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Epistasis analysis links immune cascades and cerebral amyloidosis.

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, Alzheimer’s Disease Neuroimaging Initiati - J Neuroinflammation (2015)

Bottom Line: The results were corrected for multiple comparison tests.Additionally, rs4240872 and rs7514452 SNPs were shown to be associated with CSF and plasma concentrations of IL6r protein.Certain allele combinations involving IL6r and C9 genes are associated with Aβ burden in the brain.

View Article: PubMed Central - PubMed

Affiliation: Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. andrea.benedet@mail.mcgill.ca.

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: [(18)F]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 [(18)F]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.

No MeSH data available.


Related in: MedlinePlus

Interaction between C9 and IL6r genes using the CSF Aβ1-42/p-tau ratio. The interaction between C9 and IL6r genes is associated with amyloid burden. Error bars represent the standard error. Small numbers represent the subsample size for each genotype combination
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Fig3: Interaction between C9 and IL6r genes using the CSF Aβ1-42/p-tau ratio. The interaction between C9 and IL6r genes is associated with amyloid burden. Error bars represent the standard error. Small numbers represent the subsample size for each genotype combination

Mentions: A subsample of 208 subjects (85 CN, 113 MCI, and 10 AD) who had baseline CSF measures was used to confirm the interaction model. The Aβ1-42/p-tau ratio was used as a dependent variable (CN average = 7.73, MCI average = 6.05, AD average = 2.76; difference between all groups statistically significant p = 5.3 × 10−5). The interaction analysis was replicated in the tested pair of SNPs (rs261752*rs7514452 t = −2.82, p = 0.005) (Additional file 2: Table S4). Similar observations to the findings using [18F]florbetapir were found; homozygous subjects for both minor alleles tend to have the lowest Aβ1-42/p-tau ratio (Fig. 3). However, due to sample size restrictions, group comparisons could not be performed.Fig. 3


Epistasis analysis links immune cascades and cerebral amyloidosis.

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, Alzheimer’s Disease Neuroimaging Initiati - J Neuroinflammation (2015)

Interaction between C9 and IL6r genes using the CSF Aβ1-42/p-tau ratio. The interaction between C9 and IL6r genes is associated with amyloid burden. Error bars represent the standard error. Small numbers represent the subsample size for each genotype combination
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4666175&req=5

Fig3: Interaction between C9 and IL6r genes using the CSF Aβ1-42/p-tau ratio. The interaction between C9 and IL6r genes is associated with amyloid burden. Error bars represent the standard error. Small numbers represent the subsample size for each genotype combination
Mentions: A subsample of 208 subjects (85 CN, 113 MCI, and 10 AD) who had baseline CSF measures was used to confirm the interaction model. The Aβ1-42/p-tau ratio was used as a dependent variable (CN average = 7.73, MCI average = 6.05, AD average = 2.76; difference between all groups statistically significant p = 5.3 × 10−5). The interaction analysis was replicated in the tested pair of SNPs (rs261752*rs7514452 t = −2.82, p = 0.005) (Additional file 2: Table S4). Similar observations to the findings using [18F]florbetapir were found; homozygous subjects for both minor alleles tend to have the lowest Aβ1-42/p-tau ratio (Fig. 3). However, due to sample size restrictions, group comparisons could not be performed.Fig. 3

Bottom Line: The results were corrected for multiple comparison tests.Additionally, rs4240872 and rs7514452 SNPs were shown to be associated with CSF and plasma concentrations of IL6r protein.Certain allele combinations involving IL6r and C9 genes are associated with Aβ burden in the brain.

View Article: PubMed Central - PubMed

Affiliation: Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, 6825 LaSalle Blvd, H4H 1R3, Montreal, QC, Canada. andrea.benedet@mail.mcgill.ca.

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: [(18)F]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 [(18)F]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.

No MeSH data available.


Related in: MedlinePlus