Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract.
Alzheimer's disease (AD) and age-related cataract, disorders characterized by protein aggregation causing late-onset disease, both involve oxidative stress. We hypothesize that common variants of NFE2L2 and KEAP1, the genes encoding the main regulators of the Nrf2 system, an important defence system against oxidative stress, may influence risk of AD and/or age-related cataract. This case-control study combines an AD material (725 cases and 845 controls), and a cataract material (489 cases and 182 controls). Genetic variation in NFE2L2 and KEAP1 was tagged by eight and three tag single nucleotide polymorphisms (SNPs), respectively. Single SNPs and haplotypes were analyzed for associations with disease risk, age parameters, MMSE and AD cerebrospinal fluid biomarkers. NFE2L2 and KEAP1 were not associated with risk of AD or cataract. However, one haplotype allele of NFE2L2 was associated with 2 years earlier age at AD onset (p(c)=0.013) and 4 years earlier age at surgery for posterior subcapsular cataract (p(c)=0.019). Another haplotype of NFE2L2 was associated with 4 years later age at surgery for cortical cataract (p(c)=0.009). Our findings do not support NFE2L2 or KEAP1 as susceptibility genes for AD or cataract. However, common variants of the NFE2L2 gene may affect disease progression, potentially altering clinically recognized disease onset.
von Otter
Malin
M
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Blå Stråket 15, The Sahlgrenska Academy at University of Gothenburg, S-413 45 Gothenburg, Sweden. malin.vonotter@gu.se
Landgren
Sara
S
Nilsson
Staffan
S
Zetterberg
Madeleine
M
Celojevic
Dragana
D
Bergström
Petra
P
Minthon
Lennart
L
Bogdanovic
Nenad
N
Andreasen
Niels
N
Gustafson
Deborah R
DR
Skoog
Ingmar
I
Wallin
Anders
A
Tasa
Gunnar
G
Blennow
Kaj
K
Nilsson
Michael
M
Hammarsten
Ola
O
Zetterberg
Henrik
H
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D002386:Cataract / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D008875:Middle Aged; D012306:Risk
D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1