Genetic analysis of genes involved in amyloid-β degradation and clearance in Alzheimer's disease.
Accumulation of amyloid β-peptide (Aβ) in the brain of Alzheimer's disease (AD) patients has been postulated to reflect defects in Aβ degradation or clearance. Here, we selected 12 genes (MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9) involved in Aβ catabolism on the basis of PubMed-based literature search and elucidated their genetic role in AD among Finnish case-control cohort consisting of total ∼1,300 AD patients and control subjects. Thirty one single nucleotide polymorphisms (SNPs) were selected for genotyping. In a smaller subset of AD patients, cerebrospinal fluid (CSF) levels of Aβ42 (n = 124), total-tau (n = 59), and phospho-tau (n = 54) analyses were performed with respect to SNPs. Moreover, age of onset analyses with respect to the studied SNPs were conducted among the AD patient cohort (n = 642). Association analysis of the liver X receptor α (NR1H3) gene SNPs showed a protective effect for C allele carriers of rs7120118 (OR = 0.70, 95% CI 0.53-0.93), while the total-tau and phospho-tau levels in CSF were decreased in AD patients carrying the C allele. Also, a decrease in the age of onset was observed in AD patients carrying the A allele of rs723744 and the C allele of rs3794884 in transthyretin (TTR) gene. However, after adjusting the p-values for multiple comparisons, these results were not statistically significant, suggesting that genetic variations in MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9 genes do not play major role among the Finnish AD patient cohort.
Institute of Clinical Medicine - Neurology, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
Teemu
T
Natunen
Seppo
S
Helisalmi
Saila
S
Vepsäläinen
Timo
T
Sarajärvi
Leila
L
Antikainen
Petra
P
Mäkinen
Sanna-Kaisa
SK
Herukka
Anne Maria
AM
Koivisto
Annakaisa
A
Haapasalo
Hilkka
H
Soininen
Mikko
M
Hiltunen
D000367:Age Factors; D017668:Age of Onset; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D005387:Finland; D056726:Genetic Association Studies; D006801:Humans; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors / Q000235:genetics; D010446:Peptide Fragments; D020641:Polymorphism, Single Nucleotide; D011228:Prealbumin / Q000134:cerebrospinal fluid / Q000235:genetics; D039781:PubMed / Q000706:statistics & numerical data; D012333:RNA, Messenger / Q000378:metabolism; D016875:tau Proteins
D016229:Amyloid beta-Peptides; D000071518:Liver X Receptors; C000605210:NR1H2 protein, human; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments; D011228:Prealbumin; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42); D016875:tau Proteins