alexa Association of Genetic Polymorphisms in Genes Involved
ISSN: 1747-0862

Journal of Molecular and Genetic Medicine
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Research Article

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

Amit Rai1*, Sushil Kumar Jaiswal1, Krishna Kishore Sukla2, Shravan Kumar Mishra5, Anjali Rani Lakhotia4 and Ashok Kumar3

1Centre for Genetic Disorders, Banaras Hindu University, Varanasi, Uttar Pradesh, India

2Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh, India

3Department of Pediatrics, Banaras Hindu University, Varanasi, Uttar Pradesh, India

4Department of Gynecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

5Department of Biotechnology, Veer Bahadur Singh Poorvanchal University, Jaunpur, Uttar Pradesh, India

Corresponding Author:
Amit Rai
Centre for Genetic Disorders
Banaras Hindu University
Varanasi, Uttar Pradesh, India
Tel: 09670428502
E-mail: [email protected]

Received date: December 21, 2015; Accepted date: April 05, 2016; Published date: April 10, 2016

Citation: Rai A, Jaiswal SK, Sukla KK, Mishra SK, Lakhotia AR, et al. (2016) 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. J Mol Genet Med 10:207. doi:10.4172/1747-0862.1000207

Copyright: © 2016 Rai A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



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.


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