Abstract
INTRODUCTION
Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer’s disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear.
METHODS
We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269).
RESULTS
CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10−5) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 × 10−7). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10−6) and CSF p-tau levels (P = 4.38 × 10−9).
DISCUSSION
These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels.
Highlights
Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau.
The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category.
GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer’s disease than controls.
rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia.
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This post is Copyright: Daniel J. Panyard,
Lianne M. Reus,
Muhammad Ali,
Jihua Liu,
Yuetiva K. Deming,
Qiongshi Lu,
Gwendlyn Kollmorgen,
Margherita Carboni,
Norbert Wild,
Pieter J. Visser,
Lars Bertram,
Henrik Zetterberg,
Kaj Blennow,
Johan Gobom,
Dan Western,
Yun Ju Sung,
Cynthia M. Carlsson,
Sterling C. Johnson,
Sanjay Asthana,
Carlos Cruchaga,
Betty M. Tijms,
Corinne D. Engelman,
Michael P. Snyder | May 30, 2024