Association of MTHFR and RFC1 gene polymorphism with hyperhomocysteinemia and its modulation by vitamin B12 and folic acid in an Indian population

Abstract

Background/Objectives: Unlike most Western populations, MTHFR 677T is a rare allele and a risk factor for a variety of disorders in India. What kind of nutritional (environmental) and/or genetic factors could contribute to the genetic risk is not known. To assess the incidence of hyperhomocysteinemia and its correlation with the polymorphism in homocysteine (Hcy)-pathway genes and associated cofactors in the native populations of eastern India. Subjects/Methods: Healthy population from four eastern states of India. Genotyping of SNPs, HPLC and chemiluminescencebased assay for homocysteine, vitamin B12 and folic acid.Results: Approximately 30% of the population has hyperhomocysteinemia (415 mmol/lit; hypHcy) with varying frequencies in the four states from where samples were collected (n ¼ 1426). Polymorphisms of MTR and CBS do not affect hypHcy. 677T and 1298C alleles of MTHFR and G80 RFC-1 show association with hypHcy. In contrast, RFC-1 80AA is protective even in presence of 677T MTHFR. Addition of each mutant allele has an additive effect on Hcy level. Vitamin B12 (cofactor in methionine synthesis) clearly modulates the genotypic effect on Hcy level. Although frequency of individuals with low folic acid is B11, 49% of the population is vitamin B12 deficient (o220 pg/lit) and has a significant negative correlation with Hcy. Individuals with optimum vitamin B12 and folic acid generally have low Hcy, even in risk genotypes. Conclusions: One of the plausible reasons for susceptibility of individuals with MTHFR C677T in the studied population to various disorders is the high frequency of hyperhomocysteinemia and vitamin B12 deficiency in the 'healthy population'. Apparently, supplementation of vitamin B 12 to this health-impoverished community may help lessen the risk of several multifactorial disorders.

Low Birthweight (LBW) and Neonatal Hyperbilirubinemia (NNH) in an Indian Cohort: Association of Homocysteine, Its Metabolic Pathway Genes and Micronutrients as Risk Factors

“…Studies also show that exogenous supplementation of these nutrients to mothers during and prior to pregnancy helps reduce the risk of these disorders in the children [9]. Multiple investigations from different parts of the Indian subcontinent have confirmed, with minor differences, high prevalence of elevated Hcy, deficiency of Vit-B12 and folates along with strong genotype correlation with respect to Hcy levels in the population [10,11,12,13]. Further their association with different disorders has also been demonstrated [11,12]…”

Association of MTHFR, SLC19A1 Genetic Polymorphism, Serum Folate, Vitamin B12 and Hcy Status with Cognitive Functions in Chinese Adults

“…Summers et al reported that MTHFR 1298C carriers had a higher plasma Hcy concentration than 1298AA homozygotes after the exclusion of MTHFR 677TT homozygotes in Caucasian premenopausal women rather than African-American [40]. Another cross-sectional study carried out in four eastern states of India observed similar patterns in Healthy population [41]. The inconsistency in regard to the results of these published studies could be attributed to the geographical differences in populations and physiological statuses.…”

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

“…Hyperhomocysteinemia (hypHcy), vitamin-B12 and folate deficiency was significantly higher in the studied cohort of DS mothers. We have also shown from our previous findings that the incidence of hypHcy (30%), Vitamin B12 (50%) and folic acid (11%) deficiency in a healthy population of eastern Indian populace [12].…”