RESUMO
We present a large, ten-generation family of 273 individuals with 84 people having preaxial polydactyly/triphalangeal thumb due to a pathogenic variant in the zone of polarizing activity regulatory sequence (ZRS) within the exon 5 of LMBR1. The causative change maps to position 396 of the ZRS, located at position c.423 + 4909C > T (chr7:156791480; hg38; LMBR1 ENST00000353442.10; rs606231153 NG_009240.2) in the intron 5 of LMBR1. The first affected individual with the disorder was traced back to mid-1700, when some settlers and workers established in Cervera de Buitrago, a small village about 82 km North to Madrid. Clinical and radiological studies of most of the affected members have been performed for 42 years (follow-up of the family by LFGA). Molecular studies have confirmed a pathogenic variant in the ZRS that segregates in this family. To the best of our knowledge, this is the largest family with preaxial polydactyly/triphalangeal thumb reported so far.
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Proteínas de Membrana , Polidactilia , Humanos , Proteínas de Membrana/genética , Linhagem , Polidactilia/genética , Polidactilia/patologia , Polegar/patologiaRESUMO
In this article, we analyze several works of art which portray individuals with short stature ("dwarfism"). We have focused on eight individuals who we believe have short stature due to growth hormone deficiency (GHD) or closely related disorders, rather than skeletal dysplasia. We discuss them individually, suggest the potential diagnosis, review the characteristics of their life and personal history, and briefly outline the artistic framework in which these works of art were created. This work is a posthumous tribute to the people with short stature portrayed in these works of art, who likely experienced harassment and inappropriate treatment by others and called by derogatory names. We have tried to acknowledge their identities with the respect they deserve.
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Nanismo Hipofisário , Hormônio do Crescimento Humano , Osteocondrodisplasias , Estatura , Transtornos do Crescimento , HumanosRESUMO
BACKGROUND: Historically, neural tube defects (NTDs) have predominated in female infants but the reasons remain unclear. In South America, the pre- folic acid fortification (FAF) rates of NTDs were around 18/10,000 births for females and 12/10,000 births for males, with an estimated sex ratio (male/female) of 0.67. During the post- FAF period, unpublished routine reports have indicated changes in the sex ratio for these defects while some descriptive reports are controversial. To date and to our knowledge, however, no studies specifically focusing on these changes to test this hypothesis directly have been undertaken. The aim of this study was to analyze changes in the sex ratio of infants with NTDs after FAF in South American countries. MATERIALS AND METHODS: With a descriptive cross-sectional study design, 2,597 infants with isolated NTDs born between 1990 and 2013 in 3 countries participating in the Latin American Collaborative Study of Congenital Malformations (ECLAMC) network were included: (Chile N = 521 and Argentina N = 1,619 [with FAF policies]; Venezuela N = 457 [without FAF policies; used as control]; total births = 2,229,561). The differences-in-differences method and Poisson regressions were used to evaluate the sex ratio shift from female to male before vs. after FAF, and to assess whether these differences were related to the fortification. RESULTS AND CONCLUSIONS: In Chile and Argentina the prevalence of NTDs, particularly anencephaly and cervico-thoracic spina bifida, showed a greater reduction rate in females than in males after FAF, resulting in a change of the sex ratio of infants with NTDs. Some mechanisms possibly involved in this differential reduction are proposed which might be useful to identify the pathogenesis of NTDs as a whole and specifically of those susceptible to the protective effect of folic acid.
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Ácido Fólico/administração & dosagem , Alimentos Fortificados , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/prevenção & controle , Caracteres Sexuais , Argentina/epidemiologia , Chile/epidemiologia , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Fatores SexuaisRESUMO
We compared Brazilian oral cleft (OC) frequencies between the population-based Brazilian System of Live Birth (SINASC) and the hospital-based Latin American Collaborative Study of Congenital Malformations (ECLAMC), trying to understand the paucity of cleft of lip and palate (CLP) in the first system. SINASC uses the International Classification of Disease version 10 (ICD-10) for congenital defects coding, ECLAMC uses ICD-8 with modifications. In SINASC, the CLP frequency was 1.7 per 10,000 (95% confidence limits 1.7-1.8), cleft lip (CL) 1.6 (1.5-1.7), and cleft palate (CP) 2.0 (1.9-2.1). In ECLAMC, the CLP frequency was 10.4 per 10,000 (9.0-12.1), CL 5.5 (4.5-6.7), and CP 4.4. (4.5-6.7). In SINASC, only 33% of the oral clefts were CLP, versus 51% in ECLAMC. Part of this discrepancy may have been due to the relative excess of CP and CL cases. Although congenital defect frequencies are usually lower in population than in hospital-based registries, differences in the proportion of the main OC categories are not expected and are probably due to ICD-10 coding issues, such as lumping of unilateral CL and CL without other specifications. ICD-10 codes, whose deficiency for oral clefts is fully explained in the literature, lack modifiers for severity, or clinical subtypes. This paper shows the practical aspect of the ICD-10 system deficiency in capturing cleft lip and palate (CLP) subtypes, as demonstrated in SINASC covering three million births per year. Such errors are expected to occur in any registry that uses the ICD-10 coding system, and must be adjusted, given its relevance worldwide.
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Fissura Palatina/epidemiologia , Nascido Vivo/epidemiologia , Brasil/epidemiologia , Fenda Labial/epidemiologia , Fissura Palatina/diagnóstico , Feminino , Humanos , Classificação Internacional de Doenças , Masculino , Fenótipo , Vigilância da População , Valor Preditivo dos Testes , GravidezRESUMO
The identification of clinical patterns of tooth agenesis in individuals born with craniofacial deformities may be a useful tool for risk determination of these defects. We hypothesize that specific craniofacial deformities are associated with third molar agenesis. OBJECTIVE: The aim of this study was to identify if third molar agenesis could have a relation with other craniofacial structure alterations, such as cleft lip and palate, skeletal malocclusion, or specific growth patterns in humans. DESIGN: Data were obtained from 550 individuals ascertained as part of studies aiming to identify genetic contributions to oral clefts. 831 dental records of patients aged over eight years seeking orthodontic treatment were also included. SN-GoGn angle were used to classify the growth pattern (hypo-divergent, normal and hyper-divergent), and the ANB angle was used to verify the skeletal malocclusion pattern (Class I, II and III). Panoramic radiographs were used to determine third molar agenesis. RESULTS: A high frequency of third molar agenesis among individuals born with cleft lip with or without cleft palate (55%), as well as among their relatives (93.5%) was found. Third molar agenesis was not associated to skeletal malocclusion or growth pattern. CONCLUSION: It appears that third molar agenesis is associated with the disturbances that lead to cleft lip and palate.
Assuntos
Anodontia/complicações , Anodontia/epidemiologia , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/etnologia , Dente Serotino/anormalidades , Anormalidades Múltiplas/epidemiologia , Adolescente , Adulto , Biomarcadores , Criança , Fenda Labial/epidemiologia , Fenda Labial/etnologia , Fenda Labial/genética , Fissura Palatina/epidemiologia , Feminino , Humanos , Masculino , Má Oclusão/classificação , Má Oclusão/etiologia , Mandíbula/anormalidades , Mandíbula/patologia , Maxila/anormalidades , Maxila/patologia , Ortodontia , Fenótipo , Estudos Prospectivos , Radiografia Panorâmica , Adulto JovemRESUMO
The 19q13 locus has been linked to cleft lip and palate by our group and independently by others. Here we fine mapped the region in an attempt to identify an etiological variant that can explain cleft lip and palate occurrence. A total of 2739 individuals born with cleft lip and palate, related to individuals born with cleft lip and palate, and unrelated were studied. We used linkage and association approaches to fine map the interval between D19S714 and D19S433 and genotypes were defined by the use of TaqMan chemistry. We confirmed our previous findings that markers in PVR/CD155 are associated with cleft lip and palate. We studied the mutation Ala67Thr further and calculated its penetrance. We also attempted to detect PVR/CD155 expression in human whole saliva. Our results showed that markers in PVR/CD155 are associated with cleft lip and palate and the penetrance of the Ala67Thr is very low (between 1% and 5%). We could not detect PVR/CD155 expression in adult human whole saliva and PVR/CD155 possibly interacts with maternal infection to predispose children to cleft lip only.
Assuntos
Fenda Labial , Fissura Palatina , Receptores Virais/genética , Adulto , Criança , Fenda Labial/epidemiologia , Fenda Labial/genética , Fissura Palatina/epidemiologia , Fissura Palatina/genética , Humanos , Mutação/genética , Saliva/químicaRESUMO
Objective To describe the prevalence and clinical spectrum of microcephaly in South America for the period 2005-14, before the start of the Zika epidemic in 2015, as a baseline for future surveillance as the Zika epidemic spreads and as other infectious causes may emerge in future.Design Prevalence and case-control study.Data sources ECLAMC (Latin American Collaborative Study of Congenital Malformations) database derived from 107 hospitals in 10 South American countries, 2005 to 2014. Data on microcephaly cases, four non-malformed controls per case, and all hospital births (all births for hospital based prevalence, resident within municipality for population based prevalence). For 2010-14, head circumference data were available and compared with Intergrowth charts.Results 552 microcephaly cases were registered, giving a hospital based prevalence of 4.4 (95% confidence interval 4.1 to 4.9) per 10 000 births and a population based prevalence of 3.0 (2.7 to 3.4) per 10 000. Prevalence varied significantly between countries and between regions and hospitals within countries. Thirty two per cent (n=175) of cases were prenatally diagnosed; 29% (n=159) were perinatal deaths. Twenty three per cent (n=128) were associated with a diagnosed genetic syndrome, 34% (n=189) polymalformed without a syndrome diagnosis, 12% (n=65) with associated neural malformations, and 26% (n=145) microcephaly only. In addition, 3.8% (n=21) had a STORCH (syphilis, toxoplasmosis, other including HIV, rubella, cytomegalovirus, and herpes simplex) infection diagnosis and 2.0% (n=11) had consanguineous parents. Head circumference measurements available for 184/235 cases in 2010-14 showed 45% (n=82) more than 3 SD below the mean, 24% (n=44) between 3 SD and 2 SD below the mean, and 32% (n=58) larger than -2 SD.Conclusion Extrapolated to the nearly 7 million annual births in South America, an estimated 2000-2500 microcephaly cases were diagnosed among births each year before the Zika epidemic began in 2015. Clinicians are using more than simple metrics to make microcephaly diagnoses. Endemic infections are important enduring causes of microcephaly.
Assuntos
Microcefalia , Complicações Infecciosas na Gravidez/epidemiologia , Estudos de Casos e Controles , Monitoramento Epidemiológico , Feminino , Humanos , Recém-Nascido , Masculino , Microcefalia/epidemiologia , Gravidez , Prevalência , América do Sul/epidemiologiaRESUMO
BACKGROUND: Some studies, mainly in the older literature, observed a significant association between miscarriages and birth defects (BDs) occurring in the same sibship. However, few studies examined the BD/miscarriage relationship in depth. In addition nothing has been added to the underlying mechanisms possibly linking both events. The purpose of this work was to identify specific BDs associated with maternal miscarriages. In particular, it examined whether the risk depended on the number of losses, and to suggest the existence of specific factors for each BD/miscarriage association observed. METHODS: The study relied on the Latin American Collaborative Study on Congenital Malformations (ECLAMC) database registries including 26,906 live and stillborn infants with one of 19 selected isolated BDs and 93,853 normal controls. Infants born to primigravid mothers were excluded from the present study. Demographic and reproductive variables were compared between control mothers With and Without previous miscarriages. The number, frequency, and distribution of miscarriages were observed for each BD and controls. A conditional logistic regression was applied to evaluate the miscarriage risk for each BD. RESULTS: Control mothers with previous miscarriages were older, had had more pregnancies, and were less educated. Three risk patterns of miscarriages were observed: a very high risk of miscarriages associated with gastroschisis, omphalocele, and talipes; only one miscarriage associated with spina bifida, and two or more miscarriages associated with hypospadias. CONCLUSION: These three patterns suggest that different factors underly each BD/miscarriage association: infertility for hypospadias, vascular disruption for gastroschisis and talipes, while for spina bifida, the much debated trophoblastic cell residue theory could not be discarded. Birth Defects Research 109:254-261, 2017. © 2017 Wiley Periodicals, Inc.
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Aborto Espontâneo/epidemiologia , Gastrosquise/epidemiologia , Hérnia Umbilical/epidemiologia , Hipospadia/epidemiologia , Disrafismo Espinal/epidemiologia , Pé Torto/epidemiologia , Aborto Espontâneo/diagnóstico , Aborto Espontâneo/fisiopatologia , Adulto , Fatores Etários , Argentina/epidemiologia , Estudos de Casos e Controles , Bases de Dados Factuais , Escolaridade , Feminino , Gastrosquise/diagnóstico , Gastrosquise/patologia , Número de Gestações/fisiologia , Hérnia Umbilical/diagnóstico , Hérnia Umbilical/patologia , Humanos , Hipospadia/diagnóstico , Hipospadia/patologia , Modelos Logísticos , Masculino , Paridade/fisiologia , Gravidez , Sistema de Registros , Risco , Disrafismo Espinal/diagnóstico , Disrafismo Espinal/patologia , Estatística como Assunto , Natimorto/epidemiologia , Pé Torto/diagnóstico , Pé Torto/patologiaRESUMO
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a group of common human birth defects with complex etiology. Although genome-wide association studies have successfully identified a number of risk loci, these loci only account for about 20% of the heritability of orofacial clefts. The "missing" heritability may be found in rare variants, copy number variants, or interactions. In this study, we investigated the role of low-frequency variants genotyped in 1995 cases and 1626 controls on the Illumina HumanCore + Exome chip. We performed two statistical tests, Sequence Kernel Association Test (SKAT) and Combined Multivariate and Collapsing (CMC) method using two minor allele frequency cutoffs (1% and 5%). We found that a burden of low-frequency coding variants in N4BP2, CDSN, PRTG, and AHRR were associated with increased risk of NSCL/P. Low-frequency variants in other genes were associated with decreased risk of NSCL/P. These results demonstrate that low-frequency variants contribute to the genetic etiology of NSCL/P.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Enzimas Reparadoras do DNA/genética , Glicoproteínas/genética , Proteínas de Membrana/genética , Proteínas Repressoras/genética , Alelos , Encéfalo/fisiopatologia , Fenda Labial/fisiopatologia , Fissura Palatina/fisiopatologia , Exoma/genética , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , População Branca/genéticaRESUMO
Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P (p = 1.16 × 10-8). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 (SHROOM3), 12q13.13 (KRT18), and 8p21 (NRG1). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance (p = 1.33 × 10-9). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.
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Fenda Labial/genética , Fissura Palatina/genética , Fatores de Transcrição Forkhead/genética , Estudo de Associação Genômica Ampla , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Mapeamento Cromossômico , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
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Fenda Labial/genética , Fissura Palatina/genética , Povo Asiático/genética , População Negra/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 2/genética , Etnicidade , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , População Branca/genéticaRESUMO
Increased susceptibility to cleft lip, with or without cleft palate (CL±P) has been observed in South America, as related to Amerindian ancestry, using epidemiological data, uniparental markers, and blood groups. In this study, it was evaluated whether this increased risk remains when Amerindian ancestry is estimated using autosomal markers and considered in the predictive model. Ancestry was estimated through genotyping 62 insertion and deletion (INDEL) markers in sample sets of patients with CL±P, patients with cleft palate (CP), and controls, from Patagonia in southern Argentina and Belém in northern Brazil. The Amerindian ancestry in patients from Patagonia with CL±P was greater than in controls although it did not reach statistical significance. The European ancestry in patients with CL±P from Belém and in patients with CP from Belém and Patagonia was higher than in controls and statistically significant for patients with CP who were from Belém. This high contribution of European genetic ancestry among patients with CP who were from Belém has not been previously observed in American populations. Our results do not corroborate the currently accepted risks for CL±P and CP estimated by epidemiological studies in the North American populations and probably reflect the higher admixture found in South American ethnic groups when compared with the same ethnic groups from the North American populations.
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Fenda Labial/genética , Fissura Palatina/genética , População Branca/genética , Brasil , Genótipo , HumanosRESUMO
Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.
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Fissura Palatina/genética , Proteínas de Ligação a DNA/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Animais , Estudos de Casos e Controles , Fissura Palatina/diagnóstico , Modelos Animais de Doenças , Etnicidade/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Mutação de Sentido Incorreto , Fatores de Risco , Peixe-Zebra/embriologia , Peixe-Zebra/genéticaRESUMO
OBJECTIVE: This study was designed to characterize and compare the maternal and newborn epidemiological characteristics through analysis of environmental factors, sociodemographic characteristics and clinical characteristics between the different clinical subtypes of preterm birth (PTB): Idiopathic (PTB-I), premature rupture of the membranes (PTB-PPROM) and medically indicated (PTB-M). The two subtypes PTB-I and PTB-PPROM grouped are called spontaneous preterm births (PTB-S). METHODS: A retrospective, observational study was conducted in 1.291 preterm nonmalformed singleton live-born children to nulliparous and multiparous mother's in Tucumán-Argentina between 2005 and 2010. Over 50 maternal variables and 10 newborn variables were compared between the different clinical subtypes. The comparisons were done to identify heterogeneity between subtypes of preterm birth: (PTB-S) versus (PTB-M), and within spontaneous subtype: (PTB-I) versus (PTB-PPROM). In the same way, two conditional logistic multivariate regressions were used to compare the odds ratio (OR) between PTB-S and PTB-M, as well as PTB-I and PTB-PPROM. We matched for maternal age when comparing maternal variables and gestational age when comparing infant variables. RESULTS: The PTB-I subtype was characterized by younger mothers of lower socio-economic status, PTB-PPROM was characterized by environmental factors resulting from inflammatory processes, and PTB-M was characterized by increased maternal or fetal risk pregnancies. CONCLUSIONS: The main risk factor for PTB-I and PTB-M was having had a prior preterm delivery; however, previous spontaneous abortion was not a risk factor, suggesting a reproductive selection mechanism.
Assuntos
Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Adolescente , Adulto , Fatores Etários , Análise de Variância , Argentina/epidemiologia , Feminino , Ruptura Prematura de Membranas Fetais/epidemiologia , Idade Gestacional , Humanos , Recém-Nascido , Modelos Logísticos , Razão de Chances , Gravidez , Nascimento Prematuro/etiologia , Estudos Retrospectivos , Fatores de Risco , Fatores Socioeconômicos , Adulto JovemRESUMO
Aquaporins (AQP) are water channel proteins and the genes coding for AQP2, AQP5, and AQP6 are clustered in 12q13. Since AQP5 is expressed in serous acinar cells of salivary glands, we investigated its involvement in caries. DNA samples from 1,383 individuals from six groups were studied. Genotypes of eight single nucleotide polymorphisms covering the aquaporin locus were tested for association with caries experience. Interaction with genes involved in enamel formation was tested. The association between enamel microhardness at baseline, after creation of artificial caries lesion, and after exposure to fluoride and the genetic markers in AQP5 was tested. Finally, AQP5 expression in human whole saliva, after exposure to fluoride in a mammary gland cell line, which is known to express AQP5, and in Wistar rats was also verified. Nominal associations were found between caries experience and markers in the AQP5 locus. Since these associations suggested that AQP5 may be inhibited by levels of fluoride in the drinking water that cause fluorosis, we showed that fluoride levels above optimal levels change AQP5 expression in humans, cell lines, and rats. We have shown that AQP5 is involved in the pathogenesis of caries and likely interacts with fluoride.
Assuntos
Aquaporina 5/metabolismo , Cárie Dentária/metabolismo , Fluoretos/metabolismo , Adolescente , Adulto , Animais , Aquaporina 5/genética , Linhagem Celular Tumoral , Criança , Pré-Escolar , Cárie Dentária/genética , Feminino , Marcadores Genéticos/genética , Genótipo , Humanos , Masculino , Glândulas Mamárias Humanas/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Ratos , Ratos Wistar , Saliva/metabolismo , Adulto JovemRESUMO
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.
RESUMO
OBJECTIVES: We sought to quantify how socioeconomic, health care, demographic, and geographic effects explain racial disparities in low birth weight (LBW) and preterm birth (PTB) rates in Brazil. METHODS: We employed a sample of 8949 infants born between 1995 and 2009 in 15 cities and 7 provinces in Brazil. We focused on disparities in LBW (< 2500 g) and PTB (< 37 gestational weeks) prevalence between infants of African ancestry alone or African mixed with other ancestries, and European ancestry alone. We used a decomposition model to quantify the contributions of conceptually relevant factors to these disparities. RESULTS: The model explained 45% to 94% of LBW and 64% to 94% of PTB disparities between the African ancestry groups and European ancestry. Differences in prenatal care use and geographic location were the most important contributors, followed by socioeconomic differences. The model explained the majority of the disparities for mixed African ancestry and part of the disparity for African ancestry alone. CONCLUSIONS: Public policies to improve children's health should target prenatal care and geographic location differences to reduce health disparities between infants of African and European ancestries in Brazil.
Assuntos
Disparidades nos Níveis de Saúde , Recém-Nascido de Baixo Peso , Nascimento Prematuro/etnologia , Cuidado Pré-Natal/estatística & dados numéricos , Grupos Raciais/estatística & dados numéricos , População Negra/estatística & dados numéricos , Brasil/epidemiologia , Feminino , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Humanos , Recém-Nascido , Masculino , Prevalência , Fatores Socioeconômicos , População Branca/estatística & dados numéricosRESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Assuntos
Aborto Espontâneo/epidemiologia , Gastrosquise/epidemiologia , Gastrosquise/etiologia , Hormônios Esteroides Gonadais/efeitos adversos , Idade Materna , Adolescente , Argentina/epidemiologia , Anormalidades Congênitas/epidemiologia , Feminino , Humanos , Recém-Nascido , Razão de Chances , Gravidez , Análise de Regressão , Fatores de RiscoRESUMO
OBJECTIVES: We examine disparities in birth weight and gestational age by ethnic ancestry in 2000-2011 in eight South American countries. METHODS: The sample included 60,480 singleton live births. Regression models were estimated to evaluate differences in birth outcomes by ethnic ancestry controlling for time trends. RESULTS: Significant disparities were found in seven countries. In four countries-Brazil, Ecuador, Uruguay, and Venezuela-we found significant disparities in both low birth weight and preterm birth. Disparities in preterm birth alone were observed in Argentina, Bolivia, and Colombia. Several differences in continuous birth weight, gestational age, and fetal growth rate were also observed. There were no systematic patterns of disparities between the evaluated ethnic ancestry groups across the study countries, in that no racial/ethnic group consistently had the best or worst outcomes in all countries. CONCLUSIONS: Racial/ethnic disparities in infant health are common in several South American countries. Differences across countries suggest that racial/ethnic disparities are driven by social and economic mechanisms. Researchers and policymakers should acknowledge these disparities and develop research and policy programs to effectively target them.