Impacto de polimorfismos da região 3’ não traduzida do gene MTHFR e de polimorfismo do microRNA hsa-mir-149 no risco materno para a síndrome de Down

Abstract

Down syndrome (DS) is a genetic condition characterized by the presence of three copies of chromosome 21. In most cases, the extra chromosome 21 is of maternal origin due to errors in chromosomal segregation during meiosis. Advanced maternal age at conception is the main risk factor for DS. However, studies suggest that alterations in genes involved in folate metabolism, such as MTHFR (Methylenetetrahydrofolate redutase), may increase the risk for DS regardless maternal age, due to DNA hypomethylation and, consequently, abnormal chromosomal segregation. MTHFR expression is regulated by microRNAs (miRNAs), and polymorphisms in miRNAs may also modify this metabolism with consequences on chromosome disjunction. Objective: To assess whether the presence of MTHFR rs4846048 and rs4846049 and precursor hsa-mir-149rs2292832 polymorphisms is associated with maternal risk for the occurrence of offspring with DS. Casuistic and Methods: In the present study, 167 mothers of individuals with free trisomy 21, and 296 women without previous history of abortion, mothers of individuals without syndrome and without malformation were examined. Polymorphisms were evaluated by real-time polymerase chain reaction (PCR) using the TaqMan® SNP Genotyping Assays (AppliedBiosystems®) commercial assays. Multiple logistic regression analyzes were performed for the polymorphisms in the dominant and recessive models using the Minitab v. 16.0 program. Genotypic combination analysis was performed using the Fisher exact test in the dominant model. Analysis of the haplotypes of the MTHFR polymorphisms rs4846048 and rs4846049 was performed using the Haploview v. 5.0 program. Maternal age equal or greater than to 35 years old as a risk factor for DS was analyzed using binary logistic regression. Results: Maternal age equal to 35 years old or greater was considered a risk factor for offspring with DS (P <0.0001; OR = 9.38; 95% CI = 5.70-15.45). The maternal polymorphisms rs4846048 and rs4846049 of the MTHFR gene were not associated with the occurrence of offspring with DS, regardless of maternal age. Analyzes of combined genotypes of the MTHFR rs4846048, MTHFR rs4846049 and hsa-mir-149 rs2292832 polymorphisms, as well as the MTHFR gene haplotypes, also showed no association with maternal risk for DS. An increased risk for the occurrence of offspring with DS was observed for women under 35 years old at the time of conception and carriers of the TT genotype of hsa-mir-149 rs2292832 polymorphism (OR = 2.02, 95% CI = 1.06 - 3.83). Conclusion: There is no evidence of association between maternal polymorphisms MTHFR rs4846049 and rs4846048 and risk for the occurrence of SD offspring. However, an increased maternal risk for DS is observed in women with maternal age under 35 years old and carriers of the TT genotype of the hsa-mir-149 rs2292832 polymorphism.