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DNMT3B rs2424913 as a risk factor for congenital heart defects in Down syndrome

Background: Congenital heart defects (CHDs) are the most common type of congenital malformations, present in approximately 40 to 50% of individuals with Down syndrome (DS). The most common CHDs in DS are septal defects. Altered methylation profiles of genes involved in cardiogenesis can result in CHDs in DS. The DNA methylation pattern is established and maintained by DNA methyltransferases (DNMTs). Objective: The aim of this study was to assess the association between single nucleotide polymorphisms (SNPs) of DNMT genes and CHDs in DS individuals. Methods: The study was performed in 249 participants with DS, including 132 DS individuals with CHD (DSCHD+) and 117 DS individuals without CHD (DSCHD-). Genotyping of single nucleotide polymorphisms DNMT1 (rs2228611), DNMT3A (rs1550117), DNMT3B (rs1569686), and DNMT3B (rs2424913) was performed using PCR-RFLP method. Statistical significance was considered at P≤0.05. Results: A statistically significant higher frequency of the DNMT3B rs2424913 CT (χ2=4.64 ; p=0.032) in DSCHD- and rs2424913 TT (χ2=6.82 ; p=0.011) in the DSCHD+ were observed. Additionally, significance risk for CHD under the dominant genetic model (CC+CTvsTT) for DNMT3B rs2424913 was demonstrated (χ 2 =6.82 ; p=0.011). DNMT3B rs2424913 TT genotype, as well as the T allele, had a significantly higher frequency in DS individuals with atrial septal defect (ASD) in comparison to DS individuals with other CHDs (χ 2 =4.97 ; p=0.028 ; χ 2 =5.69 ; p=0.018). Conclusions: Study results suggest that DNMT3B rs2424913 TT genotypes and CC+CTvsTT genetic model, might be a possible predisposing factor for CHDs in DS individuals, particularly in the ones with ASD.

congenital heart defect, DNA methyltransferase, DNA methylation, Down syndrome, single nucleotide polymorphism

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