title: Homocysteine metabolism and the associations of global DNA methylation with selected gene polymorphisms and nutritional factors in patients with dementia.
abstract: Epigenetics (particularly DNA methylation) together with environmental and genetic factors, are key to understanding the pathogenesis of many diseases including dementia. Disturbances in DNA methylation have already been implicated in dementia. Homocysteine metabolism, with folate and vitamin B12 as essential cofactors, is integral to methylation processes. We evaluated in a case-control study the association of global DNA methylation, homocysteine, folate and vitamin B12 status with dementia. Selected polymorphisms of genes previously associated with dementia development and the influence of various factors on DNA methylation were also investigated. 102 patients with dementia (53 with Alzheimer's disease, 17 with vascular dementia and 32 with mixed dementia) were recruited. The non-demented controls consisted of 45 age-matched subjects without dementia and 47 individuals with mild cognitive impairment. Global DNA methylation was determined by Imprint Methylated DNA Quantification Kit MDQ1 (Sigma-Aldrich, Gillingham, Dorset, UK). Plasma homocysteine, serum folate and vitamin B12 were determined by chemiluminescence. Plasma and erythrocyte 5-methyltetrahydrofolate and plasma methylmalonic acid (markers of folate and vitamin B12 status) were measured by HPLC. APOE, PON1 p.Q192R, MTHFR 677C>T (c.665C>T) and IL1B-511C>T polymorphisms were identified using PCR-RFLP methods. Patients with dementia had significantly higher concentrations of homocysteine (p=0.012) and methylmalonic acid (p=0.016) and lower folate (p=0.002) and plasma 5-methyltetrahydrofolate (p=0.005) than non-demented subjects. There was no difference in DNA methylation between patients and controls. A non-significant tendency to higher DNA methylation in patients with vascular dementia (p=0.061) was observed. Multivariate regression analysis of all recruited individuals demonstrated a significant positive association between DNA methylation and folate (p=0.013), creatinine (p=0.003) concentrations and IL1B-511T (p=0.002) and PON1 192R (p=0.049) alleles and negative association with fasting glucose (p=0.004). The biochemical results showed significantly lower folate and vitamin B12 status in demented patients than controls. Global DNA methylation was associated with markers of folate status, creatinine, glucose and PON1 and IL1B polymorphisms.
authors.affiliation: Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland. Electronic address: makaruk@ipin.edu.pl.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Bednarska-Makaruk
authors.affiliation: First Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Ałła
authors.initials: A
authors.lastname: Graban
authors.affiliation: The Nutristasis Unit and the Molecular Haemostasis and Thrombosis Laboratory, Viapath, St. Thomas' Hospital, London, UK.
authors.forename: Agata
authors.initials: A
authors.lastname: Sobczyńska-Malefora
authors.affiliation: The Nutristasis Unit and the Molecular Haemostasis and Thrombosis Laboratory, Viapath, St. Thomas' Hospital, London, UK.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Harrington
authors.affiliation: The Nutristasis Unit and the Molecular Haemostasis and Thrombosis Laboratory, Viapath, St. Thomas' Hospital, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Mitchell
authors.affiliation: The Nutristasis Unit and the Molecular Haemostasis and Thrombosis Laboratory, Viapath, St. Thomas' Hospital, London, UK.
authors.forename: Kieran
authors.initials: K
authors.lastname: Voong
authors.affiliation: The Nutristasis Unit and the Molecular Haemostasis and Thrombosis Laboratory, Viapath, St. Thomas' Hospital, London, UK.
authors.forename: Letian
authors.initials: L
authors.lastname: Dai
authors.affiliation: First Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Wanda
authors.initials: W
authors.lastname: Łojkowska
authors.affiliation: First Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Bochyńska
authors.affiliation: First Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Danuta
authors.initials: D
authors.lastname: Ryglewicz
authors.affiliation: Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wiśniewska
authors.affiliation: Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Wehr
mesh_terms: D000368:Aged; D043303:Aryldialkylphosphatase / Q000235:genetics; D016022:Case-Control Studies; D019175:DNA Methylation; D003704:Dementia / Q000097:blood* / Q000235:genetics*; D005260:Female; D005492:Folic Acid / Q000097:blood*; D005494:Folic Acid Deficiency / Q000097:blood; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011044:Poland; D012150:Polymorphism, Restriction Fragment Length; D013763:Tetrahydrofolates / Q000097:blood; D014805:Vitamin B 12 / Q000097:blood*
chemical_list: C508585:IL1B protein, human; D053583:Interleukin-1beta; D013763:Tetrahydrofolates; D006710:Homocysteine; D005492:Folic Acid; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D014805:Vitamin B 12; C005984:5-methyltetrahydrofolate
keywords: Dementia; Folate; Global DNA methylation; Homocysteine; Plasma 5-methyltetrahydrofolate; Plasma methylmalonic acid; Vitamin B12