Association of Genetic Polymorphisms in Genes Involved at the Branch Point of Nucleotide Biosynthesis and Remethylation with Down Syndrome Birth Risk: A Case-Control Study

DNA methylation and nucleic acid biosynthesis are two crucial phenomena for normal chromosomes segregation. From our earlier studies, MTHFR 677T individually and in combination with other gene polymorphisms, micronutrient deficiency and hyperhomocysteinemia was shown to be associated with risk in Down syndrome (DS) mothers. Remethylation and nucleic acid biosynthesis pathways are dependent on the activity of Methylenetetrahydrofolate reductase (MTHFR) and Thymidylate synthase (TYMS) respectively, competing for common substrate molecule 5,10-methelenetetrahydrofolate (5,10-MTHF). Role of MTHFD1 1958 Gu003eA (affecting synthesis of 5,10-MTHF), MTHFR 677 Cu003eT (affecting methylation), TYMS 5u0027UTR 28 bp repeat polymorphism and TYMS 3u0027UTR 6bp deletion polymorphism (affecting nucleic acid biosynthesis) in a cohort of 200 case mothers and 187 control mothers (also 146 case triads: mother, father, and child) were studied. We observed a significant association of MTHFR 677 Cu003eT in a co-dominant model (p=0.0428) and dominant model (0.0194) as well as TYMS 5u0027UTR 28 bp repeat polymorphism in a recessive model (p=0.0005) and dominant model (0.0161). Genetic combination analysis revealed a significant additive effect of certain genotypic combinations (especially combination of MTHFR 677T and TYMS 2R alleles with other alleles or genotypes) in increasing risk. Weak linkage disequilibrium (LD) was observed between TYMS 5u0027 and 3u0027 UTR regions polymorphism in LD analysis. Transmission disequilibrium test (TDT) analysis revealed a consistent trend of preferential alleleu0027s transmission from parents. We concluded that genetic interaction of remethylation pathway and the nucleic acid metabolic pathway was significantly associated with risk factors for DS childbirth. However, replication studies are required to validate our observation in the population.