rs5848 polymorphism and serum progranulin level.
OBJECTIVE
To assess the influence of rs5848 polymorphism in serum progranulin (PGRN) level in a cohort of subjects with Alzheimer and related dementias from a tertiary referral clinic.


BACKGROUND
Mutations in the GRN gene cause autosomal dominant frontotemporal dementia (FTD) with TDP-43 pathology (FTLD-TDP) through haploinsufficiency. It has recently been shown that homozygous carriers of the T allele of rs5848 have an elevated risk of developing FTD, and this polymorphism may play a role in the pathogenesis of other dementia by modifying progranulin level. We hypothesize that genotype of rs5848 may influence serum PGRN level in AD, FTD, and other dementias.


METHODS
Blood samples were obtained from patients with cognitive impairment and dementia referred to a tertiary dementia clinic, as well as samples from a cohort of healthy controls. Serum PGRN level was measured using an ELISA assay, and rs5848 genotype was determined by a TaqMan assay.


RESULTS
We found that rs5848 SNP significantly influenced serum PGRN level, with TT genotype having the lowest levels, and CC as the highest. This relationship is observed in each of the subgroups. We also confirmed that GRN mutation carriers had significantly lower serum PGRN levels than all other groups.


CONCLUSIONS
The rs5848 polymorphism significantly influences serum PGRN with TT carriers having a lower level of serum PGRN then CT and CC carriers. This is consistent with the finding that miR-659 binding to the high risk T allele of rs5848 may augment translational inhibition of GRN and alter risk of FTD and possibly other dementias.
Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, Canada. hsiung@interchange.ubc.ca
Ging-Yuek R
GY
Hsiung
Alice
A
Fok
Howard H
HH
Feldman
Rosa
R
Rademakers
Ian R A
IR
Mackenzie
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics*; D003704:Dementia / Q000097:blood / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins