Possible selection of host folate pathway gene polymorphisms in patients with malaria from a malaria endemic region in North East India

Abstract

Background: Recent studies in experimental mice have shown that mild deficiency of methylenetetrahydrofolate reductase (MTHFR) enzyme confers protection against malaria, thus providing an important basis for the hypothesis that MTHFR polymorphism, i.e. C677T, might have been subjected to selection pressure against malaria. The present study was undertaken in a malaria endemic region in North East India to assess whether a similar selection advantage exists for other genes in folate metabolism pathway.

Methods: A total of 401 subjects including 131 symptomatic malaria, 97 asymptomatic malaria and 173 normal healthy controls were analysed for nine polymorphisms (single-nucleotide polymorphisms [SNPs] in eight genes and insertion/deletion in one gene): MTHFR C677T, methionine synthase reductase (MTRR) A66G, glutamate carboxypeptidase II (GCPII) C1561T, cystathionine beta-synthase (CBS) 844ins68, reduced folate carrier-1 (RFC-1) G80A, serine hydroxymethyltransferase (SHMT) C1420T, methionine synthase (MTR) A2756G, MTHFR G1793A (D 919G), glycine N-methyltransferase (GNMT) 1289 by PCR-RFLP technique. Differences in frequencies of genotype distribution of each polymorphic marker between these groups were evaluated.

Results: MTRR A2756G, SHMT C1420T, GCPII C1561T, MTRR A2756G and GNMT C1289T and RFC1 G80A polymorphisms showed significantly different prevalence between different groups analyzed. No significant differences were seen in the distribution of other polymorphisms.

Conclusions: The study gives a clue for the possible selection of specific polymorphisms in the genes involved in the folate metabolism pathway by malaria parasite.

Keywords: Folate metabolism pathway polymorphisms; India; MTHFR; Malaria; Selection.

Figure 1.

Role of different enzymes in folate metabolism pathway. 10F-THF: 10-formyltetrahydrofolate; 5,10, CH-THF: 5,10-methylenetetrahydrofolate; CβS: cystathionine beta-synthase; GNMT: glycine N-methyltransferase; MTHFR: methylenetetrahydrofolate reductase; MTHFRD1: methylenetetrahydrofolate dehydrogenase; MTR: methionine synthase; MTRR: methionine synthase reductase; RFC1: reduced folate carrier-1; TCN: transcobalamin; THF: tetrahydrofolate.