Association of COMT, MTHFR, and SLC19A1(RFC-1) polymorphisms with homocysteine blood levels and cognitive impairment in Parkinson's disease.
BACKGROUND
Elevated plasma homocysteine (Hcy) concentration is an independent risk factor for cardiovascular disease, and its involvement in endothelial cell dysfunction is well established. However, the role of Hcy and folate in the pathogenesis of Parkinson's disease (PD) remains controversial.


OBJECTIVE
The study was aimed at evaluating the relationships between Hcy, vitamin B12, and folic acid levels in the blood and cognitive status in PD patients with the genetic polymorphisms of MTHFR (rs1801133: C>T-677C>T, rs1801131: A>C-1298A>C), COMT (rs4680: A>G-Val158Met, rs6269: A>G, rs4633: C>T, rs4818: C>G), or SLC19A1 (rs1051266: G>A-80G>A).


METHODS
A total of 502 participants (248 with PD and 254 age-matched and sex-matched controls) were included in the study. The Unified Parkinson's Disease Rating Scale score, Hoehn-Yahr staging, and the Schwab-England scale were used to assess motor abilities and activity during daily life. Complex psychological examination with a battery of tests was used to classify patients into groups with (PDD) and without (nPDD) dementia. Blood samples were examined for Hcy, vitamin B12, and folic acid levels, as well as polymorphisms in genes related to Hcy metabolism, such as COMT, MTHFR, and SLC19A1(RFC-1).


RESULTS
The frequency of homozygous COMT rs4680G and rs4633C allele carriers was significantly decreased in PD patients in comparison with the controls (P=0.015; odds ratio=0.60; 95% confidence interval 0.41-0.90 and P=0.020; odds ratio=0.619; 95% confidence interval 0.42-0.92, respectively). No significant differences in the distribution of MTHFR 677C>T, 1298A>C, and SLC19A1 80G>A alleles and genotypes between PD patients and the controls were found. Hcy levels were significantly increased in PD patients (18±7.8 μmol/l) as compared with the controls (14.0±9.6 μmol/l, P=10(-8)) and were significantly associated with the MTHFR 677C>T polymorphism both in PD patients and controls, in which T allele carriers were characterized by markedly elevated Hcy plasma concentrations. No association was observed between Hcy plasma level and COMT and SLC19A polymorphisms. The results of multivariate logistic regression analysis revealed age (P=0.0003) and Hcy plasma levels (P=0.07) as independent risk factors predisposing individuals to PD dementia. The studied polymorphisms were not associated with cognitive status in PD patients.


CONCLUSIONS
The genetic factors studied were not associated with cognitive status in PD patients. Only age and Hcy plasma levels were found to be independent risk factors predisposing individuals to PD dementia. However, COMT: rs4680: A>G and rs4633: C>T polymorphisms were found to significantly affect PD risk, and the MTHFR 677C>T polymorphism helped determine plasma Hcy concentrations.
Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, Poland. monika-bialecka@post.pl
Monika
M
Białecka
Mateusz
M
Kurzawski
Anna
A
Roszmann
Piotr
P
Robowski
Emilia J
EJ
Sitek
Krystyna
K
Honczarenko
Agnieszka
A
Gorzkowska
Sławomir
S
Budrewicz
Monika
M
Mak
Monika
M
Jarosz
Monika
M
Gołąb-Janowska
Ewa
E
Koziorowska-Gawron
Marek
M
Droździk
Jarosław
J
Sławek
D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003072:Cognition Disorders / Q000235:genetics*; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006710:Homocysteine / Q000097:blood* / Q000235:genetics; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D010300:Parkinson Disease / Q000097:blood / Q000235:genetics* / Q000523:psychology; D011110:Polymorphism, Genetic; D058978:Reduced Folate Carrier Protein / Q000235:genetics*; D014805:Vitamin B 12 / Q000097:blood / Q000235:genetics
D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D006710:Homocysteine; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002394:Catechol O-Methyltransferase; D014805:Vitamin B 12