RESUMO
Nonsyndromic cleft lip with or without cleft palate (NSCL ± P) is the most common orofacial birth defect, exhibiting variable prevalence around the world, often attributed to ethnic and environmental differences. Linkage analyses and genome-wide association studies have identified several genomic susceptibility regions for NSCL ± P, mostly in European-derived or Asian populations. Genetic predisposition to NSCL ± P is ethnicity-dependent, and the genetic basis of susceptibility to NSCL ± P likely varies among populations. The population of Brazil is highly admixed, with highly variable ancestry; thus, the genetic determinants of NSCL ± P susceptibility may be quite different. This study tested association of 8 single-nucleotide polymorphisms (SNPs), previously identified by genome-wide studies in other populations, with NSCL ± P in a Brazilian population with high African ancestry. SNPs rs560426, rs642961, rs1530300, rs987525, rs3758249, rs7078160, rs17085106, and rs13041247 were genotyped in 293 Brazilian patients with NSCL ± P and 352 unaffected Brazilian controls. Each sample was also genotyped for 40 biallelic short insertion/deletion polymorphic markers to characterize genetic ancestry. The average African ancestry background was 31.1% for the NSCL ± P group and 36.7% for the control group. After adjustment for ancestry and multiple testing, the minor alleles of rs3758249 (OR: 1.58, 95% CI: 1.25-2.01, P = 0.0001) and rs7078160 (OR: 1.59, 95% CI: 1.21-2.07, P = 0.0002) were significantly associated with risk of NSCL ± P. Polymorphisms located in IRF6 (rs642961) and 8q24 (rs1530300 and rs987525) showed marginal associations in this Brazilian population with high African ancestry. These results indicate that rs3758249 at 9q22 and rs7078160 at 10q25.3 represent risk loci for NSCL ± P in the Brazilian population with high African ancestry.
Assuntos
População Negra , Fenda Labial/genética , Fissura Palatina/genética , Loci Gênicos , Predisposição Genética para Doença , Alelos , Povo Asiático , Doenças Assintomáticas , Brasil , Estudos de Casos e Controles , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 8 , Cromossomos Humanos Par 9 , Fenda Labial/etnologia , Fenda Labial/patologia , Fissura Palatina/etnologia , Fissura Palatina/patologia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Padrões de Herança , Fatores Reguladores de Interferon/genética , Masculino , Polimorfismo de Nucleotídeo Único , Risco , População BrancaRESUMO
BACKGROUND: Although genome-wide association studies have identified several susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations around the world, the role of most loci is unknown in the highly heterogeneous Brazilian population. METHODS: To determine the association of 7 markers that showed genome-wide significant association in Brazilians with NSCL/P, we conducted a structured association study conditioned upon the individual ancestry proportions to evaluate markers at 1p36 (rs742071), 2p21 (rs7590268), 3p11.1 (rs7632427), 8q21.3 (rs12543318), 13q31.1 (rs8001641), 15q22.2 (rs1873147), and 17q22 (rs227731) in 505 patients with NSCL/P and 594 healthy controls recruited from 2 different geographical regions of Brazil. The polymorphisms were genotyped by TaqMan 5'-exonuclease allelic discrimination assay, and each sample was independently typed for 40 biallelic short insertion/deletion markers to characterize the genomic ancestry. RESULTS: After Bonferroni correction for multiple tests, significant associations with NSCL/P were observed for rs742071, rs1873147, and rs227731. However, the frequency of the risk alleles varied between the geographical regions, according to the proportions of European and African genomic ancestry. The group enriched by European ancestry showed significant association with rs227731 (p = 0.001), whereas the group with high African ancestry was significantly associated with rs1873147 polymorphism (p = 0.005). The significant association with rs742071 was only detected in the combined sample (p = 0.005). CONCLUSION: The findings of the present study revealed the associations of 1p36 (rs742071), 15q22 (rs1873147), and 17p22 (rs227731) with NSCL/P in the Brazilian population, and further confirmed that the genetic heterogeneity of NSCL/P may be related to the different ethnic background of the affected individuals.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Deleção de Sequência , População Negra , Brasil , Estudos de Casos e Controles , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 17 , Fenda Labial/etnologia , Fenda Labial/patologia , Fissura Palatina/etnologia , Fissura Palatina/patologia , Frequência do Gene , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Padrões de Herança , Mutagênese Insercional , Razão de Chances , População BrancaRESUMO
BACKGROUND: GREM1, which encodes Gremlin 1, an antagonist of bone morphogenic proteins with effects on proliferation and apoptosis, has been considered a candidate gene for nonsyndromic cleft lip with or without cleft palate (NSCL±P). In this study, we investigated potential associations of single nucleotide polymorphisms (SNP) in GREM1 and NSCL±P risk in the Brazilian population. Additionally, SNP-SNP interactions of GREM1 with previously reported rs1880646 variant in NTN1 (netrin 1), a gene also responsible for apoptotic phenotypes were verified. METHODS: Applying Taqman allelic discrimination assays, we evaluated the variants rs16969681, rs16969816, rs16969862, and rs1258763 in 325 case-parent trios and in 1,588 isolated samples in a case-control study. Allelic and genotypic analyses, as well as interaction tests assessing gene-environmental factor (GxE) and SNP-SNP interaction with rs1880646 variant in NTN1, were performed based on logistic regression analysis adjusted for the effects of gender and genomic ancestry proportions. RESULTS: The risk alleles of all SNP were undertransmitted in NSCL±P trios, though the case-control analysis confirmed only the association with rs16969862 alleles (OR: 0.78, 95% CI: 0.63-0.96, p = .02). The GxE interaction analysis revealed a significant interaction between maternal environmental contact with agrotoxics and rs16969816 (OR: 0.25, 95% CI: 0.08-0.74, p = .01), and pairwise interaction test with NTN1 rs1880646 yielded significant p values in the 1,000 permutation test for rs16969681, rs16969816, and rs16969862. CONCLUSION: The GREM1 is involved in the etiology of NSCL±P in the Brazilian population and reveal that the interaction between GREM1 and NTN1 may be related with the pathogenesis of this common craniofacial malformation.
Assuntos
Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adulto , Alelos , Encéfalo/metabolismo , Brasil/epidemiologia , Estudos de Casos e Controles , Fenda Labial/metabolismo , Fissura Palatina/metabolismo , Família , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Padrões de Herança , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Netrina-1/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
As condições de saúde bucal são influenciadas por fatores de diversas origens, dentre os quais se destacam as condições ocupacionais. Objetivo: este estudo tem como objetivo a realização de um inquérito epidemiológico sobre saúde bucal de trabalhadores do Salvamar (órgão da Prefeitura Municipal de Salvador responsável pelos serviços de salva-vidas), que exercem a função de salva-vidas e que, por conseguinte, encontram-se cotidianamente expostos à radiação solar. Sujeitos emétodo: trata-se de um estudo descritivo, de corte transversal, conduzido com uma amostra de conveniência de salva-vidas que, voluntariamente, se submeteram ao exame bucal que incluiu a avaliação de cárie dentária, uso de prótese, alterações periodontais e lesões de mucosa oral. Os exames foram realizados por uma estudante de graduação do curso de Odontologia da Escola Bahiana de Medicina e Saúde Pública, no decorrer do segundo semestre do ano de 2012. Resultados: os dados foram analisados descritivamente, sendo observado um CPO-D de 9,37 e o uso de prótese dentária, bem como presença de alguma alteração periodontal entre 22,54% dos salva-vidas. A prevalência de lesões de mucosa oral, na ordem de 21,13%, foi outro dado que despertou a atenção para a necessidade de implantação de ações preventivas dirigidas a esse grupo populacional no que diz respeito à saúde bucal. Conclusão: considerandoa presença e à gravidade dos agravos bucais encontrados entre os salva-vidas e o risco a que estão expostos cotidianamente, torna-se importante o plane jamento e implantação de programas de saúde bucal no local de trabalho, visando à promoção de saúde e prevenção de riscos