A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.
Frontotemporal dementia
Progranulin
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
28 Mar 2024
28 Mar 2024
Historique:
received:
27
10
2023
accepted:
25
02
2024
medline:
28
3
2024
pubmed:
28
3
2024
entrez:
28
3
2024
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 38539243
doi: 10.1186/s13195-024-01420-z
pii: 10.1186/s13195-024-01420-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
66Subventions
Organisme : JPND GENFI-PROX grant
ID : 2019-02248
Organisme : JPND GENFI-PROX grant
ID : 2019-02248
Organisme : JPND GENFI-PROX grant
ID : 2019-02248
Organisme : JPND GENFI-PROX grant
ID : 2019-02248
Organisme : JPND GENFI-PROX grant
ID : 2019-02248
Organisme : JPND GENFI-PROX grant
ID : 2019-02248
Organisme : MRC Clinician Scientist Fellowship
ID : MR/M008525/1
Organisme : MRC Clinician Scientist Fellowship
ID : MR/M008525/1
Organisme : FAPESP grant number
ID : 2013/017584
Organisme : EU Joint Programme-Neurodegenerative Diseases networks Genfi-Prox
ID : 01ED2008A
Organisme : bPride
ID : 01ED2001
Organisme : German Federal Ministry of Education and Research
ID : FTLDc 01GI1007A, Moodmarker 01EW200
Organisme : the EU
ID : MIRIADE 860197, FAIR-PARK II 633190
Organisme : German Research Foundation/DFG
ID : SFB1279
Organisme : The foundation of the state Baden-Württemberg
ID : D.3830
Organisme : Boehringer Ingelheim Ulm University BioCenter and the Thierry Latran Foundation
ID : D.5009
Organisme : Swedish State Support for Clinical Research
ID : #ALFGBG-71320
Organisme : Alzheimer Drug Discovery Foundation (ADDF), USA
ID : #201809-2016862
Organisme : AD Strategic Fund and the Alzheimer's Association
ID : #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C
Organisme : Swedish Research Council
ID : #2019-02397, #2022-01018
Organisme : the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden
ID : #FO2022-0270
Organisme : the European Union Joint Programme - Neurodegenerative Disease Research
ID : JPND2021-00694)
Organisme : UK Dementia Research Institute at UCL
ID : UKDRI-1003
Organisme : Alzheimer's Research UK
ID : ARUK-RADF2021A-003
Organisme : NIHR Rare Disease Translational Research Collaboration
ID : BRC149/NS/MH
Organisme : MRC UK GENFI grant
ID : MR/M023664/1
Informations de copyright
© 2024. The Author(s).
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