Common variant in GRN is a genetic risk factor for hippocampal sclerosis in the elderly.
BACKGROUND
Hippocampal sclerosis (HpScl) is common in elderly subjects with dementia, either alone or accompanied by other pathologic processes. It is also found in >70% of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). TDP-43 inclusions are detected in >20% of Alzheimer disease (AD) and >70% of HpScl cases. The most common cause of FTLD-TDP is mutation in the progranulin gene (GRN). Recently, a common genetic variant in the 3' untranslated region (3'UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls.


OBJECTIVE
The goal of this study was to determine if the 3'UTR variant in GRN was associated with TDP-43 immunoreactivity in AD with and without HpScl.


METHODS
644 cases of pathologically confirmed AD, including 57 with HpScl, were screened for TDP-43 immunoreactivity and were genotyped at the GRN 3'UTR single-nucleotide polymorphism rs5848 using previously published methods.


RESULTS
There was a trend (p = 0.06) for TDP-43 immunoreactivity, but a very significant (p = 0.005) association of HpScl with the variant, with 72% of AD with HpScl carrying a T-allele, compared to 51% of AD without HpScl carrying a T-allele.


CONCLUSIONS
The results suggest that a genetic variant in GRN leading to decreased levels of progranulin may be a risk factor for HpScl in AD, while its role in TDP-43 immunoreactivity in AD remains less certain.
Dickson
Dennis W
DW
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. dickson.dennis@mayo.edu
Baker
Matthew
M
Rademakers
Rosa
R
D020413:3' Untranslated Regions / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000473:pathology; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D000077153:Progranulins; D012307:Risk Factors; D012598:Sclerosis / Q000209:etiology / Q000235:genetics
D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins