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. 2009;18(3):603-12.
doi: 10.3233/JAD-2009-1170.

Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer's disease

Chiara Fenoglio  1 , Daniela Galimberti, Francesca Cortini, John S K Kauwe, Carlos Cruchaga, Eliana Venturelli, Chiara Villa, Maria Serpente, Diego Scalabrini, Kevin Mayo, Laura M Piccio, Francesca Clerici, Diego Albani, Claudio Mariani, Gianluigi Forloni, Nereo Bresolin, Alison M Goate, Elio Scarpini
Affiliations

Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer's disease

Chiara Fenoglio et al. J Alzheimers Dis. 2009.

Abstract

Mutations in the progranulin gene (GRN), causative for Frontotemporal Lobar Degeneration with ubiquitin-immunoreactive neuronal inclusions (FTLD-U), could also be associated with Alzheimer's disease (AD). The influence of GRN genetic variability on susceptibility to AD and on expression levels in a series of neuropathologically-confirmed AD patients as well as in peripheral mononuclear cells (PBMC) and in cells isolated from cerebrospinal fluid (CSF) was investigated. An association study of rs9897526 and rs5848 was carried out in an Italian population and in a replication population of European American patients and controls. None of the variants tested act as unequivocal susceptibility factor in both populations although rs9897526 anticipated the onset of the disease in the Italian population. GRN expression in the parietal lobe of AD cases showed a 0.76-fold decrease compared with controls (1.31 +/- 0.07 versus 1.73 +/- 0.12, P = 0.0025). Patients carrying the rs5848 TT genotype had the lowest GRN expression levels (0.96 +/- 0.12, P = 0.014). Despite no significant differences were found in the relative PBMC and CSF GRN expression in patients compared to controls, stratifying patients according to the presence of rs5848 T allele, a 0.57-fold decrease in GRN mRNA levels over C carriers was found in PBMC (1.22 +/- 0.23 versus 0.70 +/- 0.12, P = 0.04). Similarly to data obtained in brain samples, patients carrying the TT genotype showed the lowest GRN mRNA levels (TT = 0.46 +/- 0.14, CC = 1.22 +/- 0.23; P = 0.013). These data argue against a direct role of GRN as a susceptibility factor for sporadic AD but support a role of GRN as a disease-modifying gene, possibly contributing to the failure of neuronal survival.

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Conflict of interest statement

Conflict of Interest Statement: Authors do not have conflicts of interest, including financial, personal or other relationships with other people or organizations that could inappropriately influence this work.

Figures

Figure 1
Figure 1
A) GRN expression levels in parietal lobe from patients and controls B) association of rs5848 with GRN relative mRNA expression. Values are expressed as mean relative mRNA levels±S.E.M. Kruskall-Wallis test was used for differences related to the mRNA levels in rs5848 genotype carriers. Y-Axis represents the relative expression level taking an arbitrary reference sample as 1.
Figure 1
Figure 1
A) GRN expression levels in parietal lobe from patients and controls B) association of rs5848 with GRN relative mRNA expression. Values are expressed as mean relative mRNA levels±S.E.M. Kruskall-Wallis test was used for differences related to the mRNA levels in rs5848 genotype carriers. Y-Axis represents the relative expression level taking an arbitrary reference sample as 1.
Figure 2
Figure 2
Association of rs5848 with GRN mRNA expression in PBMC from AD patients. Values are expressed as mean relative mRNA levels±S.E.M. One way Anova test, including Holm-Sidak for multiple comparisons was performed for differences related to the mRNA levels in rs5848 genotype carriers. Y-Axis represents the relative expression level taking an arbitrary reference sample as 1.
Figure 3
Figure 3
Transcript analysis of rs9897526 variant. Agarose gel-electrophoresis of GRN amplicon obtained from PBMC cDNA from subjects carrying different genotypes: GG lane 2, GA lane 3, AA lane 4. The expected transcript length of GRN cDNA exon 2-7 (586 bp) does not differ according to rs9897526 status. DNA weight marker, lane 1: VIII (Boehringer-Roche).
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