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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Epistasis analysis links immune cascades and cerebral amyloidosis

Authors: Andréa L. Benedet, Aurélie Labbe, Philippe Lemay, Eduardo R. Zimmer, Tharick A. Pascoal, Antoine Leuzy, Sulantha Mathotaarachchi, Sara Mohades, Monica Shin, Alexandre Dionne-Laporte, Thomas Beaudry, Cynthia Picard, Serge Gauthier, Judes Poirier, Guy Rouleau, Pedro Rosa-Neto, for the Alzheimer’s Disease Neuroimaging Initiative

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

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 β (Aβ) fibrillary accumulation, we conducted an epistasis analysis on a pool of genes associated with molecular mediators of inflammation.

Methods

[18F]Florbetapir positron emission tomography (PET) imaging was employed to assess brain Aβ levels in 417 participants from ADNI-GO/2 and posteriorly 174 from ADNI-1. IL-1β, IL4, IL6, IL6r, IL10, IL12, IL18, C5, and C9 genes were chosen based on previous studies conducted in AD patients. Using the [18F]florbetapir standardized uptake value ratio (SUVR) as a quantitative measure of fibrillary Aβ, 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) Aβ1-42/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 (Aβ1-42/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 Aβ 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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Metadata
Title
Epistasis analysis links immune cascades and cerebral amyloidosis
Authors
Andréa L. Benedet
Aurélie Labbe
Philippe Lemay
Eduardo R. Zimmer
Tharick A. Pascoal
Antoine Leuzy
Sulantha Mathotaarachchi
Sara Mohades
Monica Shin
Alexandre Dionne-Laporte
Thomas Beaudry
Cynthia Picard
Serge Gauthier
Judes Poirier
Guy Rouleau
Pedro Rosa-Neto
for the Alzheimer’s Disease Neuroimaging Initiative
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0436-z

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