MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Bonella F
PROVIDER: S-EPMC4841967 | biostudies-literature | 2016
REPOSITORIES: biostudies-literature
Publications
MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis.
Bonella Francesco F Long Xiaoping X Ohshimo Shinichiro S Horimasu Yasushi Y Griese Matthias M Guzman Josune J Kohno Nobuoki N Costabel Ulrich U
Orphanet journal of rare diseases 20160423
<h4>Background</h4>KL-6, a human MUC1 mucin, is a sensitive biomarker for interstitial lung diseases including pulmonary alveolar proteinosis (PAP). A correlation between MUC1 gene single nucleotide polymorphism (SNP) rs4072037 genotype and serum KL-6 levels has been reported. This study was aimed at investigating the correlation between MUC1 SNP genotype, severity of disease and disease outcome in PAP.<h4>Methods</h4>Twenty four patients with PAP and 30 healthy volunteers were studied. MUC1 rs4 ...[more]
Similar Datasets
Project description:BackgroundKL-6 is a biomarker of the severity of pulmonary alveolar proteinosis (PAP). We noticed a significant difference in the mean serum KL-6 level between Japanese and Caucasian patients. To assess the clinical value of serum KL-6 in Chinese PAP patients, and to compare the differences in serum KL-6 levels in Chinese patients and patients of other ethnicities.MethodsFrom 2014-2016, we prospectively examined 37 Chinese Han patients with PAP, measured their serum KL-6 levels, evaluated the correlation between initial KL-6 levels and clinical variables, and compared our results with studies from Japan and Germany (similar methods were used). We searched dbSNP for the MUC1 568 (rs4072037) genotype or allele frequency distributions in China, Japan, and Germany.ResultsInitial serum KL-6 levels were significantly correlated with baseline PaO2, A-aDO2, DLCO, FVC, and LDH levels (all P<0.001). Compared with Chinese PAP patients, the mean serum KL-6 level was significantly lower in German PAP patients (P<0.001) but not in Japanese PAP patients (P>0.4). In the rs4072037 allele frequency distributions, the frequency of the A/A genotype was significantly higher while that of the G/G genotype was significantly lower in Chinese and Japanese cohorts than in Caucasian cohorts (both P<0.001).ConclusionsSerum KL-6 can be used as a biological indicator for disease monitoring in Chinese patients. The difference in serum KL-6 level among Chinese, German, and Japanese PAP patients may be associated with the distribution of the rs4072037 genotype.
| S-EPMC5334078 | biostudies-literature
Project description:BACKGROUND: It is well known that pulmonary alveolar proteinosis(PAP) is characterised by accumulation of surfactant lipids and proteins within airspaces. However, few previous data describe the serum lipid levels associated with PAP. MATERIALS AND METHODS: We retrospectively reviewed 25 patients with idiopathic PAP(iPAP). The serum lipid levels of patients with idiopathic PAP were compared with those of the healthy volunteers. In patients and healthy subjects, the LDL-C/HDL-C ratios were 2.94 ± 1.21 and 1.60 ± 0.70, respectively (p < 0.001), HDL-C were 1.11 ± 0.27 and 1.71 ± 0.71 respectively (p < 0.001). The values of LDL-C correlated significantly with those of PaO2 and PA-aO2 (r = -0.685, p = 0.003, and r = 0.688, p = 0.003, respectively). The values of LDL-C/HDL-C ratios also correlated with PaO2 levels and PA-aO2 levels (r = -0.698, p = 0.003, and r = 0.653, p = 0.006, respectively). 11 and 13 patients experienced respectively a decline in TC and LDL-C levels following whole lung lavage(WLL), the median decline was 0.71 mmol/L(p < 0.009) and 0.47 mmol/L(p < 0.003), respectively. CONCLUSIONS: the serum lipid levels, especially the levels of LDL-C and LDL-C/HDL-C, may reflect the severity of the disease in PAP patients, and predict the therapeutic effect of WLL.
| S-EPMC3271981 | biostudies-literature
Project description:Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.
| S-EPMC8604941 | biostudies-literature
Project description:Pulmonary alveolar proteinosis (PAP) comprises a heterogenous group of diseases characterized by abnormal surfactant accumulation resulting in respiratory insufficiency, and defects in alveolar macrophage- and neutrophil-mediated host defense. Basic, clinical and translational research over the past two decades have raised PAP from obscurity, identifying the molecular pathogenesis in over 90% of cases as a spectrum of diseases involving the disruption of GM-CSF signaling. Autoimmune PAP represents the vast majority of cases and is caused by neutralizing GM-CSF autoantibodies. Genetic mutations that disrupt GM-CSF receptor signaling comprise a rare form of hereditary PAP. In both autoimmune and hereditary PAP, loss of GM-CSF signaling blocks the terminal differentiation of alveolar macrophages in the lungs impairing the ability of alveolar macrophages to catabolize surfactant and to perform many host defense functions. Secondary PAP occurs in a variety of clinical diseases that presumedly cause the syndrome by reducing the numbers or functions of alveolar macrophages, thereby impairing alveolar macrophage-mediated pulmonary surfactant clearance. A similar phenotype occurs in mice deficient in the production of GM-CSF or GM-CSF receptors. PAP and related research has uncovered a critical and emerging role for GM-CSF in the regulation of pulmonary surfactant homeostasis, lung host defense, and systemic immunity.
| S-EPMC2866141 | biostudies-literature
Project description:Pulmonary Alveolar Proteinosis (PAP) patients exhibit an acquired deficiency of biologically active granulocyte-macrophage colony stimulating factor (GM-CSF) attributable to GM-CSF specific autoantibodies. PAP alveolar macrophages are foamy, lipid-filled cells with impaired surfactant clearance and markedly reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPAR?) and the PPAR?-regulated ATP binding cassette (ABC) lipid transporter, ABCG1. An open label proof of concept Phase II clinical trial was conducted in PAP patients using rituximab, a chimeric murine-human monoclonal antibody directed against B lymphocyte specific antigen CD20. Rituximab treatment decreased anti-GM-CSF antibody levels in bronchoalveolar lavage (BAL) fluid, and 7/9 patients completing the trial demonstrated clinical improvement as measured by arterial blood oxygenation.This study sought to determine whether rituximab therapy would restore lipid metabolism in PAP alveolar macrophages.BAL samples were collected from patients pre- and 6-months post-rituximab infusion for evaluation of mRNA and lipid changes.Mean PPAR? and ABCG1 mRNA expression increased 2.8 and 5.3-fold respectively (p???0.05) after treatment. Lysosomal phospholipase A2 (LPLA2) (a key enzyme in surfactant degradation) mRNA expression was severely deficient in PAP patients pre-treatment but increased 2.8-fold post-treatment. In supplemental animal studies, LPLA2 deficiency was verified in GM-CSF KO mice but was not present in macrophage-specific PPAR? KO mice compared to wild-type controls. Oil Red O intensity of PAP alveolar macrophages decreased after treatment, indicating reduced intracellular lipid while extracellular free cholesterol increased in BAL fluid. Furthermore, total protein and Surfactant protein A were significantly decreased in the BAL fluid post therapy.Reduction in GM-CSF autoantibodies by rituximab therapy improves alveolar macrophage lipid metabolism by increasing lipid transport and surfactant catabolism. Mechanisms may involve GM-CSF stimulation of alveolar macrophage ABCG1 and LPLA2 activities by distinct pathways.
| S-EPMC3432632 | biostudies-literature
Project description:This case report demonstrates 44-year old man, presenting with recurring clinical pneumonias during a period of over 1 year. The patient was clinically affected with, i.a., weight loss, finger clubbing and severely reduced diffusion capacity. Repetitive chest x-rays showed bilateral and consolidating infiltrates, and a high-resolution computed tomography of the thorax (HRCT) exposed ground glass opacities superimposed on a reticular pattern as the so-called 'crazy paving' pattern. A bronchoscopic alveolar lavage revealed alveolar proteinaceous material compatible with the diagnosis pulmonary alveolar proteinosis (PAP). PAP is a rare syndrome where surfactant is accumulated in the alveoli, causing respiratory disease in typically young to middle-aged patients with male predominance. Both symptoms and prognosis are variable, and range from spontaneous remission to terminal respiratory failure. The standard treatment is whole lung lavage, where surfactant is mechanically rinsed from the lungs. The lack of specific clinical symptoms makes it easy to overlook the diagnosis, as supported by this case report. It serves as a reminder, that the findings of a crazy paving pattern on HRCT in young adults should alert of this rare disease, and advises on the further examinations required to make the diagnosis.
| S-EPMC6282426 | biostudies-literature
Project description:BackgroundAutoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP.MethodsIn a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo2) at week 24.ResultsIn total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo2 at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group.ConclusionsIn patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).
| S-EPMC8083051 | biostudies-literature
Project description:Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Ralpha) and nonbinding affinity-enhancing (GM-CSF-Rbeta) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Ralpha-encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Ralpha, severely reducing GM-CSF binding, receptor signaling, and GM-CSF-dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP.
| S-EPMC2585845 | biostudies-literature
Project description:Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR]?=?5.2; P?=?2.4?×?10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR?=?4.8; P?=?4.8?×?10-12), followed by an additional independent risk allele at HLA-DP?1 amino acid position 8 (OR?=?0.28; P?=?3.4?×?10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (??=?0.32; P?=?0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.
| S-EPMC7884840 | biostudies-literature
Project description:Pulmonary alveolar proteinosis (PAP) is a syndrome of reduced GM-CSF-dependent, macrophage-mediated surfactant clearance, dysfunctional foamy alveolar macrophages, alveolar surfactant accumulation, and hypoxemic respiratory failure for which the pathogenetic mechanism is unknown. Here, we examine the lipids accumulating in alveolar macrophages and surfactant to define the pathogenesis of PAP and evaluate a novel pharmacotherapeutic approach. In PAP patients, alveolar macrophages have a marked increase in cholesterol but only a minor increase in phospholipids, and pulmonary surfactant has an increase in the ratio of cholesterol to phospholipids. Oral statin therapy is associated with clinical, physiological, and radiological improvement in autoimmune PAP patients, and ex vivo statin treatment reduces cholesterol levels in explanted alveolar macrophages. In Csf2rb-/- mice, statin therapy reduces cholesterol accumulation in alveolar macrophages and ameliorates PAP, and ex vivo statin treatment increases cholesterol efflux from macrophages. These results support the feasibility of statin as a novel pathogenesis-based pharmacotherapy of PAP.
| S-EPMC6081448 | biostudies-literature