DNMT3B promoter polymorphisms and maternal risk of birth of a child with Down syndrome

Are DNMT3B promoter polymorphisms among maternal risk factors for the birth of a child with Down syndrome (DS)? Present results suggest that combinations of functional DNMT3B promoter polymorphisms might modulate maternal risk of birth of a child with DS. The DNMT3B gene codes for DNA methyltransferase 3b (DNMT3b), a protein required for genome-wide de novo methylation, for the establishment of DNA methylation patterns during development and for regulating the histone code and DNA methylation at centromeric regions. Two common functional DNMT3B promoter polymorphisms, namely 149 C T (rs2424913) and 579 G T (rs1569686), have been extensively investigated in cancer genetic association studies but less is known about their role in non-cancer diseases. Early in 1999, it was supposed that impaired DNA methylation of pericentromeric regions might represent a maternal risk factor for having a baby with DS. We aimed to investigate DNMT3B 149 C T and 579 G T polymorphisms as maternal risk factors for the birth of a child with DS. The study was performed on DNA samples from 172 mothers of DS individuals (135 aged 35 years when they conceived) and 157 age-matched mothers of unaffected individuals. Genotyping was performed by means of the PCR-RFLP technique. The DNMT3B 579T allele [odds ratio (OR) 0.68; 95 confidence interval (CI) 0.480.94, P 0.02], the DNMT3B 579 GT genotype (OR 0.55; 95 CI 0.350.87 , P 0.01) and the combined DNMT3B 579 GT TT genotype (OR 0.55; 95 CI 0.360.86 , P 0.008) were associated with reduced risk of birth of a child with DS. A joint effect of the two polymorphisms was observed and the combined 579 GT/149 CC genotype resulted in decreased DS risk (OR 0.22; 95 CI 0.080.64, P 0.003). The effect remained statistically significant after Bonferronis correction for multiple comparisons. Similar results were obtained when the analysis was restricted to women who conceived a DS child before 35 years of age. To the best of our knowledge, this is the first genetic association study aimed at evaluating DNMT3B polymorphisms as maternal risk factors for DS. Replication of the findings in other populations is required. If confirmed in subsequent studies, DNMT3B promoter polymorphisms might be additional markers to be taken into account when evaluating the contribution of one-carbon (folate) metabolism to the maternal risk of birth of a child with DS. None of the authors has any competing interest. This work was partially supported by the Italian Ministry of Health and o5 per mille' funding.