Association of seven functional polymorphisms of one-carbon metabolic pathway with total plasma homocysteine levels and susceptibility to Parkinson's disease among South Indians

• PD cases exhibited hyperhomocysteinemia.
• MTRR 66 A>G showed independent association with PD risk.
• Cytosolic SHMT 1420 C>T showed inverse association with PD.
• MTRR 66 A>G, cSHMT 1420 C>T and MTHFR 677 C>T interactions influence PD risk.
• Genotype effects were attributed to changes in homocysteine.

This study from South India was performed to ascertain the impact of seven functional polymorphisms of one-carbon metabolic pathway on total plasma homocysteine levels and susceptibility to PD. A total of 151 cases of Parkinson's disease and 416 healthy controls were analyzed for fasting plasma homocysteine levels by reverse phase HPLC. PCR-RFLP approaches were used to analyze glutamate carboxypeptidase II (GCPII) 1561 C>T, reduced folate carrier 1 (RFC1) 80 G>A, cytosolic serine hydroxymethyl transferase (cSHMT) 1420 C>T, methylene tetrahydrofolate reductase (MTHFR) 677 C>T, methionine synthase (MTR) 2756 A>G and methionine synthase reductase (MTRR) 66 A>G polymorphisms. PCR-AFLP was used for the analysis of thymidylate synthase (TYMS) 5′-UTR 28 bp tandem repeat. PD cases exhibited elevated plasma homocysteine levels compared to controls (men: 28.8 ± 6.9 vs. 16.4 ± 8.8 μmol/L; women: 25.4 ± 5.3 vs. 11.2 ± 5.1 μmol/L). Homocysteine levels showed positive correlation with male gender (r = 0.39, p < 0.0001) and MTRR 66 A>G (r = 0.31, p < 0.0001) whereas an inverse correlation was observed with cSHMT 1420 C>T polymorphism. MTRR 66 A>G polymorphism showed independent risk for PD (OR: 3.42, 95% CI: 2.35–4.98) whereas cSHMT 1420 C>T conferred protection against PD (OR: 0.11, 95% CI: 0.07–0.17). Multifactor dimensionality reduction analysis showed synergistic interactions between MTHFR 677 C>T and MTRR 66 A>G, whereas cSHMT 1420 C>T exhibited counteracting interactions in altering susceptibility to PD. To conclude, PD cases exhibited hyperhomocysteinemia and MTRR 66 A>G and cSHMT 1420 C>T gene variants were shown to modulate PD risk by altering the homocysteine levels.