, DYS390*24, DYS391*10, and DYS393*13. This haplotype is the same as the one described previously as one of the most frequent founder paternal lineages in native American populations. Analysis of molecular variance indicated that the between-population variation was smaller than the within-population variation, and the comparison with mtDNA restriction data showed no evidence of differential structuring between maternally and paternally inherited genes in the Chibchan populations. The mismatch-distribution approach indicated estimated coalescence times of the Y chromosomes of the Q-M3 haplogroup of 3,113 and 13,243 years before present; for the mtDNA-restriction haplotypes the estimated coalescence time was between 7,452 and 9,834 years before present. These results are compatible with the suggested time for the origin of the Chibchan group based on archeological, linguistic, and genetic evidence.

The STR polymorphism (AAAAT)n within the intron 1 of the tumor protein 53 (TP53) locus in 17 populations of different ethnic groups of Africa, America, Asia and Europe

The STR (AAAAT)n within intron 1 of the TP53 locus was screened in 17 populations from 3 main ethnic groups: Europeans, Asiatics, and Africans, and from the hybrid population of Costa Rica (1968 samples). Three alleles, 126/7 (bp/copies of the repeat), 131/8 and 136/9 were the most prevalent in all populations. Other alleles rarely reached frequencies of 10% or higher. Observed heterozygosities ranged between 0.351 and 0.829. Patterns of diversity fit well with both the geographic origin of the samples and the history of the populations screened. A statistical test suggests that single-step mutational events have been the main mechanism producing new alleles at this locus. Fixation indexes (R(ST)) for this marker showed an effect of population subdivision on divergence only within the Asiatic group; they were insensitive at the level of major ethnic groups as well as within Africans and within Europeans.

Glaucoma in Costa Rica. Initial approaches: [minireview]

Glaucoma is the second most frequent cause of irreversible blindness worldwide. Genetic factors have been implicated in the development of the disease. So far six loci (GLC1A-GLC1F) and two genes (TIGR/MYOC and OPTN) are involved in the development of juvenile (JOAG) and adult onset or chronic primary open angle glaucoma (COAG), while two loci (GLC3A,GLC3B) and one gene (CYP1B1) are known for primary congenital glaucoma (PCG). Here we summarize the results of the first genetic studies of glaucoma in Costa Rica. Nine families: 1 with JOAG, 1 with PCG and 7 with COAG were screened for mutations at the known genes. A 10 bp duplication, 1546-1555dupTCATGCCACC, at the CYP1B1 gene, causes, in homozygous state, glaucoma in the consanguineous PCG family. This mutation has been found in different countries and generates an early stop codon that termitates protein synthesis 140 amino acids earlier than the normal allele. In exon 1 of the T1GR/MYOC the innocuous Arg76Lys variant was found in two of the COAG families. In the OPTN gene two variants in the coding region (Thr34Thr, Met 98Lys) and 7 intronic changes were found in other Costa Rican glaucoma patients. One of the COAG families was chosen for a genome scan with 379 microsatellite markers and linkage analysis. LOD scores [quot ]suggestive[quot ] of linkage were obtained for several chromosomal regions. Evidence indicates that hereditary glaucoma in Costa Rica is highly heterogeneous and that further studies in the country will probably disclose some up to now unknown genes responsible for the disease.

The dystrophinopathies in Costa Rica: [minireview]

A five-years long study aiming to describe the basic genetic epidemiology of the dystrophinopathies in Costa Rica recruited 31 patients with clinical symptoms of DMD/BMD at the National Children's Hospital (HNN). This center is the obligate reference hospital of the national health system for genetic diseases, however, the geographic origin of the patients, a low percentage of deletions and a high proportion of de novo mutations found among them indicate that a significant ascertainment bias impedes a substantial scientific approach to confront and alleviate the problems posed by these severe diseases in Costa Rica.

The dystrophinopathies in Costa Rica.

A five-years long study aiming to describe the basic genetic epidemiology of the dystrophinopathies in Costa Rica recruited 31 patients with clinical symptoms of DMD/BMD at the National Children's Hospital (HNN). This center is the obligate reference hospital of the national health system for genetic diseases, however, the geographic origin of the patients, a low percentage of deletions and a high proportion of de novo mutations found among them indicate that a significant ascertainment bias impedes a substantial scientific approach to confront and alleviate the problems posed by these severe diseases in Costa Rica.

Glaucoma in Costa Rica. Initial approaches.

Glaucoma is the second most frequent cause of irreversible blindness worldwide. Genetic factors have been implicated in the development of the disease. So far six loci (GLC1A-GLC1F) and two genes (TIGR/MYOC and OPTN) are involved in the development of juvenile (JOAG) and adult onset or chronic primary open angle glaucoma (COAG), while two loci (GLC3A,GLC3B) and one gene (CYP1B1) are known for primary congenital glaucoma (PCG). Here we summarize the results of the first genetic studies of glaucoma in Costa Rica. Nine families: 1 with JOAG, 1 with PCG and 7 with COAG were screened for mutations at the known genes. A 10 bp duplication, 1546-1555dupTCATGCCACC, at the CYP1B1 gene, causes, in homozygous state, glaucoma in the consanguineous PCG family. This mutation has been found in different countries and generates an early stop codon that termitates protein synthesis 140 amino acids earlier than the normal allele. In exon 1 of the T1GR/MYOC the innocuous Arg76Lys variant was found in two of the COAG families. In the OPTN gene two variants in the coding region (Thr34Thr, Met 98Lys) and 7 intronic changes were found in other Costa Rican glaucoma patients. One of the COAG families was chosen for a genome scan with 379 microsatellite markers and linkage analysis. LOD scores "suggestive" of linkage were obtained for several chromosomal regions. Evidence indicates that hereditary glaucoma in Costa Rica is highly heterogeneous and that further studies in the country will probably disclose some up to now unknown genes responsible for the disease.

The STR polymorphism (AAAAT)n within the intron 1 of the tumor protein 53 (TP53) locus in 17 populations of different ethnic groups of Africa, America, Asia and Europe.

The STR (AAAAT)n within intron 1 of the TP53 locus was screened in 17 populations from 3 main ethnic groups: Europeans, Asiatics, and Africans, and from the hybrid population of Costa Rica (1968 samples). Three alleles, 126/7 (bp/copies of the repeat), 131/8 and 136/9 were the most prevalent in all populations. Other alleles rarely reached frequencies of 10% or higher. Observed heterozygosities ranged between 0.351 and 0.829. Patterns of diversity fit well with both the geographic origin of the samples and the history of the populations screened. A statistical test suggests that single-step mutational events have been the main mechanism producing new alleles at this locus. Fixation indexes (R(ST)) for this marker showed an effect of population subdivision on divergence only within the Asiatic group; they were insensitive at the level of major ethnic groups as well as within Africans and within Europeans.

Primary congenital glaucoma: a novel single-nucleotide deletion and varying phenotypic expression for the 1,546-1,555dup mutation in the GLC3A (CYP1B1) gene in 2 families of different ethnic origin.

PURPOSE: To present new molecular genetic data on primary congenital glaucoma from 2 families, 1 isolated case and 3 familial cases due to mutations in the cytochrome P-450 1B1 (CYP1B1) gene. METHODS: All diagnoses were made by slit-lamp biomicroscopy, gonioscopy, cornea and optic disk measurements, ultrasound-biometry, and automated static threshold perimetry where possible. Mutation screening was performed by direct sequence analysis of DNA extracted from peripheral blood of the patients and their relatives. RESULTS: For the isolated case, a child of 4 years, a homozygous nucleotide deletion within a tetrad of cytosines (nt622-625, 622delC) was found leading to a predicted nonsense codon 93 truncating the protein by 450 amino acids. For the familial cases, the 3 affected members showed a homozygous mutation 1,546-1,555dupTCATGCCACC for which 9 healthy relatives proved to be heterozygous. The phenotypic expression of these 3 patients varied widely. CONCLUSION: Our results confirm the crucial role of CYP1B1 mutations for congenital glaucoma.

Novel mutations in the MYOC/GLC1A gene in a large group of glaucoma patients.

Mutations at the myocilin (MYOC) gene within the GLC1A locus have been revealed in 2-4% of patients suffering primary open angle glaucoma (POAG) worldwide. In our ongoing glaucoma study six hundred eighty two persons have been screened for MYOC mutations. The first group consisted of 453 patients from a long-term clinical study diagnosed either with juvenile OAG (JOAG), POAG, ocular hypertension (OHT) or normal tension glaucoma (NTG) plus 22 cases of secondary glaucoma. This group, and additional 83 healthy controls, is part of a long term study with repeated clinical examinations at the University of Erlangen-Nurnberg. An additional sample of 124 glaucoma patients or at risk persons referred from other sources were included in the mutation screening. Five novel mutations, namely Gly434Ser, Asn450Asp, Val251Ala, Ile345Met and Ser393Asn, could be identified as cause of preperimetric POAG, JOAG, normal tension POAG and POAG. Myocilin mutations were identified similar with previous reports with other ethnic populations at the rate of 11/341 (3.2%) probands.

Determinación indirecta, mediante marcadores de ADN, del estado de portadoras de distrofia muscular de Duchenne (DMD) en una familia costarricense / Indirect determination, by means of DNA markers, of the state of carriers of muscular dystrophy of Duchenne (DMD) in Costa Rican family

Objetivo: Estimar el riesgo de portadoras a mujeres emparentadas por línea materna con un paciente con DMD. Sitio de realización. Instituto de Genética Humana, Universidad Friedrich Alexander Erlange-Nuremberge INISA, Universidad de Costa Rica. Materiales y métodos. Se obtuvo ADN de 19 personas emparentadas por vía materna con un paciente afectado con DMD; para cada uno se analizaron, mediante PCR, 5 marcadores microsatelíticos ubicados en la región del gen de la distrofina. Se marcó un imprimador de cada par con un fluorocromo, se determinó el tamaño de los productos de amplificación por electroforesis capilar fluorescente y se contruyeron haplotipos para la región de interés. Resultados. Se determinó el haplotipo de riesgo en el paciente, el que también se encontró en dos primos suyos, adultos sanos y en tres de sus tías y tres primas. Los hermanos del paciente heredaron de su madre el cromosoma X portador del haplotipo normal. Conclusiones. Los resultados indican que el paciente heredó una mutación de novo, originada en la línea germinal ya sea de la madre o de la abuela materna y que ninguna de las otras mujeres de la famila está en riesgo incrementado de ser portadoras. No es posible determinar si la madre del niño es portadora de la mutación.

Estimación de dosis génetica mediante PCR-múltiplex y electroforesis capilar fluorescente en posibles portadoras de eledcciones en el gen de la distrofina. Costa Rica 1998-2001 / Estimation of genetic dose with PCR-multiplex and fluorescent capilar electroforesis in possible carriers of elections in the gene of the distrofina. Costa Rica 1998-2001

Objetivo. Estimar la dosis génica en el gen de la distrofina a mujeres a riesgo de ser portadoras de delecciones. Sitio de realización INISA y Escuela de Biología, Universidad de Costa Rica. Materiales y métodos. Se obtuvo ADN de 15 mujeres, emparentadas por línea materna con pacientes afectados con DMD o BMD causadas por deleciones en el gen de la distrofina, y que por lo tanto podría ser portadoras de esas mutaciones, para amplificar de 7 a 9 regiones del gen por medio de PCR-múltiplex. Para estimar la dosis génica, se marcó uno de los imprimadores (el F) de cada par con el fluorocromo 6-FAM; los productos de amplificación por electroforesis capilar fluorescente. Resultados. Todas las posibles portadoras mostraron dosis génicas como las de mujeres sin delecciones. Conclusiones. El resultado indica que todos los pacientes son producto de mutaciones de novo, lo que es inesperado, pues datos de otros países muestran que ese es el caso de a sólo 1/3 de los pacientes. Además, la evaluación ofrece mejores elementos de juicio para brindar consejo genético. Palabras clave: Distrofina, Duchenne, Beckerkiener, portadoras, deleciones, herencia ligada al cromosoma X, PCR, electroforesis capilar fluorescente, dosis génica.

Tamizaje de delecciones en pacientes con distrofia muscular de Duchenne (DMD) o Becker-Kiener (BMD) mediante PCR Multiplex en Costa Rica, 1998-2000 / Screening of delections in patients with muscular dystrophy of Duchenne (DMD) or Becker-Kiener (BMD) by means of PCR multiplex in Costa rica, 1998-2000

Objetivo: Iniciar los estudios genéticos moleculares sobre las distrofinopatías en Costa Rica. Materiales y Métodos: Treinta y un pacientes varones, diagnosticados con distrofia muscular, que podrían ser distronofinopáticos fueron reevaluados clínicamente. Veintitrés mostraron un fenotipo de DMD y dos de BMD. Seis no mostraron síntomas definitivos de distrofinopatías. ADN de los pacientes fue analizado mediante PCR-múltiplex en búsqueda de delecciones en el gen de la distrofina. También se realizó un diagnóstico prenatal a una portadora obligada. Resultados: Diez pacientes presentaron delecciones: en uno abarca 23 exones (del 23 al 25), en dos ocho exones (del 45 al 52 y del 12 al 19), en otro siete exones (del 60 al 66), en dos seis exones (del 45 al 50), en cuatro pacientes de la deleción comprende un único exón; el 52 en dos de ellos, el 19 y el 44. Los seis pacientes con diagnóstico dudoso no mostraron deleciones. Un hijo de la portadora obligada, afectado con DMD tiene una deleción de 37 exones (del 6 al 42), mientras que el feto no la tiene. Conclusión: El trasplante de síntomas entre las distintas distrofias musculares, la falta de pruebas diagnósticas de laboratorio y de especialistas en el dianóstico diferencial evidencian la necesidad de implementar métodos diagnósticos más discriminantes en Costa Rica. La identificación de pacientes con deleciones permite buscar estas mutaciones en las mujeres conposible riesgo de ser portadoras y que así reciban mejor consejo genético. Palabras clave: distrofia muscular, Duchenne Becker-Kiener, herencia ligada al cromosoma X, diagnóstico molecular, distrofina, distrofinopatía, deleción, PCR-múltiplex.

Genetic variation in the Bribri and Cabecar Amerindians from Talamanca, Costa Rica

Se analisaron más de 40 loci de las poblaciones amerindias bribri y cabécar de Talamanca, del sureste de Costa Rica. Se encontraron algunas diferencias en la distribuci>n (presencia o ausencia) de las bariantes, algunas de ellas privadas, de los loci de la GOT, la PEPA, el RH, la TF y la TPI, al compararse nuestros resultados con los descritos para las poblaciones bribris y cabécares de la región del Pacífico Sur del País. Se encontró mezcla con no indígenas por intermedio de los loci del ABO, de la ADA y de la G6PD. Los valores de la proporción de loci polimórficos (P) hallados fueron 17.1 en los bribris y 19.4 en los cabécares; las estimaciones de heterocigosis media (H) fueron 0,039 y 0,049 respectivamente. Los valores de Fst obtenidos (0.019 en los bribris y 0.056 en los cabécares entre sí. Tamaños efectivos pequeños de los grupos emigrantes al lado del Pacífico y flujo génico, en el caso de los bribris, pueden ser las causas de estas diferencias

Grupos sanguíneos ABO y Rh y proteínas séricas en una población amerindia, Matambú, Costa Rica / ABO and Rh blood groups and serum proteins in an Amerindian population, Matambú, Costa Rica

Se llevó a cabo un estudio de la estructura genética de la población de Matambú, Costa Rica, utilizando marcadores genéticos de 6 loci que incluyen los grupos sanguíneos ABO y Rh y la albúmina, ceruloplasmina, haptoglobina y transferrina del suero. Todos los individuos fueron Rh+ y el alelo I§ tuvo una frecuencia alta (0,89). Existen 4 alelos polimórficos de la ceruloplasmina incluyendo una posible variante nueva (3,8%). La transferrina Dchi tiene una frecuencia notablemente alta (0,11). Estos resultados indican que este grupo tiene un indudable ancestro amerindio aunque están presentes en la población genes de origen caucasoide y negroide. La constitución genética de esta población difiere de la de otros grupos amerindios de Costa Rica como el Guaymí, de lengua Chibcha, lo que apoya la hipótesis de un origen mesoamericano de este grupo