Elevated plasma YKL-40 and risk of infectious disease: a prospective study of 94665 individuals from the general population

ObjectivesYKL-40 is an acute phase protein elevated in patients with infectious and inflammatory diseases. We tested the hypothesis that baseline elevated YKL-40 is associated with increased risk of future infectious disease in healthy individuals in the general population.MethodsWe prospectively followed 94 665 individuals from the Danish general population for up to 23 years and analysed for plasma YKL-40 levels (n = 21 584) and CHI3L1 rs4950928 genotype (n = 94 184). Endpoints were any infection, bacterial pneumonia, urinary tract infection, skin infection, sepsis, diarrhoeal disease, and other infections.ResultsFor YKL-40 percentile category 91–100% versus 0–33%, the multifactorially and C-reactive protein (CRP) adjusted hazard ratios were 1.71 (95% confidence interval 1.50–1.96; p 4 × 10⁻¹⁴) for any infection, 1.97 (1.64–2.37; p 4 × 10⁻¹³) for bacterial pneumonia, 1.62 (1.24–2.11; p 0.002) for urinary tract infection, 1.74 (1.31–2.32; p 2 × 10⁻⁴) for skin infection, 1.76 (1.25–2.46; p 0.004) for sepsis, 1.90 (1.29–2.78; p 0.002) for diarrhoeal disease and 2.71 (1.38–5.35; p 0.01) for other infections. In multifactorially and CRP-adjusted models, a twofold increase in YKL-40 was associated with increased risk of all infectious disease endpoints. Mendelian randomization did not support causality, as CHI3L1 rs4950928 was associated with 94% and 190% higher YKL-40 levels (for CG and CC versus GG genotype), but not with increased risk of any infectious disease endpoint.DiscussionBaseline elevated plasma YKL-40 was not a cause but a strong marker of increased risk of future infectious diseases in individuals in the general population.     

Subcellular Localization of YKL-40 in Normal and Malignant Epithelial Cells of the Breast

YKL-40 is a new prognostic biomarker in cancer. The biological function is only poorly understood. This study aimed at determining the subcellular localization of YKL-40, using immunogold labeling, in normal epithelial cells and in malignant tumor cells of the breast by immunoelectron microscopy. YKL-40 protein expression was redistributed in carcinoma versus normal glandular tissue of the breast. A reduced expression of YKL-40 in relation to intermediate filaments and desmosomes was found in tumor cells. Changes in YKL-40 expression suggest that the function of YKL-40 in cells of epithelial origin may be related to cell motility and cell–cell adhesion, features associated with invasion and migration potential of tumor cells.     

MP-IgM、YKL-40、APOC1和IL-6在儿童支原体肺炎治疗及预后中的意义

目的探讨肺炎支原体抗体(mycoplasma pneumoniae immunoglobulin M,MP-IgM)、人软骨糖蛋白39(human cartilage glycoprotein 39,YKL-40)、载脂蛋白C1(apolipoprotein C-I,APOC1)和白细胞介素-6(interleukin 6,IL-6)在儿童支原体肺炎治疗及预后中的意义。方法选取2017年1月至2017年12月本院确诊的80例儿童支原体肺炎患儿为观察组给予对症治疗,选取同期健康体检儿童40例为对照组。分别检测两组儿童外周静脉血中MP-IgM、YKL-40、APOC1和IL-6表达水平。结果与对照组相比,观察组患儿血清YKL-40、APOC1和IL-6表达水平显著升高,血清MP-IgM呈明显阳性;观察组血清YKL-40、APOC1和IL-6表达水平治疗后显著降低,血清MP-IgM阳性(P <0.05)。儿童支原体肺炎血清YKL-40、APOC1和IL-6水平,MP-IgM阳性率与疾病严重程度存在显著的正相关关系,P<0.05。经ROC分析可知,MP-IgM、YKL-40、APOC1和IL-6这4项生物学标志物并联试验灵敏度为92.00%,串联试验特异性为100.00%,显著大于各单项生物学标志物检测(P<0.05)。与对照组相比,观察组患儿FEV_1/FVC(%)及FEV_1%预计值显著降低(P<0.05)。与治疗前相比,观察组患儿治疗后FEV_1/FVC(%)及FEV_1%预计值显著升高(P<0.05)。儿童肺炎支原体患儿YKL-40、APOC1和IL-6水平,MP-IgM阳性率与患儿肺功能存在显著的负相关关系,P<0.05。结论儿童支原体肺炎患儿血清MP-IgM、YKL-40、APOC1和IL-6表达水平异常升高;监测患儿血清MP-IgM、YKL-40、APOC1和IL-6水平变化对于辅助诊断和评价儿童支原体肺炎的病情程度和治疗具有一定的临床意义,值得推广研究。     

急性脑梗死患者血清YKL-40检测的临床意义

目的通过检测急性脑梗死患者发病后48h内血清YKL-40的表达量,探讨其与牛津郡社区卒中项目（OCSP）分型及梗死面积大小的关系,以指导临床诊治。方法对54例急性脑梗死患者和20例正常对照者进行血清YKL-40的检测,然后分析其与病情程度及临床分型的关系。结果急性脑梗死患者血清YKL-40浓度中位数为158.47ng/ml（IR：182.40）,正常对照组为50.50ng/ml（IR：34.85）,两组比较差异有统计学意义（P〈0.001）;OCSP各亚型YKL-40升高幅度不同,完全前循环梗死（TACI）型表达量明显高于其他亚型（P〈0.01）;YKL-40在大梗死型的含量显著高于其他亚型（P〈0.02）。结论脑梗死后血清YKL-40水平升高,与病灶大小相关,在不同OCSP分型之间表达量不同,血清YKL-40可能成为指导脑梗死临床分型及评估病情程度的新的生物学指标。     

Circulating YKL-40 levels during human endotoxaemia

YKL-40 is secreted by macrophages and neutrophils and patients with bacterial infections have elevated circulating YKL-40. The aim was to evaluate changes in plasma YKL-40 (determined by enzyme-linked immunosorbent assay (ELISA) at 0, 2, 4, 8, 24 and 32 h) in eight healthy volunteers after injection with Esherichia coli endotoxin or saline. Plasma YKL-40 increased after endotoxin injection from 31 microg/l (range 19-39 microg/l) to a maximum of 159 microg/l (61-552 microg/l, P < 0.01) at 24 h. The finding that plasma YKL-40 increased after endotoxin injection compared with saline (P < 0.001) suggests that YKL-40 has a functional role in infections.     

血清YKL-40蛋白水平与非肌层浸润性膀胱癌复发的临床关系研究

目的:探讨患者血清YKL-40蛋白水平与非肌层浸润性膀胱癌(non muscle-invasive bladder cancer, NMIBC)复发的临床关系.方法:选取76例NMIBC患者,其中34例为术后随访两年内确诊复发患者、42例为术后随访两年未见复发患者,及健康对照组31例,采取清晨血清样本,采用酶联接免疫吸附剂测定法(ELISA)检测患者血清中YKL-40水平.结果:NMIBC患者血清YKL-40水平显著高于健康对照组(P<0.001),同时,NMIBC复发组患者血清YKL-40水平高于非复发组(P=0.001).结论:血清YKL-40蛋白水平在非肌层浸润性膀胱癌复发中有着较高的临床诊断价值,可作为监测患者术后复发的一种新分子标志物,为患者术后相关后续治疗提供参考.     

双抗体夹心法测定血清YKL-40在肝硬化中的诊断价值研究

探讨肝硬化(liver cirrhosis,LC)患者外周血中血清YKL-40(壳多糖酶3样蛋白1)蛋白水平及其在LC中的诊断意义。采用ELISA方法共检测112例LC患者以及114例健康者血清中YKL-40蛋白水平,并进一步分析其在LC中的诊断价值及其与LC患者肝功能和现有肝纤维化指标的相关性。LC组血清YKL-40蛋白水平高于正常对照组(P0.001);将LC组和对照组作比较,ROC曲线分析血清YKL-40蛋白对LC的诊断效能,曲线下面积(area under the curve,AUC)为0.934(95%置信区间为:0.904~0.964),YKL-40在cutoff值为92.25ng/mL时,敏感度为81.3%,特异度为90.4%;通过相关性分析发现血清YKL-40蛋白水平与肝功能Child-Pugh分级和FIB-4指数正相关。YKL-40对LC具有良好的诊断效力,能辅助诊断LC并有助于判断LC的严重程度。     

Overexpression of YKL-40 is an independent prognostic marker in gastric cancer

YKL-40 is a growth factor for connective tissue cells and a migration factor for endothelial cells. Elevated serum level of YKL-40 has been associated with poor prognosis in many cancers. However, the status of YKL-40 expression and its clinical/prognostic significance in gastric cancer are unclear. In this study, the expression of YKL-40 was studied by immunohistochemistry in gastric cancer tissue microarray containing 172 primary gastric cancer cases and 70 adjacent nonneoplastic mucosa specimens. The correlations between YKL-40 expression and clinicopathologic features, as well as activation of PI3K/Akt pathways were addressed. Expression of YKL-40 was significantly higher in gastric cancer tissues than that in adjacent nonneoplastic tissues. Overexpression YKL-40 was found in 28.4% of gastric cancers and was significantly associated with tumor invasion (P = .007) and lymph node metastasis (P = .009). For survival study, overexpression of YKL-40 was significantly associated with worse outcome (P = .001). When known clinical variables were added to a multivariate analysis, TNM stage, tumor size, and overexpression of YKL-40 emerged as independent prognostic factors. Further study indicated that the oncogenic function of YKL-40 might be through the activation of Akt pathway. These results suggest that overexpression of YKL-40 is correlated with the aggressive behavior of tumor cells, which could be used as an independent molecular marker for the predicting poor prognosis of patients with gastric cancer.     

YKL-40 is directly produced by tumor cells and is inversely linked to EGFR in glioblastomas

YKL-40 is a secreted chitinase-like molecule whose expression is associated with glioma grade. Expression is higher in astrocytomas than oligodendrogliomas and has been reported to predict shorter survival and radiation resistance in glioblastomas (GBMs). Whether YKL-40 is directly produced by glioma cells or other admixed nonneo-plastic cells, and whether it correlates with 1p/19q status or other hallmark molecular abnormalities, are unclear. A rank-order list of YKL-40 expression was determined immunohistochemically in 79 untreated high-grade adult glio-mas, including 28 anaplastic oligodendrogliomas (AOs) and 51 GBMs. Relative YKL-40 expression was compared with glioma class, key molecular alterations, and immunohistochemical markers via a series of Spearman rank correlations. YKL-40 mRNA in situ hybridization with colocalization assessment via confocal microscopy was also performed. YKL-40 mRNA was abundant in glioma cells as well as reactive astrocytes, but was low in admixed neurons and macrophages. YKL-40 expression was higher in GBMs than AOs (P < 0.0001) and among GBMs, YKL-40 expression was lower in tumors with either EGFR amplification (P = 0.005) or elevated EGFR expression (P = 0.001). Among AOs, no difference in YKL-40 expression was seen in tumors with 1p19q codeletion (P = 0.3), but loss of heterozygos-ity in 10q23 correlated with increased YKL-40 expression (P = 0.03). These data suggest that YKL-40 is predominantly expressed by neoplastic glial cells and is related to certain key molecular alterations.     

Role of breast regression protein-39/YKL-40 in asthma and allergic responses

BRP-39 and its human homolog YKL-40 have been regarded as a prototype of chitinase-like proteins (CLP) in mammals. Exaggerated levels of YKL-40 protein and/or mRNA have been noted in a number of diseases characterized by inflammation, tissue remodeling, and aberrant cell growth. Asthma is an inflammatory disease characterized by airway hyperresponsiveness and airway remodeling. Recently, the novel regulatory role of BRP-39/YKL-40 in the pathogenesis of asthma has been demonstrated both in human studies and allergic animal models. The levels of YKL-40 are increased in the circulation and lungs from asthmatics where they correlate with disease severity, and CHI3L1 polymorphisms correlate with serum YKL-40 levels, asthma and abnormal lung function. Animal studies using BRP-39 null mutant mice demonstrated that BRP-39 was required for optimal allergen sensitization and Th2 inflammation. These studies suggest the potential use of BRP-39 as a biomarker as well as a therapeutic target for asthma and other allergic diseases. Here, we present an overview of chitin/chitinase biology and summarize recent findings on the role of BRP-39 in the pathogenesis of asthma and allergic responses.     

上皮性卵巢癌患者肿瘤组织及血清中YKL-40的表达及临床意义

目的探讨甲壳质酶蛋白40（YKL-40）在上皮性卵巢肿瘤发生发展中的作用。方法 （1）免疫组化法检测20例上皮性良性卵巢肿瘤、10例交界性卵巢肿瘤及30例卵巢癌组织中YKL-40的表达情况。（2）酶联免疫吸附法检测三组患者血清中YKL-40的水平。结果 （1）YKL-40在卵巢癌组织的阳性表达率高于良性组（P〈0.05）;交界组与卵巢癌组无差异（P〉0.05）,但卵巢癌组YKL-40染色强度高于交界组（P〈0.05）;早期卵巢癌（Ⅰ、Ⅱ期）组织中阳性表达率低于晚期卵巢癌（Ⅲ、Ⅳ期）组织中阳性表达率（P〈0.05）,YKL-40组织中表达水平与卵巢癌临床分期呈正相关（P〈0.05）。（2）上皮性良性卵巢肿瘤、交界性卵巢肿瘤及卵巢癌患者中,血清YKL-40的中位数分别为41.42、44.34、130.25（μg/L）。卵巢癌组血清YKL-40水平高于前二组,差异有统计学意义（P〈0.05）,前二组比较差异无统计学意义。卵巢癌患者血清YKL-40浓度与临床分期及CA125浓度呈正相关（P〈0.05）。结论 YKL-40蛋白可能参与了卵巢肿瘤的发生发展过程。     

YKL-40, a biomarker of inflammation, is elevated in patients with type 2 diabetes and is related to insulin resistance

Objective and design. YKL-40 participates in inflammatory states and vascular processes, which implies that comparison can be made with other inflammatory markers associated with insulin resistance and type 2 diabetes (T2D). In the present study levels of plasma YKL-40 and serum hsCRP were evaluated in patients with T2D. Materials and methods. Patients with T2D and age-matched healthy controls participated in the study. Insulin resistance was estimated using HOMA-IR model. Biochemical parameters were measured in venous blood after a 10 h fast. Results. Patients with T2D were insulin resistant (p < 0.001) and had raised levels of plasma YKL-40 (p < 0.001) and serum hsCRP (p < 0.001). YKL-40 was correlated with HOMA-IR (r = 0.23, p < 0.01), NEFA (r = 0.32, p < 0.001) and triglycerides (r = 0.24, p < 0.05). YKL-40 and hsCRP were not correlated (r = 0.17, p = NS). All participants with hsCRP < 1 mg/l had higher insulin sensitivity (p < 0.05 and p < 0.01, respectively). HsCRP were predicted by HOMA-IR and BMI (r² = 0.48, p < 0.01). Plasma YKL-40 was predicted by HOMA-IR and triglycerides (r² = 0.27, p < 0.01). Conclusions. YKL-40 and hsCRP are elevated in patients with T2D and are related to insulin resistance. No correlation was found between YKL-40 and hsCRP indicating that increased levels of YKL-40 occur independently from elevated plasma hsCRP. Received 17 September 2005; returned for revision 17 October 2005; accepted by I. Ahnfelt-R?nne 18 October 2005     

YKL-40, a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis

Substantial evidence supports a role of chronic subclinical inflammation and activation of the innate immune system in the pathogenesis of insulin resistance and endothelial dysfunction and the development of type 2 diabetes (T2D) and atherosclerosis. Several proinflammatory cytokines, acute phase-reactants and cell adhesion molecules play a pivotal role in this chronic subclinical inflammation but a comprehensive understanding of the interrelations of these molecules is still needed. YKL-40 is a new inflammatory marker with relation to acute and chronic inflammation as well as cancer. It is secreted in vitro from a variety of human cells, including vascular smooth muscle cells (VSMCs), activated macrophages and macrophages during late stages of differentiation and is found in vivo in subpopulations of macrophages in tissues with inflammation and extracellular tissue remodelling, such as macrophages in atherosclerotic plaques. YKL-40 promotes chemotaxis, cell attachment and migration of VSMCs and the formation of branching tubules suggesting that YKL-40 plays a role in angiogenesis. Latest studies reveal that YKL-40 is elevated in patients with T2D and is related to insulin resistance. This article reviews the studies of YKL-40 with focus on a possible role of YKL-40 in insulin resistance, endothelial dysfunction and atherosclerosis. Received 16 November 2005; returned for revision 25 January 2006; accepted by I. Ahnfelt-R?nne 8 February 2006     

血浆YKL-40浓度对危重症患者并发腹腔间隙综合征的预测作用

目的:揭示危重症患者血浆YKL-40浓度的变化,探讨其对危重症患者并发腹腔间隙综合征的预测价值。方法:收集危重症患者和健康体检人群各98例。健康体检人群静脉血体检时获得,危重症患者静脉血在入院时获得。ELISA检测血浆YKL-40浓度。结果:危重症患者血浆YKL-40浓度(146.8±79.5)ng/ml显著高于健康体检者(39.4±12.5)ng/ml(t=8.749,P<0.01),与APACHEⅡ评分,呈显著正相关性(r=0.591,P<0.01)。28例(28.6%)并发腹腔间隙综合征。多因素分析显示,血浆YKL-40浓度(OR=1.492,95%CI=1.231～2.116,P<0.01)是危重症患者并发腹腔间隙综合征的独立危险因素。ROC曲线分析显示,血浆YKL-40浓度预测危重症患者并发腹腔间隙综合征有显著预测价值(曲线下面积=0.842,95%CI=0.791～0.914,P<0.001),且判定血浆YKL-40浓度>172.4 ng/ml,对预测并发腹腔间隙综合征有82.1%的灵敏度和78.6%的特异度。结论:危重症患者并发腹腔间隙综合征后,血浆YKL-40浓度显著升高,临床检测YKL-40作为有预报价值的标志物,有助于早期判断腹腔间隙综合征的发生。     

Increased immunohistochemical expression of YKL-40 in the spleen of patients with portal hypertension

YKL-40 has been identified as a growth factor in connective tissue cells and also a migration factor in vascular smooth muscle cells. To a large extent, the increase of serum YKL-40 is attributed to liver fibrosis and asthma. However, the relationship of the expression and clinical/prognostic significance of YKL-40 to the splenomegaly of patients with portal hypertension is unclear. In the present study, the expression of YKL-40 was studied by immunohistochemistry in 48 splenomegaly tissue samples from patients with portal hypertension and in 14 normal spleen specimens. All specimens were quickly stored at -80°C after resection. Primary antibodies YKL-40 (1:150 dilution, rabbit polyclonal IgG) and MMP-9 (1:200 dilution, rabbit monoclonal IgG) and antirabbit immunoglobulins (HRP K4010) were used in this study. The relationship of clinicopathologic features with YKL-40 is presented. The expression of YKL-40 indicated by increased immunochemical reactivity was significantly up-regulated in splenomegaly tissues compared to normal spleen tissues. Overexpression of YKL-40 was found in 68.8% of splenomegaly tissues and was significantly associated with Child-Pugh classification (P = 0.000), free portal pressure (correlation coefficient = 0.499, P < 0.01) and spleen fibrosis (correlation coefficient = 0.857, P < 0.01). Further study showed a significant correlation between YKL-40 and MMP-9 (correlation coefficient = -0.839, P < 0.01), indicating that YKL-40 might be an accelerator of spleen tissue remodeling by inhibiting the expression of MMP-9. In conclusion, YKL-40 is an important factor involved in the remodeling of spleen tissue of portal hypertension patients and can be used as a therapeutic target for splenomegaly.     

血清sICAM-1、YKL-40联合心肌酶谱检测在肺炎患儿诊断及疗效观察中的价值分析

目的研究血清细胞间粘附分子(soluble intercellular adhesion molecule 1,sICAM-1)、人软骨糖蛋白39 (human cartilage glycoprotein 39,YKL-40)联合心肌酶谱检测在肺炎患儿诊断及疗效观察中的价值分析。方法选取2017年2月至2018年2月期间的100例小儿肺炎患者,另选健康人群100例作为对照组,对比普通肺炎、重症肺炎患者和正常人群血清sICAM-1、YKL-40、CK、TNF-α、IL-6、IL-8表达水平,不同病情程度患者多因素Logistic回归分析以及单独检测和联合检测对患者重症肺炎和普通肺炎的诊断和治疗效能。结果血清sICAM-1、YKL-40、CK、TNF-α、IL-6、IL-8表达水平从高到低依次为重症肺炎组、普通肺炎组以及对照组;血清sICAM-1、YKL-40、CK、TNF-α、IL-6、IL-8表达水平均可作为肺炎的独立危险因素(P <0. 001),分别将普通肺炎和重症肺炎患者与对照组展开检测效能对比,分析可得普通肺炎和重症肺炎患者的sICAM-1临界值分别为140.80 ng/mL、160.82 ng/mL, YKL-40临界值分别为29.84ng/mL、32.61ng/mL,CK临界值分别为184.21 U/L、197.15U/L;sICAM-1、YKL-40、CK指标曲线下面积高于0.7,具有较高的诊断准确性。结论血清sICAM-1、YKL-40联合心肌酶谱检测在肺炎患儿诊断及疗效观察中具有积极的作用,建议在临床工作中进行推广。     

Overexpression of chitinase-3-like protein 1 is associated with structural recurrence in patients with differentiated thyroid cancer

We previously identified that the expression of chitinase-3-like protein 1 (CHI3L1) was upregulated during thyroid cancer progression. Here, we investigated the prognostic significance of CHI3L1 expression in thyroid neoplasms and examined the potential oncogenic roles. CHI3L1 immunochemical staining was performed on tissue microarrays of benign and malignant thyroid tumours. Compared with normal thyroid tissue and benign thyroid lesions that had low or no detectable CHI3L1 expression, CHI3L1 was overexpressed in both differentiated and undifferentiated thyroid cancer. High CHI3L1 expression was associated with extrathyroidal extension, lymph node metastasis, and shorter recurrence-free survival in differentiated thyroid cancer. The biological roles of CHI3L1 were further investigated by gain- and loss-of-function assays. CHI3L1 silencing suppressed clonogenicity, migration, invasion, anoikis resistance, and angiogenesis in thyroid cancer cells, although exogenous CHI3L1 treatment promoted these malignant phenotypes. Cysteine-rich angiogenic inducer 61 (CYR61) was identified as a downstream target of CHI3L1 by RNA-seq analysis. CYR61 silencing or treatment reversed the alterations induced by CHI3L1 modulation. Our results demonstrate that CHI3L1 is overexpressed in thyroid cancer and is associated with an increased risk of disease recurrence. Additionally, CYR61 may participate in CHI3L1-mediated tumour progression. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The concomitant presence of polymorphic alleles of interleukin-1beta, interleukin-6 and apolipoprotein E is associated with an increased risk of myocardial infarction in elderly men. Results from a pilot study

Genetic background of inflammatory or anti-inflammatory molecules may be helpful in identifying subjects with increased or decrease risk of developing cardiovascular disease. Bi-allele polymorphism (C > T) in the promoter region (-511) of the interleukin-1beta (IL-1beta) gene and the bi-allele polymorphism (G > C) in the promoter region (-174) of interleukin-6 (IL-6) gene were determined in elderly men patients with myocardial infarction (MI) and healthy controls. Each subject was also genotyped for the triallelic polymorphism of the apolipoprotein E epsilon gene. The IL-6C and APOE epsilon4 alleles were independently associated with a mild or moderate increased risk of MI, whilst the allele C of the IL-1beta was not independently linked to MI risk. However, the simultaneous presence of the allele C of IL-1beta, the allele C of IL-6 and epsilon4 allele of APOE was strongly associated with the disease. Data from this cross-sectional study suggest that the functional interaction of these three genes affects pathogenetic mechanisms of MI and an impaired regulation of immune responses plays a pivotal role in the disease. Furthermore, genetic background of inflammatory genes may influence longevity of human species by affecting inflammatory responses associated to cardiovascular diseases. The administration of anti-inflammatory compounds to middle age healthy subjects with increased genetic susceptibility of developing MI might decrease the incidence and prevalence of cardiovascular events in aging.