Maternal MTHFR rs1801131 polymorphism modifies the association between maternal prenatal folate levels and developmental delay in the offspring

Abstract

Background: Micronutrient folate is crucial in neural development. Folate metabolism is affected by genomic variation in methylenetetrahydrofolate reductase (MTHRF) gene. We set out to study the effects of prenatal maternal folate levels and genomic variation in the MTHFR on offspring developmental delay (DD), and whether candidate maternal single nucleotide polymorphisms (SNPs) modify the effect of folate on the risk of DD in the offspring. Methods: The mother-child dyads in this study (n1= 456, n2 = 415, n3= 184, n4 = 192) are part of the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) - cohort. Folate levels were measured from the plasma maximum of three times during pregnancy. Maternal MTHFR SNPs (rs1801131, rs1801133, rs1999594) were genotyped with Illumina Global Screening Array. Developmental milestones were assessed by Ages and Stages Questionnaire Third edition (ASQ-3) completed by mothers between the years 2 to 5. Results: Maternal folate levels during pregnancy did not associate with the risk of DD in the offspring. Any C-alleles in the maternal rs1801131 associated with both higher folate levels during pregnancy in the mother and lower risk of DD in the offspring. Moreover, maternal rs1801131 modified the association between the early pregnancy folate levels and the risk of DD in the offspring (p-value for interaction < .05). With low early pregnancy folate levels, the risk of DD in the offspring was lower if mother carried any C-alleles compared to AA genotype. While CC genotype in the rs1801133 associated with higher folate levels during pregnancy in the mother, we found no associations between maternal rs1801133 or rs1999594 and the risk of DD in the offspring. Conclusions: The current findings suggest that C-alleles in the MTHFR SNP rs1801131 may protect early neurodevelopment in the offspring when maternal folate levels during pregnancy are low.