TY - JOUR
T1 - CSF protein changes associated with hippocampal sclerosis risk gene variants highlight impact of GRN/PGRN
AU - Fardo, David W.
AU - Katsumata, Yuriko
AU - Kauwe, John S.K.
AU - Deming, Yuetiva
AU - Harari, Oscar
AU - Cruchaga, Carlos
AU - Nelson, Peter T.
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Objective Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs). Methods Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes. Results The GRN risk SNP (rs5848) status correlated with variation in CSF proteins, with the risk allele (T) associated with increased levels of AXL Receptor Tyrosine Kinase (AXL), TNF-Related Apoptosis-Inducing Ligand Receptor 3 (TRAIL-R3), Vascular Cell Adhesion Molecule-1 (VCAM-1) and clusterin (CLU) (all p < 0.05 after Bonferroni correction). The TRAIL-R3 correlation was significant in meta-analysis with an additional dataset (p = 5.05 × 10− 5). Further, the rs5848 SNP status was associated with increased CSF tau protein – a marker of neurodegeneration (p = 0.015). These data are remarkable since this GRN SNP has been found to be a risk factor for multiple types of dementia-related brain pathologies.
AB - Objective Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs). Methods Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes. Results The GRN risk SNP (rs5848) status correlated with variation in CSF proteins, with the risk allele (T) associated with increased levels of AXL Receptor Tyrosine Kinase (AXL), TNF-Related Apoptosis-Inducing Ligand Receptor 3 (TRAIL-R3), Vascular Cell Adhesion Molecule-1 (VCAM-1) and clusterin (CLU) (all p < 0.05 after Bonferroni correction). The TRAIL-R3 correlation was significant in meta-analysis with an additional dataset (p = 5.05 × 10− 5). Further, the rs5848 SNP status was associated with increased CSF tau protein – a marker of neurodegeneration (p = 0.015). These data are remarkable since this GRN SNP has been found to be a risk factor for multiple types of dementia-related brain pathologies.
KW - Biomarkers
KW - Clusterin
KW - Granulin
KW - Neuroinflammation
KW - Progranulin
KW - Proteomics
UR - http://www.scopus.com/inward/record.url?scp=85012271409&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85012271409&partnerID=8YFLogxK
U2 - 10.1016/j.exger.2017.01.025
DO - 10.1016/j.exger.2017.01.025
M3 - Article
C2 - 28189700
AN - SCOPUS:85012271409
SN - 0531-5565
VL - 90
SP - 83
EP - 89
JO - Experimental Gerontology
JF - Experimental Gerontology
ER -