title: Association of seven functional polymorphisms of one-carbon metabolic pathway with total plasma homocysteine levels and susceptibility to Parkinson's disease among South Indians.
abstract: 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 28bp 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 ± 5.1μmol/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.
authors.affiliation: Centre for Biotechnology, Jawaharlal Nehru Technological University, Hyderabad, India.
authors.forename: Nadella
authors.initials: N
authors.lastname: Kumudini
authors.affiliation: Centre for Biotechnology, Jawaharlal Nehru Technological University, Hyderabad, India.
authors.forename: Addepally
authors.initials: A
authors.lastname: Uma
authors.affiliation: School of Chemical & Biotechnology, SASTRA University, Thanjavur, India.
authors.forename: Shaik Mohammad
authors.initials: SM
authors.lastname: Naushad
authors.affiliation: Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India.
authors.forename: Rukmini
authors.initials: R
authors.lastname: Mridula
authors.affiliation: Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India.
authors.forename: Rupam
authors.initials: R
authors.lastname: Borgohain
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, India. Electronic address: vijaykutala@gmail.com.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
mesh_terms: D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D007194:India; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D012737:Sex Factors
chemical_list: D006710:Homocysteine
keywords: Homocysteine; One-carbon metabolism; Parkinson’ disease; Polymorphism