DNA (cytosine-5)-methyltransferase 3B ( DNMT 3B ) polymorphism and risk of Down syndrome offspring

Abstract

Down syndrome (DS) is the most common form of human genetic mental retardation. Several polymorphisms in genes coding folic acid cycle enzymes have been associated to the risk of bearing a DS child; however, the results are controversial. S-adenosyl-l-methionine (SAM) is an important intermediate of folic acid pathway and acts as methyl donor and substrate for DNA (cytosine-5)-methyltransferase 3B ( - EC 2.1.1.37) methylation processes during embryogenesis. Recent studies suggest that a functional polymorphism of in maternal genotype may be associated with a decreased risk of having a DS child. We herein investigate the association of this polymorphism with the occurrence of DS in a Brazilian population. We have genotyped 111 mothers of DS infants (MDS) and 212 control mothers (CM) through PCR-RFLP. The observed genotypic frequencies were CC = 0.22; CT = 0.49 and TT = 0.29 in CM, and CC = 0.30; CT = 0.52 and TT = 0.18 in MDS. Allelic frequencies were C = 0.47 and T = 0.53 in CM and C = 0.56 and T = 0.44 in MDS. No deviation of HWE was observed, and both rs2424913 genotype (χ2 = 4.53; DF = 1; P = 0.03) and allelic (χ2 = 4.90; DF = 1; P = 0.03) frequencies show significant differences between MDS and CM. The presence of the mutant allele decreases 30% the risk of bearing a DS child (OR = 0.69; 95% CI: 0.50-0.96; P = 0.03), and the risk is diminished up to 45% in association with the homozygous genotype (OR = 0.54; 95% CI: 0.31-0.96; = 0.04). Our results suggest that women harboring the single nucleotide polymorphism rs2424913 have a decreased risk of a DS pregnancy, and further studies are necessary to confirm this protective effect.

Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

“…Indeed, the contribution of DNMT3B polymorphisms to human disease has been investigated in many other diseases than cancer. For example, increasing evidence suggests that the DNMT3B -149C>T polymorphism, either alone or in haplotype combination with other non-coding DNMT3B polymorphisms, contributes to the maternal risk for having a child with Down syndrome [47,48,49], and has been associated with an increased risk of prematurity [30], with childhood immune thrombocytopenia [50,51] and autoimmune thyroid disease [52]. The association of the DNMT3B -149C>T polymorphism with neurological and neurodegenerative diseases, either alone or in haplotype combination, is still controversial [53,54,55,56].…”