CSF protein changes associated with hippocampal sclerosis risk gene variants highlight impact of GRN/PGRN

Exp Gerontol. 2017 Apr:90:83-89. doi: 10.1016/j.exger.2017.01.025. Epub 2017 Feb 9.

Abstract

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.

Keywords: Biomarkers; Clusterin; Granulin; Neuroinflammation; Progranulin; Proteomics.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / cerebrospinal fluid*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Biomarkers / cerebrospinal fluid*
  • Clusterin / cerebrospinal fluid
  • Databases, Factual
  • Dementia / cerebrospinal fluid
  • Dementia / genetics*
  • Female
  • GPI-Linked Proteins / cerebrospinal fluid
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Hippocampus / pathology*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Male
  • Polymorphism, Single Nucleotide
  • Progranulins
  • Receptors, Tumor Necrosis Factor, Member 10c / cerebrospinal fluid
  • Regression Analysis
  • Risk Factors
  • Sclerosis
  • Vascular Cell Adhesion Molecule-1 / cerebrospinal fluid
  • tau Proteins / cerebrospinal fluid

Substances

  • Amyloid beta-Peptides
  • Biomarkers
  • Clusterin
  • GPI-Linked Proteins
  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
  • Receptors, Tumor Necrosis Factor, Member 10c
  • TNFRSF10C protein, human
  • Vascular Cell Adhesion Molecule-1
  • tau Proteins