A GSTM3 polymorphism associated with an etiopathogenetic mechanism in Alzheimer disease.
Brain-specific glutathione S-transferase Mu 3 (GSTM3) colocalizes with amyloid-beta plaques in Alzheimer's disease (AD). A functional polymorphism rs7483 in GSTM3 may contribute to the decrease in GSTM3 expression in AD. The association of the rs7483 SNP with late-onset AD and mild cognitive impairment (MCI) was evaluated and the impact of a SNP background on gene expression was analyzed in blood mononuclear cells (BMC). The allelic association of the GSTM3 allele with AD was significant in women and in APOEvarepsilon4-negative stratum. A significant association was also found in both MCI and AD subjects with AD family history. GSTM3 transcript levels in BMC were lower in AD than in normal elderly controls, and the presence of the risk allele was associated with further mRNA reduction. Diminished GSTM3 mRNA levels correlated with decreased minichromosome maintenance deficient 3 (MCM3) mRNA levels in a diagnostic and SNP-dependent fashion. Reduced antioxidant defense and genome maintenance associated with the GSTM3 polymorphism suggest a common hub of regulatory networks which, when impaired, may lead to AD.
Maes
Olivier C
OC
Gheens Center on Aging, Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
Schipper
Hyman M
HM
Chong
George
G
Chertkow
Howard M
HM
Wang
Eugenia
E
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D000975:Antioxidants / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism
D000975:Antioxidants; D005819:Genetic Markers; D012333:RNA, Messenger; C483009:GSTM3 protein, human; D005982:Glutathione Transferase