Genetic variability in
            <i>progranulin</i>
            contributes to risk for clinically diagnosed Alzheimer disease

Brouwers, Nathalie; Sleegers, Kristel; Engelborghs, Sebastiaan; Maurer‐Stroh, Sebastian; Gijselinck, Ilse; Zee, Julie van der; Pickut, Barbara A.; Broeck, Marleen Van den; Mattheijssens, Maria; Peeters, Karin; Schymkowitz, Joost; Rousseau, Frédéric; Martin, J.J.; Cruts, Marc; Deyn, Peter Paul De; Broeckhoven, Christine Van

doi:10.1212/01.wnl.0000319688.89790.7a

Cited by 153 publications

(104 citation statements)

References 32 publications

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“…18 The p.Gly35Glufs*19 mutation is a deletion of one out of four consecutive cytosines, and three substitutions in this sequence have previously been reported, c.99C4A, c.99C4T and c.102C4T, indicating that this region is a possible hotspot for mutations. 18,[23][24][25]28 The family of patient A01 and the Karolinska family shared an B297 kbp common disease haplotype as shown by comparing the disease haplotypes in the respective families. However, because they do not share a SNP (rs3859268) located 883 bp away from the mutation, we suggest that the mutation has arisen twice or that the two families must be very distantly related.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration

et al. 2013

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Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration

et al. 2013

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“…So far, a risk effect due to SNPs in this gene has been shown in neurodegenerative diseases, including FTLD, 5,6 Alzheimer's disease 8 and amyotrophic lateral sclerosis. 9 MS is considered mainly an inflammatory disease, but the possibility that PPMS is a primary neurodegenerative disease with variable and secondary demyelination has been recently raised.…”

Section: Progranulin Gene Variability In Ppms C Fenoglio Et Almentioning

confidence: 99%

“…4 A contribution of GRN variability has also been previously shown in sporadic FTLD, 5,6 although another study did not confirm these data. 7 GRN haplotypes influence the risk of developing Alzheimer's disease 8 as well as the age at onset and the duration of survival in patients with amyotrophic lateral sclerosis, 9 whereas GRN variability has likely no major role in susceptibility to Parkinson's disease. 10 Multiple sclerosis (MS) is considered predominantly an inflammatory autoimmune disease of the central nervous system, with myelin proteins supposed to act as autoantigens, starting with aberrant activation of specific populations of autoreactive T lymphocytes in the periphery, followed by T-cell recruitment into the brain.…”

Section: Introductionmentioning

confidence: 99%

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

et al. 2010

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Progranulin (GRN) gene variability has been analyzed in a sample of 354 patients with multiple sclerosis (MS) compared with 343 controls. No significant differences were observed, but by stratifying according to MS subtypes, a significant increased frequency of the rs2879096 TT genotype was found in primary progressive MS (PPMS) patients versus controls (16.0 vs 3.5%, P ¼ 0.023, odds ratio (OR) 5.2, 95% confidence interval (CI) 1.2-21.4). In addition, in PPMS, an association with the C allele of rs4792938 was observed (55.3 vs 33.5%, P ¼ 0.011, OR 2.4, 95% CI 1.2-4.7). An independent population was studied as replication, failing to confirm results previously obtained. Stratifying according to gender, an association with rs4792938 C allele was found in male PPMS patients compared with controls (40.7 vs 26.9%, P ¼ 0.002, OR 1.87, 95% CI 1.2-2.8). An association with the rs2879096T allele was observed (29.2 in patients compared with 18.9% in controls, P ¼ 0.012, OR 1.77, 95% CI 1.1-2.8). Haplotype analysis showed that TC haplotype frequency is increased in PPMS male patients compared with male controls (25.7 vs 16.6%; P ¼ 0.02, OR 1.69, 95% CI 1.1-2.7), whereas the respective GC haplotype seems to exert a protective effect, as its frequency is decreased in patients compared with controls (55.8% vs 70.9%; P ¼ 0.001, OR 0.52, 95% CI 0.4-0.8). Therefore, GRN haplotypes likely influence the risk of developing PPMS in males.

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“…Mutations in the GRN gene may contribute to the risk of developing AD 8, 12. Additionally, progranulin localizes at the margins of amyloid plaques in both mouse and human postmortem brain tissue, and increased progranulin mRNA levels have been reported in the brains of multiple AD‐mouse models 13.…”

Section: Introductionmentioning

confidence: 99%

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

Cooper

Nachun

Dokuru

et al. 2018

Ann Clin Transl Neurol

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ObjectiveChanges in progranulin (GRN) expression have been hypothesized to alter risk for Alzheimer's disease (AD). We investigated the relationship between GRN expression in peripheral blood and clinical diagnosis of AD and mild cognitive impairment (MCI).MethodsPeripheral blood progranulin gene expression was measured, using microarrays from Alzheimer's (n = 186), MCI (n = 118), and control (n = 204) subjects from the University of California San Francisco Memory and Aging Center (UCSF‐MAC) and two independent published series (AddNeuroMed and ADNI). GRN gene expression was correlated with clinical, demographic, and genetic data, including APOE haplotype and the GRN rs5848 single‐nucleotide polymorphism. Finally, we assessed progranulin protein levels, using enzyme‐linked immunosorbent assay, and methylation status using methylation microarrays.ResultsWe observed an increase in blood progranulin gene expression and a decrease in GRN promoter methylation in males (P = 0.007). Progranulin expression was 13% higher in AD and MCI patients compared with controls in the UCSF‐MAC cohort (F 2,505 = 10.41, P = 3.72*10−5). This finding was replicated in the AddNeuroMed (F 2,271 = 17.9, P = 4.83*10−8) but not the ADNI series. The rs5848 SNP (T‐allele) predicted decreased blood progranulin gene expression (P = 0.03). The APOE4 haplotype was positively associated with progranulin expression independent of diagnosis (P = 0.04). Finally, we did not identify differences in plasma progranulin protein levels or gene methylation between diagnostic categories.InterpretationProgranulin mRNA is elevated in peripheral blood of patients with AD and MCI and its expression is associated with numerous genetic and demographic factors. These data suggest a role in the pathogenesis of neurodegenerative dementias besides frontotemporal dementia.

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Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease

Cited by 153 publications

References 32 publications

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

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