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Epistasis analysis links immune cascades and cerebral amyloidosis #MMPMID26626881
J Neuroinflammation 2015[]; 12 (ä): ä PMID26626881show 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: [18F]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 [18F]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. Electronic supplementary material: The online version of this article (doi:10.1186/s12974-015-0436-z) contains supplementary material, which is available to authorized users.
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J+Neuroinflammation 2015 ; 12 (ä): ä
