Nutritional Modulation of Gene Function in Disease Susceptibility: Homocysteine-Folate Metabolism Pathway

Abstract

In this paper the interaction of genetic and nutritional variables in the homocysteine (Hcy) metabolic pathway genes and its cofactors have been reviewed to assess their influence on general health. Hcy metabolism leads to the synthesis of 2 amino acids- methionine that gives rise to S-Adenosyl-methionine (SAM), the main methyl donor to cellular biomolecules, and cysteine. Hyperhomocysteinemia (hypHcy) is a potential risk condition for various disorders like Neural Tube Defects (NTD), Congenital Heart Disease (CHD). It is shown how mutations in certain Hcy-pathway genes, especially
MTHFR C677T, become a risk for NTD and CHD and other diseases in one population but not in the other, exemplifying the importance of gene-nutrition interaction in disease manifestation. Deficiency of micronutrients folates and vitamin B12, which are important constituents of the Hcy-pathway, can independently act as strong risk factors for the same diseases. A survey in the eastern part of India records that almost 50% population is deficient in vitamin B12, 11% in folates, and nearly 30% is hyperhomocysteinemic, indicating high disease predisposition. Globally the highest incidence of undernutrition and low birth weight occurs in this region. A high proportion of individuals afflicted with cleft lip±palate, male infertility, recurrent pregnancy failures and the chromosomal disorder, Down syndrome, have MTHFR 677T homozygosity as a risk factor but the extent of risk is modulated depending upon the levels of vitamin B12, folates and Hcy. Thus the genetic disease burden is influenced by the level of micronutrients. It is recommended that supplementation of both folates and vitamin B12 should be considered for prospective mothers during pregnancy.