Cognitive impairment viz-a-viz genetic and biochemical variations in one carbon metabolic pathway: A population-based study from North India

Abstract

Disturbances in the one‑carbon metabolic pathway (OCMP) have been reported to be associated with cognitive impairment (CI). The study aimed to examine the association of MTR A2756G, MTRR A66G, and CBS 844ins68 polymorphisms present at critical steps of OCMP with CI independently and in light of vitamin B12, folate deficiencies, and hyperhomocysteinemia. The study also aimed to understand gene-gene interactions among selected markers linked with OCMP in CI using multifactor dimensionality reduction (MDR) analysis. A total of 808 individuals, aged 30–70 years of either sex, were recruited from Haryana, North India. Participants were screened for CI using MMSE. Individuals with mild CI were considered as case-1 and moderate/severe CI as case-2. Sociodemographic data were collected using an interview schedule. Biochemical and genetic analyses were performed using standard protocols. In the present study, CI was not found to be associated with MTR A2756G or CBS 844ins68 polymorphisms. AG and AA+AG genotypes of MTRR A66G polymorphism, with GG as the reference genotype, were found to pose 1.97 to 2.59-folds significantly increased risk for case-1 and case-2 CI. These associations, however, lost statistical significance for normal levels of vitamin B12 and homocysteine. In MDR analysis, two-loci models with MTHFR+MTRR for case-1 and MTR+MTRR for case-2 were found to have the highest TA% and CVC. Overall, MTRR A66G polymorphism appears to be a risk factor for CI in the studied population. Vitamin B12 seems to modulate the association of CI with MTRR A66G. MDR analysis suggests the involvement methionine cycle of OCMP in CI.