Polymorphisms of folate metabolism regulators increase risk of meiosis II nondisjunction of chromosome 21 in oocyte

We have tested maternal polymorphic variants MTR A2756G (rs1805087), MTRR A66G (rs1801394), MTHFR C677T (rs1801133) and MTHFR A1298C (rs1801131) for their association with meiotic errors in oocyte and Down syndrome birth among 730 controls and 1019 case mothers having Down syndrome child from Bengali speaking population of India. We demonstrated significant association of MTR A2756G (rs1805087), MTRR A66G (rs1801394), MTHFR A1298C (rs1801131), but not MTHFR C677T (rs1801133) variants with maternal meiosis II nondisjunction in maternal age independent manner. Moreover, the mutant genotypes of two tested loci when co-occurred exhibited synergistic effect and increase the risk of Down syndrome birth many folds. In silico analyses predicted the probable damages of the transcripts or proteins from respective genes owing to said polymorphisms among the women. These findings from the largest sample population tested ever bring us a significant step closer towards understanding the relation between folate metabolism, meiotic error and Down syndrome birth.