PGRN Is Associated with Late-Onset Alzheimer’s Disease: a Case–Control Replication Study and Meta-analysis

Abstract

Progranulin (PGRN) plays an important role in Alzheimer's disease (AD) through participating in altering neurite outgrowth and neuronal survival. Previous studies identified that rs5848 in the 3'-untranslated region (3'-UTR) of the PGRN gene (GRN) is strongly associated with AD in Caucasians. In order to assess the involvement of the GRN polymorphism in the risk of late-onset AD (LOAD), we analyzed the genotype and allele distributions of rs5848 in 2350 Han Chinese subjects (AD, 992; control, 1358). The minor T allele of rs5848 was significantly associated with an increased risk of LOAD (P = 0.005, odds ratio (OR) = 1.197, 95 % confidence interval (CI) = 1.057-1.355). Moreover, the association was further validated in the multivariate logistic regression analysis (dominant model: OR = 1.195, P = 0.038, recessive model: OR = 1.386, P = 0.025; additive model: OR = 1.187, P = 0.009). Interestingly, we observed that the interaction between apolipoprotein E (APOE) and rs5848 significantly altered the risk for AD. The rs5848 polymorphism was only significantly associated with LOAD in APOE ε4 allele carriers. Then we included five studies (including the present study) and conducted a meta-analysis which consisted of 3236 cases (male, 1152; female, 2084) and 3405 (male, 1436; female, 1969) controls. The result of the meta-analysis supported T allele of rs5848 within GRN as a risk factor for AD. In conclusion, our results demonstrated that rs5848 polymorphism within GRN was associated with LOAD.

Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point?

“…Interestingly, it has been recently described that CSF progranulin but not serum/plasma progranulin, is reduced also in GRN -negative FTD (Wilke et al, 2017 ): this reduction seems extend beyond the recognized modification of CSF progranulin levels by the SNP rs5848 (Nicholson et al, 2014 ) and it is not directly linked to tau alterations. The GRN rs5848 TT genotype is associated with reduced progranulin levels in FTD and AD (Rademakers et al, 2008 ; Hsiung et al, 2011 ) and has been described as risk factor for neurodegenerative diseases (Rademakers et al, 2008 ; Chen et al, 2015 ; Xu et al, 2017 ).…”

Genetic Regulation of Neuronal Progranulin Reveals a Critical Role for the Autophagy-Lysosome Pathway

“…Rare individuals nullizygous for GRN develop neuronal ceroid lipofuscinosis, which has an onset much earlier than FTLD (Smith et al, 2012;Götzl et al, 2014). Recently, polymorphisms that decrease GRN expression were linked to increased risk for AD and boosting levels of progranulin in mouse models of AD suppresses neuroinflammatory-, pathological-, and cognitivebased disease phenotypes (Pereson et al, 2009;Hsiung et al, 2011;Kämäläinen et al, 2013;Perry et al, 2013;Minami et al, 2014;Chen et al, 2015;Hosokawa et al, 2015;Xu et al, 2017). Therefore, differing levels of progranulin deficiency in the brain lead to different neurodegenerative syndromes, showing that loss of progranulin function contributes to disease development.…”

CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM 2, neurodegeneration and cognitive decline

“…Reduced PGRN protein in plasma, serum or cerebrospinal fluid (CSF) has been shown to be a reliable diagnostic biomarker for early detection of progranulin (GRN) mutation carriers (Ghidoni et al, 2008;Finch et al, 2009;Sleegers et al, 2009). Certain GRN variants may also increase the risk for Alzheimer's disease (AD) (Brouwers et al, 2008;Rademakers et al, 2008;Viswanathan et al, 2009;Lee et al, 2011;Cruchaga et al, 2012;Sheng et al, 2014;Xu et al, 2017), yet associations could not be confirmed in some other studies (Fenoglio et al, 2009;Mateo et al, 2013). Studies in AD mouse models indicated that PGRN is strongly increased in microglia clustering around amyloid plaques (Pereson et al, 2009) and may also affect amyloid b-peptide (Ab) and tau deposition.…”