Progranulin, sICAM-1, and sVCAM-1 May Predict an Increased Risk for Ventricular Arrhythmias in Patients with Systemic Sclerosis.

In systemic sclerosis (SSc), fibrosis of the myocardium along with ongoing autoimmune inflammation can alter the electric function of the cardiac myocytes, which may increase the risk for ventricular arrhythmias and sudden cardiac death. We analyzed the electrocardiographic (ECG) variables describing ventricular repolarization such as QT interval, QT dispersion (QTd), T wave peak-to-end interval (Tpe), and arrhythmogeneity index (AIX) of 26 patients with SSc and 36 healthy controls. Furthermore, echocardiographic and laboratory parameters were examined, with a focus on inflammatory proteins like C-reactive ptotein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), and progranulin (PGRN). The CRP, sICAM-1, and sVCAM-1 levels were positively correlated with the length of the QT interval. Although the serum PGRN levels were not increased in the SSc group compared to the controls, in SSc patients, the PGRN levels were positively correlated with the QT interval and the AIX. According to our results, we conclude that there may be a potential association between autoimmune inflammation and the risk for ventricular arrhythmias in patients with SSc. We emphasize that the measurement of laboratory parameters of inflammatory activity including CRP, PGRN, sVCAM-1, and sICAM-1 could be helpful in the prediction of sudden cardiac death in patients with SSc.

Elevated serum level of progranulin is associated with increased mortality in critically ill patients with candidemia.

Candidemia is a severe disease with high mortality in both intensive care unit (ICU) and non-ICU settings. Considering that progranulin (PGRN) is a potential therapeutic target for the candidemia caused by Candida albicans, we determined the serum level of PGRN after candidemia and evaluated its association with mortality. A retrospective discovery cohort (62 patients) and a validation cohort (70 patients) were enrolled. Blood was collected on day of first blood culture positivity for C. albicans, and serum PGRN levels were then measured. In the discovery cohort, all serum PGRN studied were expressed at higher levels in candidemia patients than in bacteremia patients and healthy volunteers, non-survivors presented with significantly higher serum PGRN concentrations when compared with survivors. Serum PGRN concentration was associated with 30-day mortality and patients at a higher risk of death showed higher serum PGRN levels. These results were confirmed in the independent validation cohort. Interestingly, in vitro study demonstrated that macrophages, neutrophils and lymphocytes may be the major source of PGRN production after C. albicans infection instead of epithelial cells. Our findings highlight that serum PGRN appears as a biomarker in candidemia patients and as a promising tool for mortality risk stratification in managing candidemia.

Circulating progranulin in human infants: relation to prenatal growth and early postnatal nutrition.

BACKGROUND: Progranulin (PGRN) displays pleiotropic biological functions and has been proposed as a biomarker for metabolic diseases. We longitudinally assessed PGRN concentrations in infants born appropriate (AGA) or small for gestational age (SGA), the latter being at risk for obesity and type 2 diabetes, especially if they experience an excessive postnatal catch-up in weight and are formula-fed (FF). METHODS: The study population consisted of 183 infants who were exclusively breast-fed [(BF), AGA, n = 66; SGA, n = 40], or FF (AGA, n = 31; SGA, n = 46) over the first 4 months. Assessments included auxology, fasting glucose, insulin, IGF-1, high-molecular-weight adiponectin, PGRN and body composition (by DXA), at birth, and at age 4 and 12 months. RESULTS: PGRN levels were low at birth and unaffected by prenatal growth. PGRN increased at 4 and 12 months, although to a lesser extent in SGA infants, and was unrelated to the mode of feeding. PGRN correlated with markers of adiposity, inflammation and insulin resistance in both AGA and SGA infants, especially in those FF. CONCLUSIONS: The attenuated increase of PGRN levels in SGA infants over the first year of life, along with the association to markers of unhealthy metabolic profile, might point to a role of PGRN in future disease risks. IMPACT: Progranulin (PGRN) displays pleiotropic biological functions and has been proposed as a biomarker for metabolic diseases. In healthy infants, PGRN concentrations are low at birth and experience a significant and progressive increase up to age 12 months, which is less marked in infants born small for gestational age (SGA) and is unrelated to the mode of feeding. Circulating PGRN is related to markers of adiposity, inflammation, and insulin sensitivity, especially in formula-fed SGA infants. PGRN may play a role in the metabolic adaptations of SGA infants during early life, potentially contributing to the risk for obesity and type 2 diabetes in this population.

TNFR-1 and GDF-15 Are Associated With Plasma Neurofilament Light Chain and Progranulin Among Community-Dwelling Older Adults: A Secondary Analysis of the MAPT Study.

There is growing evidence that cognitive decline can be affected by both nutritional aspects and inflammation. Plasma neurodegenerative biomarkers stand out as minimally invasive useful measures to monitor the potential risk of cognitive decline. This study aimed to investigate the associations between biomarkers of neurodegeneration, nutrition, and inflammation among community-dwelling older adults, and to verify if associations differed according to apolipoprotein E (APOE) ε4 status. This cross-sectional analysis included 475 participants ≥70 years old from the Multidomain Alzheimer Preventive Trial (MAPT), mean age 76.8 years (SD = 4.5), 59.4% women. Biomarkers of neurodegeneration (plasma amyloid-ß 42/40-Aß 42/40, neurofilament light chain-NfL, progranulin), nutrition (erythrocyte docosahexaenoic acid, eicosapentaenoic acid, omega-3 index; plasma homocysteine-Hcy, 25 hydroxyvitamin D), inflammation (plasma tumor necrosis factor receptor 1-TNFR-1, monocyte chemoattractant protein 1-MCP-1, interleukin 6-IL-6), and cellular stress (plasma growth differentiation factor 15-GDF-15) were assessed. Linear regression analyses were performed to investigate the associations between nutritional and inflammatory biomarkers (independent variables) and neurodegenerative biomarkers (dependent variables), with adjustments for age, sex, education, body mass index, physical activity, allocation to MAPT groups, and APOE ε4 status. After adjusting for confounders, Aß 42/40 was not associated with nutritional or inflammatory markers. NfL was positively associated with GDF-15, TNFR-1, IL-6, and Hcy. Progranulin was positively associated with GDF-15, TNFR-1, and MCP-1. Analyses restricted to APOE ε4 carriers (n = 116; 26.9%) or noncarriers were mostly similar. Our cross-sectional study with community-dwelling older adults corroborates previous evidence that inflammatory pathways are associated to plasma markers of neurodegeneration. Clinical Trials Registration Number: NCT00672685.

Assessment of progranulin and FAM19A5 protein blood levels in patients with metabolic syndrome.

Progranulin and family with sequence similarity 19, member A5 (FAM19A5) protein are adipokines with growing importance in the context of metabolic diseases. The study aimed to determine the serum concentration of progranulin and FAM19A5 in people with metabolic syndrome (MS) compared to those without MS. The concentration of progranulin and FAM19A5 was determined in 45 people with MS (group A) and in 35 healthy people without MS (group B). Body composition analysis, blood pressure, blood oxygen saturation and anthropometric measurements were performed. There were no differences in the blood levels of progranulin and FAM19A5 between the groups. In group A, the level of progranulin was 29.25±36.92 pg/ml and in group B it was 46.00±60.12pg/ml (p=0.2693). The level of FAM19A5 was 163.16±55.11 pg/ml and 197.57±112.89 pg/ml (p=0.1341) in subjects with and without metabolic syndrome, respectively. In group A, there was a correlation between FAM19A5 and diastolic blood pressure (DBP) (R= -0.40) and high-density lipoprotein (HDL) level (R= -0.37). In group B, correlations were found between progranulin and waist circumference (R= -0.43) and progranulin and triglyceride (TG) levels (R= -0.42). Both groups together showed correlations between progranulin level and body mass index (R= -0.24), HDL (R=0.25) and TG levels (R= -0.25) and between FAM19A5 level and DBP (R= -0.34). In conclusion, patients with and without MS do not differ in the range of progranulin and FAM19A5 serum levels. In patients with MS, elevated FAM19A5 serum levels may be an indicator of dyslipidaemia development. FAM19A5 appears to be a better predictor of MS than progranulin.

Increased progranulin as an independent predictive biomarker for poor prognosis in sepsis.

BACKGROUND: Recently, many diagnostic biomarkers were reported, but each had its own limitation. However, there is a need for an effective sensitivity and specificity of biomarker in diagnosis and prognosis of sepsis. In this context, progranulin (PGRN), at elevated levels, has been associated with poor prognosis in infectious diseases. Moreover, increased PGRN levels were seen in septic mice. As the prognostic value of PGRN in humans is unclear, we aimed to identify the predictive value of serum PGRN for the prognosis of sepsis. METHODS: A total of 128 participants with sepsis and 58 healthy controls were recruited in this study. The levels of serum PGRN were detected by enzyme-linked immunosorbent assay. According to the outcomes, patients were divided into survival and non-survival groups. RESULTS: Serum PGRN levels had upregulated in patients with sepsis compared with those in healthy controls (P < 0.001) as well as in non­survivors compared with those in survivors (P < 0.001). Furthermore, serum PGRN levels exhibited positive correlation with hypersensitive C-reactive protein, procalcitonin, sepsis­related organ failure assessment (SOFA) scores, and acute physiology and chronic health evaluation II (APACHE II) scores. PGRN had a higher predictive effect, especially the 28-day in-hospital mortality (p < 0.001), when using it with SOFA or APACHE II scores. Cox proportional regression analysis showed that PGRN was an independent predictor for 28-day mortality risk in sepsis. CONCLUSIONS: PGRN, as a biomarker of sepsis, could improve the prognostic power of traditional parameters. This study is the first to report the clinical significance of PGRN levels in terms of the severity and prognosis of sepsis.

High Serum Progranulin Levels in COVID-19 Patients: A Pilot Study.

In this study, we aimed to determine whether the progranulin level in serum predicts the course and severity of the disease in COVID-19 (+) patients and whether it can be used as a biomarker in these patients. Therefore, we sampled 61 people infected with COVID-19, and the cases were divided into the following groups: asymptomatic, noncomplicated, moderate, and severe. Concentrations of progranulin, TNF-α, IL-6 from in serum obtained from all participants were measured using commercially available ELISA kits, as well as WBC, PLT, NE, LY, ALT, AST, Hb, PCT, and CRP were examined with clinical analyzer. All measurements obtained for the patient samples were compared with those of 20 healthy individuals. The serum progranulin concentration was statistically higher in the COVID-19 (+) patient group than in the control group of healthy individuals [112.6 ± 54.8, 0.0 (0.0-54.2 pg/ml, respectively p = 0.000)]. ROC analysis was performed to evaluate the progranulin potential as a biomarker for COVID-19 (+) patients. A larger AUC (0.931 ± 0.08) value and a more significant p-value for progranulin than for CRP (p = 0.000) was detected. As a result, we believe that progranulin reaches high levels in the COVID-19 disease and may be a determinant in diagnosis and prognosis, and may be a better biomarker than CRP.

Serum progranulin is not associated with rs5848 polymorphism in Korean patients with neurodegenerative diseases.

Low serum progranulin (PGRN) is known to be associated with granulin (GRN) gene mutation and T alleles of GRN rs5848 polymorphism. However, there have been only a few Asian studies exploring these. We investigated the serum PGRN levels, rs5848 genotypes, and their relations with cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in the Korean population. Serum PGRN levels, GRN rs5848 polymorphism, and GRN mutations were evaluated in 239 participants (22 cognitively unimpaired participants and 217 patients with neurodegenerative diseases). CSF AD biomarkers were also evaluated in 214 participants. There was no significant difference in the serum PGRN levels among the diagnostic groups. We could not find any GRN mutation carrier in our sample. The differences in the frequencies of the rs5848 genotypes among the clinical groups or the effects of the rs5848 genotypes on serum PGRN were not observed. There was no correlation between the serum PGRN level or rs5848 genotype and CSF AD biomarkers. Neither the T allele nor the TT genotype had an effect on the development of AD. Our results showed that serum PGRN levels were not associated with rs5848 genotypes, indicating that multiple single nucleotide polymorphisms might affect PGRN concentrations in an ethnicity-specific manner.

Progranulin Suppressed Autoimmune Uveitis and Autoimmune Neuroinflammation by Inhibiting Th1/Th17 Cells and Promoting Treg Cells and M2 Macrophages.

BACKGROUND AND OBJECTIVES: Progranulin (PGRN) is an important immune regulatory molecule in several immune-mediated diseases. The objective of this study is to investigate the role of PGRN in uveitis and its counterpart, experimental autoimmune uveitis (EAU), and experimental autoimmune encephalomyelitis (EAE). METHODS: Serum PGRN levels in patients with Behcet disease (BD) or Vogt-Koyanagi-Harada (VKH) disease and normal controls were measured by ELISA. EAE and EAU were induced in B10RIII, wild-type, and PGRN-/- mice to evaluate the effect of PGRN on the development of these 2 immune-mediated disease models. The local and systemic immunologic alterations were detected by ELISA, flow cytometry, and real-time PCR. RNA sequencing was performed to identify the hub genes and key signaling pathway. RESULTS: A significantly decreased PGRN expression was observed in patients with active BD and active VKH. Recombinant PGRN significantly reduced EAU severity in association with a decreased frequency of Th17 and Th1 cells. PGRN-/- mice developed an exacerbated EAU and EAE in association with strikingly increased frequency of Th1 and Th17 cells and reduced frequency of regulatory T (Treg) cells. In vitro studies revealed that rPGRN could inhibit IRBP161-180-specific Th1 and Th17 cell response and promote Treg cell expansion. It promoted non-antigen-specific Treg cell polarization from naive CD4+ T cells in association with increased STAT5 phosphorylation. Using RAN sequencing, we identified 5 shared hub genes including Tnf, Il6, Il1b, Cxcl2, and Ccl2 and the most significantly enriched MAPK and tumor necrosis factor signaling pathway in PGRN-/- EAU mice. The aggravated EAE activity in PGRN-/- mice was associated with a skew from M2 to M1 macrophages. DISCUSSION: Our results collectively reveal an important protective role of PGRN in EAU and EAE. These studies suggest that PGRN could serve as an immunoregulatory target in the study of prevention and treatment for the Th1/Th17-mediated diseases.

Serum progranulin as a predictive marker for high activity of antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: This study investigated whether serum progranulin could act as a predictive marker for high disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Fifty-eight AAV patients were included in this study. Clinical and laboratory data were obtained at blood collection. The Short-Form 36-Item Health Survey Physical and Mental Component Summaries (SF-36 PCS and SF-36 MCS), Birmingham Vasculitis activity score (BVAS), Five-Factor Score (FFS), and Vasculitis Damage Index (VDI) were assessed as AAV-specific indices. Whole blood was collected and serum samples were isolated and stored at -80°C. Serum progranulin concentration was quantified by ELISA kits. RESULTS: The median age of patients was 63.0 years (19 men). The median BVAS was 11.0, and the median serum progranulin level was 49.0 ng/ml. Serum progranulin was significantly correlated with BVAS, FFS, erythrocyte sedimentation rate, C-reactive protein level, SF-36 PCS, haemoglobin, and serum albumin. Severe AAV was arbitrarily defined as the highest tertile of BVAS (BVAS ≥16). When the cut-offs of serum progranulin were set as 55.16 ng/ml and 43.01 ng/ml for severe AAV, AAV patients with serum progranulin ≥55.16 and 43.01 ng/ml had significantly higher risks of severe AAV than those without (relative risk (RR) 4.167 and 4.524, respectively). CONCLUSIONS: Progranulin might play an anti-inflammatory role in AAV pathogenesis and serum progranulin could be used as a predictive marker for high activity of AAV.

Progranulin and tumor necrosis factor-alpha in lean polycystic ovary syndrome patients.

OBJECTIVE: In this study, levels of progranulin (PGRN) and tumor necrosis factor-alpha (TNF-α) were measured to detect the presence of inflammation in lean polycystic ovary (PCOS) patients. METHODS: 40 lean PCOS patients were assessed by Rotterdam criteria. Forty healthy women with regular menstrual cycles and without biochemical and clinical hyperandrogenism were involved in our study. Blood samples were taken from the patient and control groups for the measurement of progranulin (PGRN), tumor necrosis factor-alpha (TNF-α), lipid parameters, glucose, insulin, and other hormones. RESULTS: Serum PGRN and TNF-α levels were significantly higher in patients with lean PCOS, compared with the control group (p = .037, p = .041). PGRN levels were positively correlated with TNF-α levels in lean PCOS patients. CONCLUSION: PGRN is known as a ligand for the TNF-α receptor. PGRN level increase in lean PCOS patients may be due to inhibiting the inflammatory effects of TNF-α. To observe the PGRN and TNF-α connection in obesity, further study is needed in obese PCOS patients and obese control groups.

Serum progranulin to TNF-α ratio in patients with gonarthrosis.

OBJECTIVE: Progranulin (PGRN) is a growth factor that has antiinflammatory, immunosuppressive, and chondroprotective effects. It blocks Tumor Necrosis Factor-α (TNF-α) signal pathway by binding its receptor. Recently, it has been claimed that PGRN may be overexpressed in patients with Osteoarthritis (OA). However, these patients tend to be obese and obesity also may be one of the factors that affect PGRN levels. The aim of this study was to compare the PGRN levels of patients with Knee OA (KOA) with that of healthy controls by eliminating the effect of obesity and to evaluate PGRN-to-Tumor Necrosis Factor-α (TNF-α) ratio in KOA, both of which were investigated first in literature by this study. METHODS: A total of 80 individuals (40 patients with KOA and 40 healthy controls) were included in this study. The patients and controls were divided into two groups according to their Body Mass Indexes (BMI): nonobese (BMI between 18.5 and 24.9) and obese (BMI of 30 or higher). Each of the groups included 20 subjects and had an equal number of men and women. Blood samples were obtained from all participants, and the serum PGRN and TNF-α levels were measured using commercial ELISA kits. RESULTS: There was no difference among groups in terms of age (P = 0.416) and gender distribution. There was no statistical difference among study groups with regard to serum PGRN levels. Serum TNF-α levels were significantly higher in obese controls (P < 0.001) and nonobese patients (P = 0.003) compared to that of nonobese healthy controls. Correspondingly, serum PGRN-to-TNF-α ratio was considerably lower in obese controls (P < 0.001) and nonobese patients (P < 0.001) by comparison with that of nonobese healthy controls. CONCLUSION: We determined that both obesity and KOA increased serum TNF-α levels and concordantly decreased serum PGRNto- TNF-α ratio. The results of the study suggest that the activation of the PGRN pathway and/or the inhibition of the TNFα pathway may be essential in terms of the reestablishment of the disrupted inflammatory balance in patients with KOA. LEVEL OF EVIDENCE: Level III, Diagnostic study.

Diagnostic Value of Circulating Progranulin and Its Receptor EphA2 in Predicting the Atheroma Burden in Patients with Coronary Artery Disease.

BACKGROUND: Progranulin (PGRN) and its potential receptor Eph-receptor tyrosine kinase-type A2 (EphA2) are inflammation-related molecules that present on the atherosclerotic plaques. However, the roles of circulating PGRN and EphA2 in coronary artery disease (CAD) remain unclear. OBJECTIVE: To study the clinical significance of circulating PGRN and EphA2 levels in Chinese patients undergoing coronary angiography. METHODS: Levels of circulating EphA2 fragments and PGRN were examined in 201 consecutive individuals who underwent coronary angiography for suspected CAD in our center from Jan 2020 to Oct 2020. Demographic characteristics, results of biochemical and auxiliary examinations, and other relevant information were collected. The coronary atheroma burden was quantified by the Gensini score and the existence of chronic total occlusion (CTO). Univariate analysis and multivariate logistic regression analysis were used to analyze the risk factors for acute coronary syndrome (ACS). In patients with ACS and SAP, a receiver operating characteristic (ROC) curve was generated to detect the accuracy and discriminative ability of levels of EphA2 and PGRN, the Gensini score, and cardiac injury biomarkers as surrogate endpoints for CTO. RESULTS: Circulating EphA2 levels were significantly higher in patients with ACS than in subjects with stable angina pectoris (SAP) or control subjects (p < 0.001). A positive linear correlation was verified between EphA2 levels and the Gensini score (r = 0.306, p < 0.001), and negative correlation was detected with the left ventricular ejection fraction (LVEF) (r = -0.405, p < 0.001). Both PGRN and EphA2 were positively associated with cardiac injury biomarkers (i.e., NT-proBNP, cTnT, and hs-CRP) (p < 0.05). The area under the ROC curve of PGRN and EphA2 was 0.604 and 0.686, respectively (p < 0.01). CONCLUSIONS: Higher circulating EphA2 and PGRN levels were detected in patients with ACS than in patients with SAP. Circulating EphA2 and PGRN levels might be diagnostic factors for predicting the atheroma burden in patients with CAD.

Elevated serum and urine levels of progranulin (PGRN) as a predictor of microglia activation in the early phase of traumatic brain injury: a further link with the development of neurodegenerative diseases.

Traumatic brain injury (TBI) is a frequent finding during forensic autopsies and neuropathological examinations in medico-legal practices. Despite the unprecedented attention currently focused on TBI pathogenesis, there is a need to improve its diagnostics through the use of novel biomarkers to facilitate detection, treatment, and prognosis. Recently, growth factor progranulin (PGRN) has attracted significant attention because of its neurotrophic and anti-inflammatory activities. The role of PGRN in TBI has not been widely discussed, although PGRN-related neuroinflammatory and neurodegenerative phenomena have been described. The aim of this study was to identify PGRN concentration levels in biofluids and examine PGRN and CD68 protein expression in brain tissue using immunohistochemical staining in individuals with fatal TBI in its early phase. The study was performed using cases (n = 30) of fatal head injury and control cases (n = 30) of sudden death. The serum and urine were collected within ~24 h after death and compared using the ELISA test, where brain specimens were stained with anti-PGRN and anti-CD68 antibodies. In our study, we observed elevated concentration levels of PGRN in the serum and urine of TBI individuals in the early phase of TBI. These changes were accompanied by increased expression of PGRN in the frontal cortex (1st-3rd layers), in which anti-CD68 immunostaining revealed disseminated cortical microglia activation. The possible implementation of performing such assays offers a novel and interesting tool for investigation and research regarding TBI diagnosis and pathogenesis. Furthermore, the above-mentioned surrogate biofluid assays may be useful in clinical prognosis and risk calculation of non-fatal cases of TBI, considering the development of neurodegenerative conditions of TBI individuals.

Serum Progranulin As a Risk Predictor in Patients with Acute Myocardial Infarction.

BACKGROUND Although progranulin was recently proposed as an adipokine that may be involved in glucose metabolic and inflammatory diseases, the role of serum progranulin in cardiovascular disease is elusive and remains disputed. The aim of our research was to determine the concentration of serum progranulin in Chinese patients with cardiovascular disease, notably in acute myocardial infarction (AMI), and its relationship to other cardiometabolic risk factors. MATERIAL AND METHODS This prospective observational study included 342 Chinese AMI patients and 255 healthy control subjects. Serum progranulin concentrations and various cardiometabolic risk factor levels were investigated. We assessed the relationship between progranulin and other cardiometabolic risk factors. Logistic regression analysis was applied to evaluate risk factors in patients with AMI. RESULTS Progranulin levels were obviously elevated in AMI patients compared to control subjects (P=0.0001). Correlation analysis showed that progranulin levels were positively associated with coronary artery disease severity (r=0.380, P=0.0001), glucose (r=0.195, P=0.015), and myeloperoxidase (r=0.198, P=0.014). In logistic regression analysis, serum progranulin (Exp(B)=1.104, 95% CI=1.043-1.168, P=0.001), myeloperoxidase (Exp(B)=1.006, 95% CI=1.003-1.008, P=0.0001), and uric acid (Exp(B)=1.020, 95% CI=1.009-1.032, P=0.0001) were independent risk factors in AMI patients. CONCLUSIONS Patients with AMI had significantly higher serum progranulin concentrations than control subjects. This study suggests that serum progranulin is an independent risk predictor in Chinese patients with AMI.

Serum Protein Profiling Reveals a Specific Upregulation of the Immunomodulatory Protein Progranulin in Coronavirus Disease 2019.

BACKGROUND: Severe courses of coronavirus disease 2019 (COVID-19) are associated with elevated levels of interleukin 6 (IL-6). However, there is a growing body of evidence pointing to a broad and more complex disorder of proinflammatory and antiviral responses with disturbed interferon signaling in COVID-19. METHODS: In this prospective, single-center registry, we included severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients and patients with similar symptoms and severity of disease but negative for SARS-CoV-2 admitted to the emergency department and compared their serum protein expression profiles. RESULTS: IL-6 abundance was similar in SARS-CoV-2-positive patients (n = 24) compared with SARS-CoV-2-negative controls (n = 61). In contrast, we observed a specific upregulation of the immunomodulatory protein progranulin (GRN). High GRN abundance was associated with adverse outcomes and increased expression of IL-6 in COVID-19. CONCLUSIONS: The data from this registry reveal that GRN is specifically upregulated in SARS-CoV-2-positive patients while IL-6 may serve as marker for disease severity. The potential of GRN as a biomarker and a possible impact of increased GRN expression on interferon signaling, virus elimination, and virus-induced lung tissue damage in COVID-19 should be further explored.

Serum progranulin levels are associated with frailty in middle-aged individuals.

BACKGROUND AND OBJECTIVE: A recent study identified progranulin as a candidate biomarker for frailty, based on gene expression databases. In the present study, we investigated associations between serum progranulin levels and frailty in a population-based sample of late middle-age and older adults. METHODS: We utilized a cohort study that included 358 African Americans (baseline ages 49-65). Frailty was assessed by three established methods: the interview-based FRAIL scale, the Cardiovascular Health Study (CHS) frailty scale that includes performance-based measurements, and the Frailty Index (FI) that is based on cumulative deficits. Serum levels of the following proteins and metabolites were measured: progranulin, cystatin C, fructosamine, soluble cytokine receptors (interleukin-2 and -6, tumor necrosis factor α-1 and -2), and C-reactive protein. Sarcopenia was assessed using the SARC-F index. Vital status was determined by matching through the National Death Index (NDI). RESULTS: Serum progranulin levels were associated with frailty for all indices (FRAIL, CHS, and FI) but not with sarcopenia. Inflammatory markers indicated by soluble cytokine receptors (sIL-2R, sIL-6R, sTNFR1, sTNFR2) were positively associated serum progranulin. Increased serum progranulin levels at baseline predicted poorer outcomes including future frailty as measured by the FRAIL scale and 15-year all-cause mortality independent of age, gender, and frailty. CONCLUSIONS: Our findings suggest that serum progranulin levels may be a candidate biomarker for physical frailty, independent of sarcopenia. Further studies are needed to validate this association and assess the utility of serum progranulin levels as a potential biomarker for prevalent frailty, for risk for developing incident frailty, and for mortality risk over and above the effect of baseline frailty.

Identification of progranulin as a novel diagnostic biomarker for early-onset sepsis in neonates.

Neonatal early-onset sepsis (EOS) is associated with high morbidity and mortality. Accurate early diagnosis is crucial for prompt treatment and a better clinical outcome. We aimed to identify new biomarkers for the diagnosis of EOS. A total of 152 neonates with a risk of EOS were divided into an EOS group and a non-EOS group according to the conventional diagnostic criteria. Blood samples were collected within 0-24, 24-48, and 48-72 h after birth. Serum levels of progranulin (PGRN), interleukin (IL)-33, IL-17a, IL-23, IL-6, tumor necrosis factors α (TNF-α), interferon γ (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), procalcitonin (PCT), and C-reactive protein (CRP) were determined. PGRN levels were significantly elevated in the EOS neonates compared with the levels in the non-EOS neonates (1.53 vs. 0.77 ng/ml (median), P < 0.001), with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.76 (P < 0.001). Compared with PGRN, IL-33, IL-17a, IL-23, IL-6, PCT, and CRP showed significant (AUC > 0.70) but slightly less predictive power for EOS within the same time range. Stepwise multivariate regression analysis identified PGRN, IL-33, and PCT as independent predictors of EOS. In addition, the combined measurements of PGRN, IL-33, and PCT showed significantly higher predictive power for EOS than any of the three markers alone. PGRN showed greater efficacy for predicting EOS than the traditional markers PCT and CRP as well as other potential markers tested in this study. PGRN may serve as an effective biomarker for the early diagnosis of EOS.

Genetically programmed changes in transcription of the novel progranulin regulator.

Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggested PSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation of PSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function of Sall > 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and electrophoretic mobility shift assays (EMSA). In parallel, blood DNA promoter methylation of two regions was tested in subjects with a very high (N = 100) or a very low (N = 100) serum progranulin. Luciferase assays revealed lower activities in vectors carrying the rs629301-A compared with the C allele. Moreover, EMSA indicated a different binding pattern for the two rs629301 alleles, with an additional prominent band for the A allele, which was finally confirmed with the supershift for the Yin Yang 1 transcription factor (YY1). Subjects with high progranulin levels manifested a significantly higher mean DNA methylation (P < 1 × 10-7) in one promoter region, which was in line with a significantly lower PSRC1 mRNA expression levels in blood (P = 1 × 10-3). Consistently, rs629301-A allele was associated with lower PSRC1 mRNA expression (P < 1 × 10-7). Our data suggest that the progranulin-associated variant rs629301 modifies the transcription of PSRC1 through alteration of YY1 binding capacity. DNA methylation studies further support the role of PSRC1 in regulation of progranulin serum levels. KEY MESSAGES: PSRC1 (proline and serine rich coiled-coil 1) SNPs are associated with serum progranulin levels. rs629301 regulates PSRC1 expression by affecting Yin Yang 1 transcription factor (YY1) binding. PSRC1 is also epigenetically regulated in subjects with high progranulin levels.

Serum Adiponectin and Progranulin Level in Patients with Benign Thyroid Nodule or Papillary Thyroid Cancer.

BACKGROUND: Obesity is associated with thyroid cancer risk. Adiponectin has insulin-sensitizing and anti-inflammatory effects, while progranulin is associated with inflammation and tumorigenesis. We investigated serum adiponectin and progranulin levels in patients with benign thyroid nodule (benign group) and papillary thyroid cancer (PTC; PTC group). The associations between these levels and the clinicopathological features of PTC were evaluated. METHODS: We included 157 patients who underwent thyroid surgery (17% of benign and 83% of PTC group). Clinicopathological features including size, lymph node metastasis, extrathyroidal extension (ETE), multifocality, American Thyroid Association risk stratification were evaluated. RESULTS: The age was 42.0 years, and 69% were female. Serum adiponectin and progranulin levels were 6.3 µg/mL and 101.5 ng/mL in the benign group and 5.4 µg/mL and 106.1 ng/mL in the PTC group, respectively (P=0.6 and P=0.4, respectively). Serum adiponectin levels showed no significant differences according to clinicopathological features of PTC. The proportions of patients with primary tumor size >1 cm were 3%, 5%, 8%, and 8% according to serum progranulin level quartiles, respectively (P=0.03). The proportions of patients with microscopic/gross ETE were 8%/0%, 9%/1%, 11%/1%, and 11%/2% according to serum progranulin level quartiles, respectively. Median serum progranulin level was significantly higher in patients with PTC >1 cm than in patients with papillary thyroid microcarcinoma (P=0.04, 115.3 ng/mL and 104.7 ng/mL, respectively). CONCLUSION: Serum adiponectin and progranulin levels showed no significant difference between benign and PTC groups. Increased serum progranulin levels were significantly associated with PTC >1 cm and microscopic and gross ETE.