RESUMO
OBJECTIVE: Previous studies suggest individuals born with oral clefts and their families have a higher susceptibility for cancer, which raises the hypothesis that these two conditions share common molecular pathways. This study evaluated the association between oral clefts and polymorphisms in genes that play a role in craniofacial and tumor development. MATERIALS AND METHODS: Four hundred and ninety-seven subjects born with oral clefts and 823 unaffected subjects were recruited. Twenty-nine markers in 13 genes were genotyped by the Taqman method. Chi-square was used to compare allele and genotype frequencies. Bonferroni correction for multiple testing was used and the established alpha was 0.0003. This study also used logistic regression to test if genetic variants were associated with oral clefts using positive family history of cancer and age as covariates. RESULTS: There was no association between family history of cancer and oral clefts (p = 0.51). None of the 1320 study participants had a diagnosis of cancer at the time of participation in the study. The marker rs4980700 in FGF3 was associated with oral clefts (p = 0.0002). Logistic regression analysis also provided evidence for gene-gene interaction between FGF3 (rs4980700) and PAX9 (rs2073242), increasing the risk for isolated oral clefts (p = 0.0003). CONCLUSION: FGF3 is associated with oral clefts and may interact with PAX9.
Assuntos
Carcinogênese/genética , Fenda Labial/genética , Fissura Palatina/genética , Fator 3 de Crescimento de Fibroblastos/genética , Predisposição Genética para Doença/genética , Fator de Transcrição PAX9/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Epistasia Genética/genética , Feminino , Frequência do Gene/genética , Variação Genética/genética , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Adulto JovemRESUMO
Objectives To evaluate the association between hypoxia during embryo development and oral clefts in an animal model, and to evaluate the association between polymorphisms in the HIF-1A gene with oral clefts in human families. Material and Methods The study with the animal model used zebrafish embryos at 8 hours post-fertilization submitted to 30% and 50% hypoxia for 24 hours. At 5 days post-fertilization, the larvae were fixed. The cartilage structures were stained to evaluate craniofacial phenotypes. The family-based association study included 148 Brazilian nuclear families with oral clefts. The association between the genetic polymorphisms rs2301113 and rs2057482 in HIF-1A with oral clefts was tested. We used real time PCR genotyping approach. ANOVA with Tukey's post-test was used to compare means. The transmission/disequilibrium test was used to analyze the distortion of the inheritance of alleles from parents to their affected offspring. Results For the hypoxic animal model, the anterior portion of the ethmoid plate presented a gap in the anterior edge, forming a cleft. The hypoxia level was associated with the severity of the phenotype (p<0.0001). For the families, there was no under-transmitted allele among the affected progeny (p>0.05). Conclusion Hypoxia is involved in the oral cleft etiology, however, polymorphisms in HIF-1A are not associated with oral clefts in humans.
Assuntos
Fenda Labial/embriologia , Fenda Labial/etiologia , Fissura Palatina/embriologia , Fissura Palatina/etiologia , Hipóxia Fetal/complicações , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Polimorfismo Genético , Adolescente , Adulto , Idoso , Análise de Variância , Animais , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Hipóxia Fetal/genética , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Adulto Jovem , Peixe-ZebraRESUMO
OBJECTIVE: It has been suggested that oral clefts and cancer share a common genetic background. This study aimed to investigate the epidemiological and molecular association between oral clefts and cancer. METHODS: One hundred forty-eight nuclear families with oral clefts and 162 subjects with no birth defect were recruited. Data on self-reported family history of cancer among first, second, and third degree relatives of each patient were collected via a structured questionnaire. We also investigated the association between polymorphisms in the genes AXIN2, BMP2, BMP4, BMP7, DLX1, DLX2, and MMP3 and oral cleft with and without history of cancer. Markers in these genes were genotyped using real time PCR. Chi-square and t-test were used to assess the differences about self-reported family history of cancer between oral cleft and non-cleft individuals. The transmission disequilibrium test (TDT) was used to analyze the distortion of the inheritance of alleles from parents to their affected offspring. RESULTS: Families with oral clefts had an increased risk of having a family history of cancer (p=0.01; odds ratio=1.79; 95% confidence interval, 1.07-1.87). TDT results showed an association between DLX1 and cleft lip and palate, in which the A allele was undertransmited (p=0.022). For MMP3, G was undertransmited among affected progeny (p=0.019) in cleft palate subgroup. CONCLUSION: Oral clefts were associated with positive self-reported family history of cancer and with variants in DLX1 and MMP3. The association between oral clefts and cancer raises interesting possibilities to identify risk markers for cancer.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Proteínas de Homeodomínio/genética , Metaloproteinase 3 da Matriz/genética , Fatores de Transcrição/genética , Adulto , Alelos , Criança , Feminino , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Inquéritos e QuestionáriosRESUMO
Abstract Objectives To evaluate the association between hypoxia during embryo development and oral clefts in an animal model, and to evaluate the association between polymorphisms in the HIF-1A gene with oral clefts in human families. Material and Methods The study with the animal model used zebrafish embryos at 8 hours post-fertilization submitted to 30% and 50% hypoxia for 24 hours. At 5 days post-fertilization, the larvae were fixed. The cartilage structures were stained to evaluate craniofacial phenotypes. The family-based association study included 148 Brazilian nuclear families with oral clefts. The association between the genetic polymorphisms rs2301113 and rs2057482 in HIF-1A with oral clefts was tested. We used real time PCR genotyping approach. ANOVA with Tukey's post-test was used to compare means. The transmission/disequilibrium test was used to analyze the distortion of the inheritance of alleles from parents to their affected offspring. Results For the hypoxic animal model, the anterior portion of the ethmoid plate presented a gap in the anterior edge, forming a cleft. The hypoxia level was associated with the severity of the phenotype (p<0.0001). For the families, there was no under-transmitted allele among the affected progeny (p>0.05). Conclusion Hypoxia is involved in the oral cleft etiology, however, polymorphisms in HIF-1A are not associated with oral clefts in humans.