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2015 ; 12
(ä): 227
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Epistasis analysis links immune cascades and cerebral amyloidosis
#MMPMID26626881
Benedet AL
; Labbe A
; Lemay P
; Zimmer ER
; Pascoal TA
; Leuzy A
; Mathotaarachchi S
; Mohades S
; Shin M
; Dionne-Laporte A
; Beaudry T
; Picard C
; Gauthier S
; Poirier J
; Rouleau G
; Rosa-Neto P
J Neuroinflammation
2015[Dec]; 12
(ä): 227
PMID26626881
show ga
BACKGROUND: Several lines of evidence suggest the involvement of
neuroinflammatory changes in Alzheimer's disease (AD) pathophysiology such as
amyloidosis and neurodegeneration. In fact, genome-wide association studies
(GWAS) have shown a link between genes involved in neuroinflammation and AD. In
order to further investigate whether interactions between candidate genetic
variances coding for neuroinflammatory molecules are associated with brain
amyloid ? (A?) fibrillary accumulation, we conducted an epistasis analysis on a
pool of genes associated with molecular mediators of inflammation. METHODS:
[(18)F]Florbetapir positron emission tomography (PET) imaging was employed to
assess brain A? levels in 417 participants from ADNI-GO/2 and posteriorly 174
from ADNI-1. IL-1?, IL4, IL6, IL6r, IL10, IL12, IL18, C5, and C9 genes were
chosen based on previous studies conducted in AD patients. Using the
[(18)F]florbetapir standardized uptake value ratio (SUVR) as a quantitative
measure of fibrillary A?, epistasis analyses were performed between two sets of
markers of immune-related genes using gender, diagnosis, and apolipoprotein E
(APOE) as covariates. Voxel-based analyses were also conducted. The results were
corrected for multiple comparison tests. Cerebrospinal fluid (CSF)
A?1-42/phosphorylated tau (p-tau) ratio concentrations were used to confirm such
associations. RESULTS: Epistasis analysis unveiled two significant single
nucleotide polymorphism (SNP)-SNP interactions (false discovery rate (FDR)
threshold 0.1), both interactions between C9 gene (rs261752) and IL6r gene
(rs4240872, rs7514452). In a combined sample, the interactions were confirmed
(p???10-5) and associated with amyloid accumulation within cognitively normal and
AD spectrum groups. Voxel-based analysis corroborated initial findings. CSF
biomarker (A?1-42/p-tau) confirmed the genetic interaction. Additionally,
rs4240872 and rs7514452 SNPs were shown to be associated with CSF and plasma
concentrations of IL6r protein. CONCLUSIONS: Certain allele combinations
involving IL6r and C9 genes are associated with A? burden in the brain.
Hypothesis-driven search for epistasis is a valuable strategy for investigating
imaging endophenotypes in complex neurodegenerative diseases.
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