Cleft lip and/or palate (CL/P) is the most common orofacial birth defect, resulting in a series of orofacial, behavioral and psychosocial complications. Approximately 70% of cases are isolated defects, receiving the denomination of nonsyndromic CL/P (NSCL/P). NSCL/P are caused by a complex interplay between environmental exposures, genetic and epigenetic factors (multifactorial disease), but the molecular basis remains largely unknown. In part, our knowledge is limited because most of the studies in this field did not combine genetic and environment aspects (gene-environment interactions) into the analysis. More recently this approach has been used, revealing important aspects associated with the development of NSCL/P. In this line, our group revealed that RAD51 rs1801321 may influence the risk of nonsyndromic cleft lip with or without cleft palate (NSCL±P) through interaction with maternal exposure to cigarette smoking. Development is characterized by the embryonic activation of a large number of genes and pathways ensuring the intense expansion of precursor populations prior to differentiation. During those processes, reactive oxygen species (ROS), molecules that are naturally occurring and essential to life while are simultaneously capable of causing oxidative stress and have an important role in pathological conditions, are produced. Excess of ROS may induce several cellular damages, particularly irreversible DNA mutation. Normal cells protect themselves from ROS (oxidative stress) using both neutralizing enzymes and non-enzymatic antioxidants, including vitamins and minerals. We postulated that mutagenic environmental factors that induce ROS accumulation during pregnancy (though increased production or reduced inactivation), including cigarette smoking, consumption of alcohol and drugs, agrotoxics, diet poor in antioxidants, hyperhomocysteinemia (due to folic acid metabolic alterations) and chronic diseases (all environmental factors with participation on oral cleft etiology), in the presence of polymorphic variants in genes associated with neutralization of ROS may be associated with the risk of NSCL±P. The aim of this study is to evaluate interactions of single nucleotide polymorphisms (SNPs) in genes associated with neutralization of oxidative stress (superoxide dismutase-SOD and paraoxonase-PON gene families) and its effects (oxaguanine glycosylase 1-OGG1) with common maternal exposures in the risk of NSCL±P. This study will include, at least, 500 trios (two living biological parents and one child affected with NSCL±P) obtained from five Brazilian reference Centers for orofacial cleft treatment located in Minas Gerais (Centro de Reabilitação de Anomalias Craniofaciais da Universidade de Alfenas, Alfenas), Bahia (Centrinho do Hospital Santo Antonio das Obras Assistenciais Irmã Dulce, Salvador), Paraíba (Hospital Universitário Alcides Carneiro, Universidade Federal da Paraíba, João Pessoa), Paraná (Associação de Portadores de Fissura Lábio-Palatal, Cascavel) e Pará (Hospital Ophir Loyola, Belém). Samples will be genotyped using TaqMan 52-exonuclease allelic discrimination assay and subjected to association tests including allelic (aTDT) and genotypic (gTDT) transmission disequilibrium test and gene-environment (GxE) interactions. This study may contribute for the understanding of the etiologic factors related to NSCL±P pathogenesis, as well as reveal the environment and genetics factors of risk for NSCL±P in the Brazilian population. (AU)
Articles published in Agência FAPESP Newsletter about the research grant:
MACHADO, RENATO ASSIS;
RIBEIRO PARANAIBA, LIVIA MARIS;
MELO-FILHO, MARIO RODRIGUES;
DE SOUZA, THAYS TEIXEIRA;
SAYED PICCIANI, BRUNA LAVINAS;
SILVA-JUNIOR, GERALDO OLIVEIRA;
CANTISANO, MARILIA HEFFER;
ROCHA, BRENO AMARAL;
PIRES, FABIO RAMOA;
COLETTA, RICARDO D.
Variable expressivity and novel PTEN mutations in Cowden syndrome.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY,
Web of Science Citations: 2.