A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors

Abstract

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations.

Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data.

Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers.

Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Keywords: Frontotemporal dementia; Progranulin.

Fig. 1

A Plasma PGRN concentrations across individual GRN variants. Light grey shading denotes exonic regions and darker grey shading intronic regions. Dotted lines denote previously published with cut-offs for pathogenicity 61.55 [14] and 71.00 [30] and average non-GRN plasma PGRN concentration (156.02 ng/mL). Different colours represent different types of variants. B Plasma PGRN concentrations by mutation type. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001, two-tailed Mann–Whitney Test. Small sample sizes in deletions (n = 4) and missense in signal peptide (n = 10). C Plasma PGRN concentrations in different GRN missense variants. Dotted lines denote cut-offs previously published of 61.55 [14] and 71.00 [30]. Error bars indicate standard error of the mean (SEM)

Fig. 2

A PGRN plasma concentrations in GRN mutation carriers (GRN) and non-mutation carriers (Non-GRN). Cut-off determined using the optimal Youden’s index. B PGRN CSF concentrations in GRN mutation carriers (GRN) and non-mutation carriers (non-GRN). Cut-off determined using the optimal Youden’s index. C Serum PGRN concentrations in both GRN mutation carriers (GRN) and non-mutation carriers (non-GRN). Cut-off determined using the optimal Youden’s index. Error bars indicate standard error of the mean (SEM)

Fig. 3

A Plasma PGRN concentrations across different clinical diagnoses. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001, two-tailed Mann–Whitney Test. Significant differences compared with controls are shown on the graph. Additionally, PGRN concentrations were significantly different for bvFTD v CBS (**), FTD-ALS (*), MCI (***) and PCA (**); lvPPA v PPA-NOS (**), FTD-ALS (***), MCI (****) and PCA (*); nfvPPA v CBS (*), FTD-ALS (***), MCI (**) and PCA (**); svPPA v PPA-NOS(**), CBS (*), FTD-ALS(**), MCI (****) and PCA (**); PPA-NOS v FTD-ALS (***), AD (*), LBD (*) and PCA (****); CBS v AD (**), LBD (*) and MCI (****); PSP v PCA (**); FTD-ALS v CBS (***), AD (**), LBD (**) and PCA (***); ALS v PCA (**); AD v MCI (****) and PCA (***); MCI v LBD (**) and PCA (****); LBD v PCA (**). (bvFTD: behavioural variant FTD, PPA: primary progressive aphasia, nfvPPA: nonfluent variant PPA, svPPA: semantic variant PPA, lvPPA: logopenic variant PPA, FTD-ALS: frontotemporal dementia—amyotrophic lateral sclerosis, ALS: amyotrophic lateral sclerosis, CBS: corticobasal syndrome, PSP: progressive supranuclear palsy, AD: Alzheimer’s disease, MCI: mild cognitive impairment, LBD: lewy body disease, PCA: posterior cortical atrophy). Small sample sizes in ALS (n = 1), PCA (n = 10), PPA-NOS (n = 11), FTD-ALS (n = 18), PSP (n = 16). B Plasma and C CSF PGRN concentrations in females and males in both GRN mutation carriers (GRN) and non-mutation carriers (non-GRN). * P < 0.05, ** P < 0.01, two-tailed Mann–Whitney Test. D Plasma PGRN concentrations in those with different GRN rs5848 and E TMEM106b rs1990622 polymorphisms in both GRN mutation carriers (GRN) and non-mutation carriers (non-GRN). * P < 0.05, ** P < 0.01, two-tailed Mann–Whitney Test. Error bars indicate standard error of the mean (SEM)