Department of Neurodegenerative Disease, Dementia Research Institute, UCL Institute of Neurology, Queen Square, London, UK.
Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Alzheimers Res Ther. 2024 Mar 28;16(1):66. doi: 10.1186/s13195-024-01420-z.
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.
颗粒蛋白前体（PGRN）基因的致病性杂合突变是额颞叶痴呆（FTD）的一个关键病因，导致脑脊液和血清中的 PGRN 蛋白浓度显著降低。这导致了许多正在进行的治疗试验，旨在通过增加突变携带者的 PGRN 水平来治疗这种形式的 FTD。然而，我们目前还不完全了解影响 PGRN 水平的因素，以及潜在的测量方法差异。在这里，我们旨在通过系统地综述已发表的关于生物流体 PGRN 浓度的文献来填补这一知识空白。
从 75 篇文献中收集了 7071 名个体的已发表数据，包括生物流体 PGRN 浓度、年龄、性别、诊断和 GRN 突变。大多数分析（72%）集中在血浆 PGRN 浓度上，其中许多（56%）使用单一的检测类型（Adipogen）进行测量，因此在数据的这一部分中，我们研究了突变类型、发病年龄、性别和诊断对血浆 PGRN 浓度的影响。
我们基于 3301 名个体，使用 Adipogen 检测建立了一个血浆 PGRN 浓度截断值，用于区分致病性突变携带者和非携带者，截断值为 74.8ng/ml，脑脊液的截断值为 3.43ng/ml。GRN 突变类型和无 GRN 突变患者的临床诊断均影响血浆 PGRN 浓度。在 GRN 突变携带者中，女性的血浆 PGRN 浓度显著高于男性（p=0.007），而非携带者中也存在这种趋势（p=0.062），且在突变携带者和非携带者中，血浆 PGRN 浓度与年龄呈显著正相关，但相关性较弱。在突变携带者和非携带者中，体重或 TMEM106B rs1990622 基因型与血浆 PGRN 浓度无显著相关性。然而，在 GRN 突变携带者和非携带者中，GRN rs5848 CC 基因型与较高的血浆 PGRN 水平相关。
这些结果进一步支持了 PGRN 浓度在识别 GRN 基因中大多数致病性突变中的作用。此外，这些结果强调了在解释 PGRN 浓度时，需要考虑其他因素，如突变类型、性别和年龄。这在我们进入颗粒蛋白关联型额颞叶痴呆的试验时代后尤为重要。
