Abstract
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 G>A (affecting synthesis of 5,10-MTHF), MTHFR 677 C>T (affecting methylation), TYMS 5'UTR 28 bp repeat polymorphism and TYMS 3'UTR 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 C>T in a co-dominant model (p=0.0428) and dominant model (0.0194) as well as TYMS 5'UTR 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 5' and 3' UTR regions polymorphism in LD analysis. Transmission disequilibrium test (TDT) analysis revealed a consistent trend of preferential allele's 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.
Highlights
Chromosomal basis of Down syndrome (DS) due to abnormal segregation of chromosome 21 has been known for many years
James et al hypothesized that maternal genetic polymorphism (MTHFR 677T) may cause hypomethylation in the pericentromeric region of the chromosome, thereby leading to nondisjunction of chromosome 21 and further predicted that impaired folate metabolism might act as a maternal risk factor for having a DS child [2]
In a very recent study on Eastern Indian Cohort we have shown that Methylenetetrahydrofolate reductase (MTHFR) 677T is an associated genetic risk factor and gene-gene interactions have a significant role in genetic predisposition in DS mothers [11]
Summary
Chromosomal basis of Down syndrome (DS) due to abnormal segregation of chromosome 21 has been known for many years. The mechanism behind mal-segregation of the chromosome is still unknown. Advanced maternal age during conception and reduced recombination are the only well-established known associated factors for mal-segregation of chromosome 21 [1]. James et al hypothesized that maternal genetic polymorphism (MTHFR 677T) may cause hypomethylation in the pericentromeric region of the chromosome, thereby leading to nondisjunction of chromosome 21 and further predicted that impaired folate metabolism might act as a maternal risk factor for having a DS child [2]. Several comparable studies done on populations from different regions of the world have yielded conflicting results; in developing countries, MTHFR 677T was a significant genetic predisposing factor, while in studies from Europe and the Americas it was not an associated risk factor [3]. Studies on other folatehomocysteine pathway genes [4,5,6] have shown a much heterogeneity, like that of MTHFR 677T in association with Down syndrome
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