RESUMO
Orofacial clefts are common developmental disorders that pose significant clinical, economical and psychological problems. We conducted genome-wide association analyses for cleft palate only (CPO) and cleft lip with or without palate (CL/P) with ~17 million markers in sub-Saharan Africans. After replication and combined analyses, we identified novel loci for CPO at or near genome-wide significance on chromosomes 2 (near CTNNA2) and 19 (near SULT2A1). In situ hybridization of Sult2a1 in mice showed expression of SULT2A1 in mesenchymal cells in palate, palatal rugae and palatal epithelium in the fused palate. The previously reported 8q24 was the most significant locus for CL/P in our study, and we replicated several previously reported loci including PAX7 and VAX1.
Assuntos
População Negra/genética , Fissura Palatina/genética , Genética Populacional , Genoma Humano , Genômica , Locos de Características Quantitativas , Alelos , Animais , Mapeamento Cromossômico , Modelos Animais de Doenças , Elementos Facilitadores Genéticos , Feminino , Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Genótipo , Humanos , Masculino , Camundongos , Razão de Chances , Polimorfismo de Nucleotídeo ÚnicoRESUMO
While several studies have investigated maternal exposures as risk factors for oral clefts, few have examined paternal factors. We conducted an international multi-centered case-control study to better understand paternal risk exposures for oral clefts (cases = 392 and controls = 234). Participants were recruited from local hospitals and oral cleft repair surgical missions in Vietnam, the Philippines, Honduras, and Morocco. Questionnaires were administered to fathers and mothers separately to elicit risk factor and family history data. Associations between paternal exposures and risk of clefts were assessed using logistic regression adjusting for potential confounders. A father's personal/family history of clefts was associated with significantly increased risk (adjusted OR: 4.77; 95% CI: 2.41-9.45). No other significant associations were identified for other suspected risk factors, including education (none/primary school v. university adjusted OR: 1.29; 95% CI: 0.74-2.24), advanced paternal age (5-year adjusted OR: 0.98; 95% CI: 0.84-1.16), or pre-pregnancy tobacco use (adjusted OR: 0.96; 95% CI: 0.67-1.37). Although sample size was limited, significantly decreased risks were observed for fathers with selected occupations. Further research is needed to investigate paternal environmental exposures as cleft risk factors.
Assuntos
Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Exposição Paterna/efeitos adversos , Estudos de Casos e Controles , Pré-Escolar , Fenda Labial/etiologia , Fissura Palatina/etiologia , Honduras/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Marrocos/epidemiologia , Filipinas/epidemiologia , Fatores de Risco , Fatores Socioeconômicos , Vietnã/epidemiologiaRESUMO
BACKGROUND: Several lifestyle and environmental exposures have been suspected as risk factors for oral clefts, although few have been convincingly demonstrated. Studies across global diverse populations could offer additional insight given varying types and levels of exposures. METHODS: We performed an international case-control study in the Democratic Republic of the Congo (133 cases, 301 controls), Vietnam (75 cases, 158 controls), the Philippines (102 cases, 152 controls), and Honduras (120 cases, 143 controls). Mothers were recruited from hospitals and their exposures were collected from interviewer-administered questionnaires. We used logistic regression modeling to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Family history of clefts was strongly associated with increased risk (maternal: OR = 4.7; 95% CI, 3.0-7.2; paternal: OR = 10.5; 95% CI, 5.9-18.8; siblings: OR = 5.3; 95% CI, 1.4-19.9). Advanced maternal age (5 year OR = 1.2; 95% CI, 1.0-1.3), pregestational hypertension (OR = 2.6; 95% CI, 1.3-5.1), and gestational seizures (OR = 2.9; 95% CI, 1.1-7.4) were statistically significant risk factors. Lower maternal (secondary school OR = 1.6; 95% CI, 1.2-2.2; primary school OR = 2.4, 95% CI, 1.6-2.8) and paternal education (OR = 1.9; 95% CI, 1.4-2.5; and OR = 1.8; 95% CI, 1.1-2.9, respectively) and paternal tobacco smoking (OR = 1.5, 95% CI, 1.1-1.9) were associated with an increased risk. No other significant associations between maternal and paternal factors were found; some environmental factors including rural residency, indoor cooking with wood, chemicals and water source appeared to be associated with an increased risk in adjusted models. CONCLUSION: Our study represents one of the first international studies investigating risk factors for clefts among multiethnic underserved populations. Our findings suggest a multifactorial etiology including both maternal and paternal factors.
