« Back

Study of Genetic Susceptibility to Neural Tube Defects and its Association with Maternal Vitamin B12 and Folate Status (Neural Tube Defect Study)

Funded By:  Department of Biotechnology, Government of India
Month & Year of Commencement:  January 2007 December 2009
Current Status: Completed

Principal Investigator:  Dr.Koumudi Godbole, KEM Hospital & Research Centre,Pune,India
Dr.C.S.Yajnik, Director ,Diabetes Unit, KEM Hospital and Research Centre,Pune,India
Dr. G. R. Chandak, Medical Geneticist ,Center for Cellular and Molecular Biology, Andhra Pradesh ,India
Dr. S. Suresh, Founder , Fetal Care Research Foundation
Dr. Jayesh Sheth,Honorary Director, Foundation for Research in Genetics & Endocrinology

» Background
» Objectives
» Methodology and Design
» Results

Maternal nutritional status including low vitamin B 12 and/or folate levels (in turn resulting in increased homocysteine levels) and polymorphisms in the genes involved in one-carbon metabolism are associated with increased risk of NTDs in their offspring, in the Indian population. Polymorphisms in the genes involved in one- carbon metabolism of the fetus will influence this relationship and therefore the risk of being affected with NTDs.
Neural tube defects (NTDs) are among the most common severe congenital malformations, representing a long-term public health burden in India. A deranged one-carbon metabolism and genes regulating this metabolism have been linked to NTDs. Vitamin B(12) deficiency is reported to be more prevalent than folate deficiency in the Indian population. We investigated the role of maternal nutritional and genetic markers related to one-carbon metabolism in the etiology of NTDs.


To study association between

  • Maternal deficiencies of vitamin B12 and folate (and increased homocysteine levels) and NTDs in their offspring
  • Polymorphisms in one-carbon metabolism genes including MTHFR, MTR, MTRR, TYMS, BHMT and TC-II, (singly or in combination) and increased homocysteine levels in mothers
  • Polymorphisms in the abovementioned genes (singly or in combination) in the couple with occurrence of NTDs in their offspring
  • Polymorphisms in the abovementioned genes (singly or in combination), in the fetus with the occurrence of NTDs

Methodology and Design

We conducted a multicenter case-control study to compare plasma folate, vitamin B(12) , homocysteine and holo-transcobalamin levels, and polymorphisms in methylenetetrahydrofolate reductase (MTHFR, 677C>T, 1298A>C, 1781G>A and 236+724A>G) and transcobalamin (TCN2, 776C>G) genes, in 318 women with NTD-affected offspring (cases) and 702 women with apparently healthy offspring (controls). The samples were collected at diagnosis in cases and at delivery in controls.

We observed a significant association of high maternal plasma homocysteine concentrations with NTDs in the offspring (p = 0.026). There was no association of maternal folate or B(12) levels with NTDs (p > 0.05) but low maternal holo-transcobalamin predicted strong risk of NTDs in the offspring (p = 0.003). The commonly associated maternal polymorphism 677C>T in the MTHFR gene did not predict risk of NTDs in the offspring (p > 0.05) and 1298A>C and 1781G>A polymorphisms in MTHFR were protective (p = 0.024 and 0.0004 respectively). Maternal 776C>G polymorphism in TCN2 was strongly predictive of NTD in the offspring (p = 0.006).
Our study has demonstrated a possible role for maternal B(12) deficiency in the etiology of NTDs in India over and above the well-established role of folate deficiency.