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The birth prevalence rate (BPR) of congenital anomalies (CAs) is heterogeneous and exhibits geographical and sociocultural variations throughout the world. In South America (SA), high birth prevalence regions of congenital anomalies have been observed. The aim of this study was to identify, describe, and characterize geographical clusters of congenital anomalies in SA.This observational descriptive study is based on clinical epidemiological data registered by the Latin-American Collaborative Study of Congenital Malformations network. Between 1995 and 2012, a total of 25,082 malformed newborns were ascertained from 2,557,424 births at 129 hospitals in SA. The spatial scan statistic was used to determine geographical regions with high BPR of CAs. The BPR was obtained with a Poisson regression model. Odds ratios were estimated for several risk factors inside the geographical clusters.We confirmed the existence of high BPR regions of CAs in SA. Indicators of low socioeconomic conditions, such as a low maternal education, extreme age childbearing, infectious diseases, and medicine use during pregnancy were detected as risk factors inside these regions. Native and African ancestries with high frequency of consanguineous marriages could explain partially these high BPR clusters.The recognition of clusters could be a starting point in the identification of susceptibility genes associated with the occurrence of CA in high BPR regions.

The etiology of cleft lip with or without cleft palate (CL±P) is complex and heterogeneous, and multiple genetic and environmental factors are involved. Some candidate genes reported to be associated with oral clefts are located on the X chromosome. At least three genes causing X‐linked syndromes [midline 1 (MID1), oral‐facial‐digital syndrome 1 (OFD1), and dystrophin (DMD)] were previously found to be associated with isolated CL±P. We attempted to confirm the role of X‐linked genes in the etiology of isolated CL±P in a South American population through a family‐based genome‐wide scan. We studied 27 affected children and their mothers, from 26 families, in a Patagonian population with a high prevalence of CL±P. We conducted an exploratory analysis of the X chromosome to identify candidate regions associated with CL±P. Four genomic segments were identified, two of which showed a statistically significant association with CL±P. One is an 11‐kb region of Xp21.1 containing the DMD gene, and the other is an intergenic region (8.7 kb; Xp11.4). Our results are consistent with recent data on the involvement of the DMD gene in the etiology of CL±P. The MID1 and OFD1 genes were not included in the four potential CL±P‐associated X‐chromosome genomic segments. Fil: Fonseca, Renata F.. Universidade Federal do Rio de Janeiro; Brasil. National Institute of Population Medical Genetics; Brasil Fil: de Carvalho, Flávia M.. Universidade Federal do Rio de Janeiro; Brasil. National Institute of Population Medical Genetics; Brasil. Instituto Oswaldo Cruz; Brasil Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina. National Institute of Population Medical Genetics; Brasil. Instituto Oswaldo Cruz; Brasil Fil: Montaner, David. Centro de Investigación Biomédica en Red de Enfermedades Raras; España. Centro de Investigaciones Príncipe Felipe; España Fil: Dopazo, Joaquin. Centro de Investigación Biomédica en Red de Enfermedades Raras; España. Centro de Investigaciones Príncipe Felipe; España Fil: Mereb, Juan C.. Provincia de Río Negro. Ministerio de Salud. Hospital De Área El Bolsón; Argentina Fil: Moreira, Miguel A. M.. National Cancer Institute; Brasil Fil: Seuanez, Hector N.. National Cancer Institute; Brasil. Universidade Federal do Rio de Janeiro; Brasil Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos Fil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina. National Institute of Population Medical Genetics; Brasil. Instituto Oswaldo Cruz; Brasil Fil: Orioli, Iêda M.. Universidade Federal do Rio de Janeiro; Brasil. National Institute of Population Medical Genetics; Brasil

Although young maternal age has been identified as a risk factor for gastroschisis, its role remains undisclosed. To our knowledge, the differences between young mothers of infants with gastroschisis and young mothers of infants with other pregnancy outcomes have not been established. The aim of this work was to compare characteristics of young mothers whose newborn had gastroschisis with same aged mothers of malformed and nonmalformed control infants, diagnosed within the ECLAMC maternity hospital network.Data base records of live and stillborn infants of one of three groups (with isolated gastroschisis, with 1 of 5 other isolated birth defects, and nonmalformed), and whose mothers were younger than 20 years, were selected. Secular trends were obtained for all birth defects; frequencies and odds ratios (OR) of demographic and reproductive variables were compared among the 3 groups. Significantly associated variables were adjusted with a multivariate regression.The association was higher with gastroschisis 1) than with other birth defects for African ancestry, smoking, adequate prenatal control and diagnosis 2) than with nonmalformed controls for maternal illnesses and alcohol 3) and than both for previous pregnancy loss and medication, mainly sex hormones. After adjustment, only previous pregnancy loss maintained its significance when compared with malformed (OR = 2.34; 1.37-3.97; P = 0.002), as well as with nonmalformed (OR = 3.43; 2.07-5.66; P 0.001) controls.A previous pregnancy loss was identified as the main risk factor for gastroschisis, while an increased use of sex hormones, perhaps related to the previous loss, could trigger a disruptive mechanism, due to their thrombophilic effect.

Several studies on neurobiology have contributed to our understanding of the genesis, survival and death of neurons, unquestionably the stars of the Central Nervous System (CNS). However, they would not be so famous without their close associates: the glial cells. Since novel studies have demonstrated new and important functions for glial cells, they are beginning to gain significant importance in brain research to allow us to reinterpret long known functions on the basis of new concepts. Here, we review recent progress in our understanding of the role of glial cells in the biology of tissue development and maturation.

BACKGROUND: There is disagreement about the association between cleft lip with or without cleft palate and multigravidity, which could be explained by differences of adjusting for maternal age, Amerindian ancestry, and socioeconomic status. OBJECTIVE: The aim was to evaluate gravidity 4+ (four or more gestations) as a risk factor for cleft lip with or without cleft palate in South America. DESIGN: We used a matched (1:1) case-control study with structural equation modeling for related causes. Data were obtained from 1,371,575 consecutive newborn infants weighing ≥500 g who were born in the hospitals of the Estudio Colaborativo Latinoamericano de Malformaciones Congénitas (ECLAMC) network between 1982 and 1999. There were a total of 1,271 cases with cleft lip with or without cleft palate (excluding midline and atypical cleft lip with or without cleft palate). A total of 1,227 case-control pairs were obtained, matched by maternal age, newborn gender, and year and place of birth. Potential confounders and intermediary variables were analyzed with structural equation modeling. RESULTS: The crude risk of gravidity 4+ was 1.41 and the 95% confidence interval was 1.14 to 1.61. When applying structural equation modeling, the effect of multigravidity on the risk of cleft lip with or without cleft palate was 1.22 and the 95% confidence interval was 0.91 to 1.39. CoONCLUSIONS: Multigravid mothers (more than four gestations) showed no greater risk of bearing children who had cleft lip with or without cleft palate than mothers with two or three births. Therefore, the often observed and reported association between multigravidity and oral clefts likely reflects the effect of other risk factors related to low socioeconomic status in South American populations. Fil: Gili, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Campaña, Hebe. No especifica; Fil: Comas, Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Pawluk, Mariela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Rittler, Mónica. Gobierno de la Ciudad de Buenos Aires. Hospital Materno Infantil "Ramòn Sardá"; Argentina Fil: López Camelo, Jorge Santiago. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina

BACKGROUND: Congenital forms of hearing impairment can be caused by mutations in the estrogen related receptor beta (ESRRB) gene. Our initial linkage studies suggested the ESRRB locus is linked to high caries experience in humans. METHODS: We tested for association between the ESRRB locus and dental caries in 1,731 subjects, if ESRRB was expressed in whole saliva, if ESRRB was associated with the microhardness of the dental enamel, and if ESRRB was expressed during enamel development of mice. RESULTS: Two families with recessive ESRRB mutations and DFNB35 hearing impairment showed more extensive dental destruction by caries. Expression levels of ESRRB in whole saliva samples showed differences depending on sex and dental caries experience. CONCLUSIONS: The common etiology of dental caries and hearing impairment provides a venue to assist in the identification of individuals at risk to either condition and provides options for the development of new caries prevention strategies, if the associated ESRRB genetic variants are correlated with efficacy. Fil: Weber, Megan L.. University of Pittsburgh; Estados Unidos Fil: Hsin, Hong Yuan. University of Pittsburgh; Estados Unidos Fil: Kalay, Ersan. Karadeniz Technical University; Turquía Fil: Brožková, Dana Š. Charles University; República Checa. University Hospital Motol; República Checa Fil: Shimizu, Takehiko. Nihon University. School of Dentistry; Japón Fil: Bayram, Merve. Medipol Istanbul University; Turquía Fil: Deeley, Kathleen. University of Pittsburgh; Estados Unidos Fil: Küchler, Erika C.. University of Pittsburgh; Estados Unidos Fil: Forella, Jessalyn. University of Pittsburgh; Estados Unidos Fil: Ruff, Timothy D.. University of Pittsburgh; Estados Unidos Fil: Trombetta, Vanessa M.. University of Pittsburgh; Estados Unidos Fil: Sencak, Regina C.. University of Pittsburgh; Estados Unidos Fil: Hummel, Michael. University of Pittsburgh; Estados Unidos Fil: Briseño Ruiz, Jessica. University of Pittsburgh; Estados Unidos Fil: Revu, Shankar K.. University of Pittsburgh; Estados Unidos Fil: Granjeiro, José M.. Universidade Federal Fluminense; Brasil Fil: Antunes, Leonardo S.. Universidade Federal Fluminense; Brasil Fil: Antunes, Livia A.. Universidade Federal Fluminense; Brasil Fil: Abreu, Fernanda V.. Universidade Federal Fluminense; Brasil Fil: Costabel, Marcelo C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Tannure, Patricia N.. Veiga de Almeida University; Brasil. Salgado de Oliveira University; Brasil Fil: Koruyucu, Mine. Istanbul University; Turquía Fil: Patir, Asli. Medipol Istanbul University; Turquía Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Mereb, Juan C.. Estudio Colaborativo Latino Americano de Malformaciones Congénitas; Argentina Fil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Orioli, Iêda M.. Universidade Federal do Rio de Janeiro; Brasil Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos Fil: Ouyang, Hongjiao. University of Pittsburgh; Estados Unidos Fil: Jayaraman, Thottala. University of Pittsburgh; Estados Unidos Fil: Seymen, Figen. Istanbul University; Turquía Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos

Seasonal variation studies on chromosomal abnormalities, especially Down syndrome, have been previously reported (Kallen and Masback, 1988). Different hypotheses have been made including hormonal imbalance and exposure to ionizing radiation. A very comprehensive review article on seasonal variation at birth concluded that there is no real evidence of seasonality in the birth prevalence of Down syndrome (Stolwijk et al., 1997). One of the various criticisms of the reviewed studies was that they did not take into account those fetuses with chromosomal anomalies that would be lost before term. It was, therefore, suggested that data obtained from prenatal diagnosis closer to the month of conception should be studied.

Introducción. Diferentes trabajos han relacionando condiciones sociales adversas a nivel familiar y regional con resultados perinatales (mortalidad neonatal, bajo peso y prematuridad); sin embargo, pocos estudiaron el efecto de la pobreza sobre anomalías congénitas. Objetivo. Evaluar el riesgo de ocurrencia de 25 anomalías congénitas y determinantes sociales adversos según el nivel socioeconómico de la familia y de la región. Población y métodos. Estudio caso-control exploratorio, en el que se utilizaron datos del Estudio Colaborativo Latinoamericano de Malformaciones Congénitas (ECLAMC). La muestra consistió en 3786 recién nacidos vivos con una única malformación y 13 344 controles, seleccionados entre 546 129 nacimientos, ocurridos en 39 hospitales de Argentina durante el período 1992-2001. Se estimaron los riesgos (OR) directos, indirectos (a través de la región de residencia) y la interacción entre el nivel socioeconómico individual y residencial para cada uno de los 25 defectos congénitos. Resultados. Los defectos labio leporino con/sin paladar hendido (OR= 1,43) y comunicación interventricular (OR= 1,38) mostraron un riesgo significativamente mayor en el nivel socioeconómico más bajo. Los niveles socioeconómicos bajos se asociaron de manera significativa con una mayor frecuencia de consanguinidad parental, ancestros nativos, edad materna menor de 19 años, más de 4 embarazos, bajo número de visitas prenatales y residencia en regiones desfavorables. Conclusión. La fisura labial con o sin paladar hendido y los defectos del tabique interventricular estuvieron asociados significativamente con un nivel socioeconómico más bajo. La falta de planificación familiar, de control prenatal y la exposición a agentes ambientales o teratógenos pueden explicar estos hallazgos. Introduction.Different studies have related familiar and regional adverse social conditions to perinatal outcome (neonatal mortality, low birth weight and prematurity); however, few studies have studied the effect of poverty on congenital anomalies. Objective.To assess the hazard ratio of 25 congenital anomalies and adverse social determinants as per the socioeconomic level of families and regions. Population and methods.Exploratory, casecontrol study using data from the Latin-American Collaborative Study of Congenital Malformations (Estudio Colaborativo Latinoamericano de Malformaciones Congénitas, ECLAMC). The sample consisted of 3786live newborn infants with a single malformation and 13 344 controls selected among 546 129 births occurred in 39hospitals from Argentina in the 1992- 2001 period. Both direct and indirect (residence) risks (OR) were estimated, together with the interaction between the individual and residential socioeconomic levels for each of the 25 congenital anomalies. Results.Cleft lip with/without cleft palate (OR= 1.43) and ventricular septal defect (OR= 1.38) showed a significantly higher risk in the lower socioeconomic level. Low socioeconomic levels were significantly associated with a higher frequency of parental sibship (blood relationship), native descent, maternal age younger than 19 years old, more than four pregnancies, a low number of antenatal care visits, and residence in deprived regions. Conclusion. Cleft lip with/without cleft palate and ventricular septal defects were significantly associated with a lower socioeconomic level. Lack of family planning and antenatal care, and exposure to environmental or teratogenic agents may account for these findings.

BACKGROUND: For the past 46 years, the Latin American Collaborative Study of Congenital Malformations (ECLAMC) has successfully dealt with a low-priority health problem in the region, using installed capacity and low technological complexity, aimed at research rather than health information and action. Originally planned for a city, but rapidly expanded to whole South America and beyond, involving more than 200 hospitals from 12 Latin American countries: Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, Paraguay, Peru, Uruguay, and Venezuela. In the present study, the ECLAMC structure is shown as a social network with the aim to facilitate its transfer. METHODS: Data from 261 hospitals from 12 countries that have participated in the ECLAMC program during 1967-2012 were included in this work. Three types of data were evaluated for network analysis: data collection, participation in special research projects, and co-authorships. Indicators as total size (number of nodes), path count, density, degree centrality, closeness centrality, and betweenness centrality were estimated to compare the structural characteristics and attributes of the networks. RESULTS: The ECLAMC networks can be defined, from the social network analysis point of view, as a centralized, unimodal, afferent network for data collection; as a decentralized, bimodal, interactive network for special projects; and co-authorship of published papers. Conclusions: The key elements in the ECLAMC program are: collaboration between motivated expert people, voluntarily accepting the same research protocol, with a sense of belonging to the working-team, based on mutual trustfulness within a transparent framework, with explicit rules, aimed at producing data of internationally competitive quality. This example is proposed for future health programs, mainly in low- and middle-income areas. Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas ; Argentina. Instituto Nacional de Genética Médica Populacional; Brasil Fil: Gili, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas ; Argentina Fil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas ; Argentina. Instituto Nacional de Genética Médica Populacional; Brasil

Background: Our previous genome-wide linkage scan mapped five loci for caries experience. The purpose of this study was to fine map one of these loci, the locus 13q31.1, in order to identify genetic contributors to caries. Methods: Seventy-two pedigrees from the Philippines were studied. Caries experience was recorded and DNA was extracted from blood samples obtained from all subjects. Sixty-one single nucleotide polymorphisms (SNPs) in 13q31.1 were genotyped. Association between caries experience and alleles was tested. We also studied 1,481 DNA samples obtained from saliva of subjects from the USA, 918 children from Brazil, and 275 children from Turkey, in order to follow up the results found in the Filipino families. We used the AliBaba2.1 software to determine if the nucleotide changes of the associated SNPs changed the prediction of the presence of transcription-binding site sequences and we also analyzed the gene expression of the genes selected based on binding predictions. Mutation analysis was also performed in 33 Filipino individuals of a segment of 13q31.1 that is highly conserved in mammals. Results: Statistically significant association with high caries experience was found for 11 markers in 13q31.1 in the Filipino families. Haplotype analysis also confirmed these results. In the populations used for follow-up purposes, associations were found between high caries experience and a subset of these markers. Regarding the prediction of the transcription-binding site, the base change of the SNP rs17074565 was found to change the predicted-binding of genes that could be involved in the pathogenesis of caries. When the sequence has the allele C of rs17074565, the potential transcription factors binding the sequence are GR and GATA1. When the subject carries the G allele of rs17074565, the potential transcription factor predicted to bind to the sequence is GATA3. The expression of GR in whole saliva was higher in individuals with low caries experience when compared to individuals with high caries experience (p = 0.046). No mutations were found in the highly conserved sequence. Conclusions: Genetic factors contributing to caries experience may exist in 13q31.1. The rs17074565 is located in an intergenic region and is predicted to disrupt the binding sites of two different transcription factors that might be involved with caries experience. GR expression in saliva may be a biomarker for caries risk and should be further explored. Fil: Küchler, Erika C.. University of Pittsburgh; Estados Unidos Fil: Deeley, Kathleen. University of Pittsburgh; Estados Unidos Fil: Ho, Bao. University of Pittsburgh; Estados Unidos Fil: Linkowski, Samantha. University of Pittsburgh; Estados Unidos Fil: Meyer, Chelsea. University of Pittsburgh; Estados Unidos Fil: Noel, Jacqueline. University of Pittsburgh; Estados Unidos Fil: Kouzbari, M. Zahir. University of Pittsburgh; Estados Unidos Fil: Bezamat, Mariana. University of Pittsburgh; Estados Unidos Fil: Granjeiro, José M.. Universidade Federal Fluminense; Brasil Fil: Antunes, Leonardo S.. Universidade Federal Fluminense; Brasil Fil: Antunes, Livia Azeredo. Universidade Federal Fluminense; Brasil Fil: Abreu, Fernanda Volpe de. Universidade Federal Fluminense; Brasil Fil: Costa, Marcelo C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Tannure, Patricia N.. Veiga de Almeida; Brasil. Salgado de Oliveira University; Brasil Fil: Seymen, Figen. Istanbul University; Turquía Fil: Koruyucu, Mine. Istanbul University; Turquía Fil: Patir, Asli. Istanbul University; Turquía Fil: Mereb, Juan C.. Estudio Colaborativo Latinoamericano de Malformaciones Congénitas; Argentina. Hospital de Área El Boóon; Argentina Fil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina. Oswaldo Cruz Foundation; Brasil Fil: Castilla, Eduardo Enrique. Oswaldo Cruz Foundation; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; Argentina Fil: Orioli, Ieda M.. Universidade Federal do Rio de Janeiro; Brasil Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos

Background Minor anomalies (mAs) are morphological features with little clinical relevance that have been mentioned as possible predictors of major defects (MDs). Objectives To identify the preferential associations between selected MDs and mAs and to establish if mAs can serve as predictors for specific MDs. Study Design Information of newborns with birth defects was obtained from the ECLAMC (Latin American Collaborative Study of Congenital Malformations) database. The sample consisted of 27,247 live- and stillborn newborns with multiple malformations that included at least one of the selected MDs or mAs. The odds ratio and predictive values were calculated for significant associations, and concurrence rates in first degree relatives. Results A total of 33 significant minor–major associations were identified. Single umbilical artery (SUA) and preauricular tags were the most frequent mAs; the former was associated with 10 MDs, the latter only with microtia. The highest positive predictive value was shown by SUA for anal atresia. Newborns with preauricular tags had significantly more relatives with microtia than expected. Conclusions No new relevant associations between MDs and mAs were identified and few mAs seem to serve as predictors for specific MDs in the same newborn. However, preauricular tags can predict the occurrence of microtia in other family members. Fil: Campaña, Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Rittler, Monica. Universidad de Buenos Aires; Argentina Fil: Poletta, Fernando Adrián. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; Argentina Fil: Gili, Juan Antonio. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; Argentina Fil: Pawluk, Mariela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Scala, Sandra Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Camelo, Jorge Santiago López. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; Argentina

Caries is the most common chronic, multifactorial disease in the world today; and little is still known about the genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified five loci related to caries susceptibility: 5q13.3, 13q31.1, 14q11.2, 14q 24.3, and Xq27. In the present study, we fine mapped the 14q11.2 locus to identify genetic contributors to caries susceptibility. Four hundred seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. An additional 387 DNA samples from unrelated individuals were used to determine allele frequencies. For replication purposes, a total of 1,446 independent subjects from four different populations were analyzed based on their caries experience (low versus high). Forty-eight markers in 14q11.2 were genotyped using TaqMan chemistry. Transmission disequilibrium test was used to detect over transmission of alleles in the Filipino families, and Chi-square, Fisher’s exact and logistic regression were used to test for association between low caries experience and variant alleles in the replication data sets. We finally assessed the mRNA expression of TRAV4 in the saliva of 143 study subjects. In the Filipino families, statistically significant associations were found between low caries experience and markers in TRAV4. We were able to replicate these results in the populations studied that were characteristically from underserved areas. Direct sequencing of 22 subjects carrying the associated alleles detects one missense mutation (Y30R) that is predicted to be probably damaging. Finally, we observed higher expression in children and teenagers with low caries experience, correlating with specific alleles in TRAV4. Our results suggest that TRAV4 may have a role in protecting against caries. Fil: Briseño Ruiz, Jessica. University of Pittsburgh; Estados Unidos Fil: Shimizu, Takehiko. Nihon University of Dentistry at Matsudo; Japón Fil: Deeley, Kathleen. University of Pittsburgh; Estados Unidos Fil: Dizak, Piper M.. University of Pittsburgh; Estados Unidos Fil: Ruff, Timothy D. University of Pittsburgh; Estados Unidos Fil: Faraco Jr., Italo M.. University of Pittsburgh; Estados Unidos Fil: Poletta, Fernando Adrián. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina. Estudio Colaborativo Latino Americano de Malformaciones Congénitas. Buenos Aires; Argentina. Instituto de investigación en Porto Alegre; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Brancher, Joao A.. Universidade Federal do Paraná; Brasil Fil: Pecharki, Giovana D.. Universidade Federal do Paraná; Brasil Fil: Kuchler, Erika C. University of Pittsburgh; Estados Unidos Fil: Tannure, Patricia N.. Universidade Federal do Rio de Janeiro; Brasil Fil: Lips, Andrea. Universidade Federal Fluminense; Brasil Fil: Vieira, Thays C. S.. Universidade Federal Fluminense; Brasil Fil: Patir, Asli. Istanbul Medipol University; Turquía Fil: Koruyucu, Mine. Istanbul University; Turquía Fil: Mereb, J. C.. Estudio Colaborativo Latino Americano de Malformaciones Congénita; Argentina Fil: Resick, Judith M.. University of Pittsburgh; Estados Unidos Fil: Brandon, Carla A.. University of Pittsburgh; Estados Unidos Fil: Letra, Ariadme. University of Texas Health Science Center at Houston; Estados Unidos Fil: Silva, Renato M.. University of Texas Health Science Center at Houston; Estados Unidos Fil: Cooper, Margaret E.. University of Pittsburgh; Estados Unidos Fil: Seymen, Figen. Istanbul University; Turquía Fil: Costa, Marcelo C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Granjeiro, Jose M. Universidade Federal Fluminense; Brasil Fil: Trevilatto, Paula C.. Universidade Federal do Paraná; Brasil Fil: Orioli, Eeda M.. Instituto Nacional de Metrologia, Qualidade e Tecnologia; Brasil Fil: Castilla, Eduardo Enrique. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina. Estudio Colaborativo Latino Americano de Malformaciones Congénitas. Buenos Aires; Argentina. Instituto de investigación en Porto Alegre; Brasil Fil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos Fil: Vieira, Alexandre R.. University of Pittsburgh; Estados Unidos

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs. Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10(-8)), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10(-8)). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10(-8)) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.

We have previously shown the association of AXIN2 with oral clefts in a US population. Here, we expanded our study to explore the association of 11 AXIN2 markers in 682 cleft families from multiple populations. Alleles for each AXIN2 marker were tested for transmission distortion with clefts by means of the Family-based Association Test. We observed an association with SNP rs7224837 and all clefts in the combined populations (p = 0.001), and with SNP rs3923086 and cleft lip and palate in Asian populations (p = 0.004). We confirmed our association findings in an additional 528 cleft families from the United States (p < 0.009). We tested for gene-gene interaction between AXIN2 and additional cleft susceptibility loci. We assessed and detected Axin2 mRNA and protein expression during murine palatogenesis. In addition, we also observed co-localization of Axin2 with Irf6 proteins, particularly in the epithelium. Our results continue to support a role for AXIN2 in the etiology of human clefting. Additional studies should be performed to improve our understanding of the biological mechanisms linking AXIN2 to oral clefts.

Background: Different approaches have been used in case-control studies to estimate maternal exposure to medications and the risk of birth defects. However, the performance of these approaches and how they affect the odds ratio (OR) estimates have not been evaluated using birth-defect surveillance programmes. The aim of this study was to evaluate the scope and limitations of three case-control approaches to assess the teratogenic risk of birth defects in mothers exposed to antiepileptic medications, insulin, or acetaminophen. Methodology/Principal Findings: We studied 110,814 non-malformed newborns and 58,514 live newborns with birth defects registered by the Latin American Collaborative Study of Congenital Anomalies (ECLAMC) between 1967 and 2008. Four controls were randomly selected for each case in the same hospital and period, and three different control groups were used: non-malformed newborns (HEALTHY), malformed newborns (SICK), and a subgroup of SICK, only-exposed cases (OECA). Associations were evaluated using OR and Pearson's chi-square (P, Instituto Multidisciplinario de Biología Celular

The identification of individuals at a higher risk of developing caries is of great interest. Isolated forms of cleft lip and palate are among the most common craniofacial congenital anomalies in humans. Historically, several reports suggest that individuals born with clefts have a higher risk for caries. Caries continues to be the most common infectious noncontagious disease worldwide and a great burden to any health system. The identification of individuals of higher susceptibility to caries is of great interest. In this paper, we assessed caries experience of 1,593 individuals from three distinct populations. The study included individuals born with clefts, their unaffected relatives, and unrelated unaffected controls that were recruited from areas with similar cultural pressures and limited access to dental care. DMFT/dmft scores were obtained, and caries experience rates were compared among the three groups in each geographic area. Individuals born with clefts did not present higher caries experience in comparison to their unaffected relatives or unrelated unaffected controls. Women tend to present higher caries rates in comparison to men. Our work provides strong evidence that individuals born with clefts are not at higher risk to caries; however, women tend to have more severe caries experience., Instituto Multidisciplinario de Biología Celular

OBJETIVOS: Determinar la frecuencia de tabaquismo y exposicion ambiental al humo de tabaco en mujeres embarazadas de Ecuador y describir los perfiles sociodemograficos asociados con esos factores de riesgo perinatal. METODOS: Estudio descriptivo transversal mediante una encuesta aplicada a mujeres de 18 a 46 anos con mas de 3 meses de embarazo que asistieron entre octubre de 2004 y septiembre de 2005 a sus consultas de seguimiento en siete servicios de maternidad de seis ciudades de Ecuador. Se analizaron los datos demograficos y de exposicion medioambiental (variables independientes) y su relacion con el habito de fumar cigarrillos y la exposicion ambiental al humo de tabaco. RESULTADOS: De las 746 mujeres analizadas, 53,3% habia fumado ocasionalmente y 4,3% habia fumado habitualmente; de estas, 75,0% habia dejado de fumar antes o durante el embarazo. De las encuestadas, 12,9% estuvo expuesta con frecuencia o siempre al humo de tabaco en ambientes cerrados. Tener mayor educacion (11 anos o mas) y un nivel socioeconomico medio o alto, ser caucasica y considerar aceptable que las mujeres de su comunidad fumen se asocio significativa y directamente con el habito de fumar cigarrillos (P < 0,001). En general, 12,9% de las mujeres estuvo expuesta al humo de tabaco y esto se asocio significativamente con ser soltera y cohabitar con fumadores o trabajadores vinculados con la industria del tabaco (P < 0,001). CONCLUSIONES: Se deben disenar e implementar medidas especificas dirigidas no solo a estimular el abandono de este habito en las embarazadas, sino tambien a prevenir que las mujeres en edad reproductiva comiencen a fumar y controlar el entorno fumador en el hogar.

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect due to both genetic and environmental factors. Whorl lip print patterns are circular grooves on the central upper lip and/or the left and right lower lip. To determine if whorls are more common in families with CL/P than in controls, the Pittsburgh Orofacial Cleft Study collected lip prints from over 450 subjects, that is, individuals with CL/P, their relatives, and unrelated controls-from the U.S., Argentina, and Hungary. Using a narrow definition of lower-lip whorl, the frequency of whorls in the U.S. sample was significantly elevated in cleft individuals and their family members, compared to unrelated controls (14.8% and 13.2% vs. 2.3%; P = 0.003 and 0.001, respectively). Whorls were more frequent in CL/P families from Argentina than in CL/P families from the U.S. or Hungary. If these results are confirmed, whorl lip print patterns could be part of an expanded phenotypic spectrum of nonsyndromic CL/P. As such, they may eventually be useful in a clinical setting, allowing recurrence risk calculations to incorporate individual phenotypic information in addition to family history data.

To determine the frequency of smoking and second-hand smoke exposure among pregnant women in Ecuador and to describe the sociodemographic profiles associated with these perinatal risk factors.A cross-sectional descriptive study using a survey of women 18-46 years of age who were more than three months pregnant and attended follow-up consultations in seven maternity clinics in six cities in Ecuador between October 2004 and September 2005. Demographics and environmental exposure (independent variables) data and their relationship to cigarette smoking and secondhand-smoke exposure were analyzed.Of the 746 women studied, 53.3% had smoked occasionally, and 4.3%, regularly; of these, 75% had quit smoking before or during pregnancy. Of the respondents, 12.9% were frequently or always exposed to secondhand smoke indoors. Having more education (11 or more years), being in the middle or upper socioeconomic classes, being Caucasian, and it being considered acceptable for women in the community to smoke were significantly and directly associated with cigarette smoking (P0.001). Overall, 12.9% of women were being exposed to secondhand smoke and this was significantly associated with being single and cohabiting with smokers or employees connected to the tobacco industry (P0.001).Specific measures must be designed and implemented to not only encourage smoking cessation during pregnancy, but also to prevent women of reproductive age from taking up smoking and to limit smoking in the home environment.

The aim of this work was to search for unequal birth prevalence rates (BPRs) of cleft lip +/- cleft palate (CL/P), and cleft palate only (CPO), among different geographic areas in South America, and to analyze phenotypic characteristics and associated risk factors in each identified cluster. Included were 5,128 CL/P cases, 1,745 CPO cases, and 3,712 controls (like-sexed, non-malformed liveborn infant, born immediately after a malformed one, in the same hospital), over 4,199,630 consecutive births. They were ascertained between 1967 and 2004, in 190 maternity hospitals of the ECLAMC (Estudio Colaborativo Latinoamericano de Malformaciones Congenitas) network, in 102 cities of all 10 South American countries. Non-predefined geographical areas with significantly unusual cleft BPRs were identified with Kulldorf and Nagarwalla's spatial scan statistic, employing number of cases and births, and exact location of each hospital. Expected values were cleft BPRs registered for the entire ECLAMC hospital network. Syndromic and non-syndromic clefts were considered for cluster analysis, and phenotypic characterization, while only non-syndromic for risk factor analysis. Seven clusters for CL/P, and four for CPO, with unusual BPRs were identified. CL/P cases in high BPR areas were more severe than elsewhere in the sample, similar to a previous ECLAMC report on microtia. For CL/P, high BPR clusters were associated with high altitude above sea level, Amerindian ancestry, and low socioeconomic strata; low BPR clusters showed association with African Black ancestry. Advanced maternal age, a recognized risk factor for CPO, was also associated with the only identified geographic cluster for CPO.

e12515 Background: Sequence data related to inherited cancers associated genes is scarce for South America population. Genetic variants of the BRCA1/2 genes, as a result of 15 years of experience i...

Several studies of South American populations showed that altitude is associated with low birth weight and intrauterine growth retardation. Although some of them analyzed the altitude-birth weight association, only a few assessed the effect of the interaction between altitude and socioeconomic factors on birth weight. The purpose of this research is to evaluate such effects on birth weight, after adjustment for confounding factors. This observational descriptive study includes a sample of 37,022 live-born infants without congenital anomalies, weighing >or=500 g, from 75 South American maternity hospitals, during 1982-1999. Of the total sample, 1,187 infants were born in two South American cities located at more than 2,000-m altitude: La Paz, Bolivia (N = 974 at 3,600 m) and Bogota, Colombia (N = 274 at 2,600 m). Among the seven risk factors analyzed, altitude was the main predictor of birth weight (except for gestational age). After adjustment for the other risk factors, birth weight at cities located above 2,000 m showed a decrease of approximately 200 g. When comparing highest and lowest socioeconomic levels, birth weight also showed differences for levels of altitude analyzed (lowland

WOS: 000309554700021 PubMed ID: 23028741 There is evidence for a genetic component in caries susceptibility, and studies in humans have suggested that variation in enamel formation genes may contribute to caries. For the present study, we used DNA samples collected from 1,831 individuals from various population data sets. Single nucleotide polymorphism markers were genotyped in selected genes (ameloblastin, amelogenin, enamelin, tuftelin, and tuftelin interacting protein 11) that influence enamel formation. Allele and genotype frequencies were compared between groups with distinct caries experience. Associations with caries experience can be detected but they are not necessarily replicated in all population groups and the most expressive results was for a marker in AMELX (p = 0.0007). To help interpret these results, we evaluated if enamel microhardness changes under simulated cariogenic challenges are associated with genetic variations in these same genes. After creating an artificial caries lesion, associations could be seen between genetic variation in TUFT1 (p = 0.006) and TUIP11 (p = 0.0006) with enamel microhardness. Our results suggest that the influence of genetic variation of enamel formation genes may influence the dynamic interactions between the enamel surface and the oral cavity. National Institutes of Health [R01-DE018914, R01-DE016148] This research is supported by National Institutes of Health grants R01-DE018914 and R01-DE016148. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.