ORIGINAL ARTICLE

Plasma Pentraxin 3 as a Biomarker of Metabolic Syndrome

Fatih Kardas & Leyla Akın & Selim Kurtoglu &

Mustafa Kendirci & Zehra Kardas

Received: 7 April 2014 /Accepted: 10 July 2014# Dr. K C Chaudhuri Foundation 2014

AbstractObjective To assess the plasma Pentraxin 3 (PTX3) concen-trations in obese children and to investigate the relationshipbetween PTX3 levels and metabolic syndrome (MS)components.Methods Seventy-seven obese patients aged 10–16 y (38girls, 39 boys) were included in the study. PTX3 levels werecompared between the groups with or without MS. In addi-tion, PTX3 was analysed separately by subgroups accordingto the presence of specific MS components.Results Plasma PTX3 concentrations were significantlyhigher in obese children and adolescents with metabolic syn-drome than in those without MS (2.1±1.2 ng/ml and 1.4±0.9 ng/ml respectively; P=0.02). Patients with low HDLlevels (<40 mg/dl) had higher plasma PTX3 concentrationsthan those with normal HDL levels (P=0.05). Similarly, thosewho had high triglyceride levels (≥150 mg/dl) had higherPTX3 levels (P=0.01). PTX3 levels were negatively correlat-ed with HDL cholesterol (r=−0.32, P=0.003) among allpatients.Conclusions PTX3 levels are higher in obese children andadolescents with metabolic syndrome than in those withoutMS. Thus, PTX3 levels might be a useful biomarker forchildren and adolescents with metabolic syndrome, dyslipid-emia, and cardiovascular risks.

Keywords Pentraxin 3 .Metabolic syndrome . Children .

Adolescents

Introduction

The prevalence of overweight and obese children have in-creased in recent years all over the world, especially in devel-oped countries and, to a lesser degree, in developing countries.As a result of the increased prevalence of obesity, metabolicsyndrome (MS), which includes glucose intolerance, insulinresistance, central obesity, dyslipidemia, and hypertension, isincreasing as well [1, 2].

It is known that obesity causes a chronic systemic inflam-matory state that is initiated by elevated levels of severalsubstances, such as C - reactive protein (CRP) and tumornecrois factor - alpha (TNF - α) [3, 4]. Pentraxin 3 (PTX3),a novel inflammatory marker, is a member of the long pentra-xin family. It is expressed in cell types such as mononuclearphagocytes, fibroblasts, liver cells, endothelial cells and adi-pocytes in response to cytokines such as interleukin - 1 (IL - 1)and TNF - α and is present specifically in cardiac muscles[5–7]. PTX3 is produced as a response to tissue damage,especially in adipocytes, cardiac and skeletal muscle cells[8]. In recent decades, the pathogenic relationship betweenobesity and cardiovascular risk has been intensively investi-gated. The association of plasma PTX3 concentrations withcardiovascular diseases, such as acute myocardial infarction,chronic heart failure, and metabolic syndrome has been re-ported in adults. However, the results of these studies areconflicting [4, 6, 9]. In a recent study conducted on a total of57 obese and overweight children, Chu et al. [8] investigatedthe association of PTX3 and insulin resistance. Obesity andMS are risk factors for cardiovascular diseases for children inthe future; therefore, it would be logical to evaluate the

F. Kardas (*)Department of Pediatric Nutrition and Metabolism,Erciyes University, 38039 Kayseri, Turkeye-mail: fkardas@erciyes.edu.tr

L. Akın : S. Kurtoglu :M. KendirciDepartment of Pediatric Endocrinology, Erciyes University,Kayseri, Turkey

Z. KardasDepartment of Pediatrics, State Educational and Research Hospitalof the Government, Kayseri, Turkey

Indian J PediatrDOI 10.1007/s12098-014-1542-0

association of plasma PTX3 concentrations with cardiometa-bolic risk factors that characterise MS in obese children.

This is the first study to investigate the relationshipbetween PTX3 levels and MS in obese children andadolescents.

Material and Methods

A total of 77 children and adolescents (age, 10–16 y) whowere admitted to the Unit of PediatricMetabolism of the ChildHospital of Erciyes University Medical Faculty (KayseriProvince, Turkey) from April to August 2013 were enrolled.

The participants were divided into two groups according tometabolic syndrome status. Thirty-one (12 girls, 19 boys)obese patients with metabolic syndrome comprised group Aand 46 (26 girls, 20 boys) obese patients without metabolicsyndrome group B. Obesity is defined as having a BodyMassIndex (BMI)>90th percentile according to the reference bodymass index curves for Turkish children [10]. The diagnosis ofmetabolic syndrome was performed according to the MSdefinition of the International Diabetes Federation (IDF).MS was diagnosed when a patient had a waist circumfer-ence≥90th percentile, and two of the following criteria werepresent: fasting blood glucose≥100 mg/dl, triglycerides≥150 mg/dl, HDL - C<40 mg/dl, systolic blood pressure≥130 mmHg or diastolic blood pressure≥85 mmHg [11, 12].

The exclusion criteria for the children included acute orchronic inflammatory disorders, renal insufficiency definedby a serum creatinine concentration>2 mg/dl, a life-limitingmalignancy or hepatic diseases.

Patients and parents were informed in detail about the studyand gave written consent before entering the study.

The study protocol was approved by the Ethics Committeeof Erciyes University, Medical Faculty.

Height and weight measurements were performed withstandard devices. Body mass index was calculated as weight(in kilograms) divided by height (in meters) squared. Waistcircumference 1 (WC1) was measured at the end of expirationat the level of maximumwaist narrowing [13]. Blood pressurewas measured by using a standard mercury sphygmomanom-eter. Total and segmental body fat was measured by a seg-mental body composition analyzer, Tanita BC - 418MA(Tanita Corporation, Tokyo, Japan).

Blood samples were collected in the morning after anovernight fast. Plasma glucose, plasma triglycerides, totalcholesterol (T - C), high density lipoprotein cholesterol(HDL - C), and low density lipoprotein cholesterol (LDL -C) were measured using standard kits (Abbott, WiessbadenGermany). Plasma PTX3 concentrations were measured byusing a commercial enzyme-linked immunosorbent assays(ELISA) (Quantikine DPTX 30, R&D systems Inc.,Minneapolis, USA).

Statistical analysis was performed using SPSS version 15.0(Chicago, IL, USA). Data were expressed as the mean±SD.The Kolmogorov-Smirnov test was used to test the normalityof the data distribution. The differences between the groupswere analysed by Student’s t-test or Mann-Whitney U test, asappropriate. The bivariate and partial correlation tests wereused to analyse the correlations between PTX and other pa-rameters. P values<0.05 were considered statisticallysignificant.

Results

The clinical characteristics, biochemical parameters and plas-ma PTX levels of the participants are shown in Table 1.Plasma PTX3 concentrations were significantly higher inobese children and adolescents with MS than in those withoutMS (2.1±1.2 ng/ml and 1.4±0.9 ng/ml respectively, P=0.02).The PTX3 levels of patients were further analysed via com-pared in subgroups analysis according to the presence ofvarious MS components. Patients with low HDL - C levels(<40 mg/dl) had higher plasma PTX3 concentrations thanthose with normal HDL - C levels (P=0.05). Similarly, thosewho had high triglyceride levels (≥150 mg/dl) had higherPTX3 levels (P=0.01). However, PTX3 levels were not dif-ferent between subjects with or without hypertension (P=0.49). Likewise, there was no difference in PTX3 levels inobese children and adolescents with or without high bloodsugar (≥100 mg/dl) (P=0.53). In correlation analysis, PTX3levels negatively correlated with HDL - C (r=−0.32, P=0.003) across the whole group. When adjusted for age andgender the correlation was still statistically significant(r=−0.23, P=0.04). On the other hand, after adjustment, apositive correlation between PTX3 levels and waist circum-ference (r=0.29, P=0.01) was found (Table 2). There were nocorrelations between plasma PTX3 concentrations and anthro-pometric parameters including height, weight, BMI, or bodyfat percentage. There were no correlations between PTX3 andglucose or homeostasis model assessment of insulin resistance(HOMA – IR) values.

Discussion

Pentraxin 3 is an acute-phase protein that is expressed andsecreted by mononuclear phagocytes, atherosclerotic lesions,endothelial cells, adipocytes, and dendritic cells, in responseto stimulation with cytokines [6, 7]. Obesity and MS areassociated with a chronic inflammatory state [3]. There areseveral studies in adults investigating the relationship betweenPTX3 and obesity as well asMS. However, the results of thesestudies are quite controversial [4, 6, 9, 14]. This is the firststudy in obese children that provides data showing that PTX3

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levels are higher in obese patients with MS than in thosewithout MS.

Recent studies indicate the association of PTX3 levels withcardiovascular risk factors and decreased arterial distensibilitydue to obesity in adults [15]. Increased PTX3 levels werereported in select populations with a higher incidence ofcardiovascular disease [16, 17]. High PTX3 levels are associ-ated with an increased severity of MS [18]. On the otherhand,Ogawa et al. [4] found that PTX3 negatively correlates withbody weight, BMI, waist circumference and triglyceride levelin a study conducted on 226 apparently healthymen. Based ontheir results, the authors concluded that PTX3 has both tissueprotective and anti-inflammatory roles.

Alberti et al. [6] also found that PTX3 expression washigher in adult patients with visceral obesity than in thosewith subcutaneous obesity. Waist circumference is well

known to be associated with visceral adiposity. In the indexstudy group, plasma PTX3 concentrations were positivelycorrelated with waist circumference after adjustment for ageand gender, which may indicate a relationship between PTX3and abdominal obesity in children as well.

There are several studies reporting the association of PTX3with atherosclerosis [19, 20]. Given the fact that PTX3 in-creases in the presence of atherosclerosis, the authors thoughtthat studying the PTX3 levels in an obese population ofchildren and evaluating the relationship of cardiovascular riskfactors would be helpful in understanding the role of PTX3 inthe pathogenesis of atherosclerosis. The results indicate thatPTX3 levels are increased in children with MS, probablyparallel to the decreased HDL - C levels and increased triglyc-erides but not with increased blood pressure or high serumglucose concentrations. This is probably due to the associationbetween PTX3 and the atherogenic lipid profile. The associ-ation of abdominal obesity and PTX3 levels might also con-tribute to the increased PTX3 levels in obese children withMS. Controvesially, a current study reported an inverse asso-ciation between PTX3 levels and BMI [21].

It was reported that PTX3 production is stimulated bycardiovascular risk factors, such as oxidised LDLs [22].Low HDL - C is a risk factor for cardiovascular disease[23]. The authors found that PTX3 levels were negativelycorrelated with HDL - C. Although there was no positivecorrelation between PTX3 and triglyceride levels, PTX3was higher in the subgroup with hypertriglyceridemia inthe index study population. These findings indicate thatdyslipidemia may trigger PTX3 production in obese chil-dren and adolescents.

Chu et al., in the only study in the literature investigatingPTX3 levels in obese children demonstrated a negative asso-ciation of PTX3 with insulin and HOMA-IR even after con-trolling for gender and BMI [8]. In the present study, norelationship was found between PTX3 and insulin orHOMA - IR in obese children. PTX3 levels were negativelycorrelated with obesity and insulin secretion in a study report-ed by Osorio-Conles et al. [24]. Controversially PTX3 levelswere correlated positively with HOMA-IR in patients withpolycystic ovary syndrome in another study [25].

According to the above studies, the authors concluded thatMS is an inflammatory state that induces high levels of diverseinflammatory cytokines, such as IL −1 and TNF - α, and thatthese cytokines stimulate the expression and secretion ofPTX3. The authors suggest that inflammation is more severeinMS than in obesity; thus, the PTX3 levels are higher inMS.Therefore, long-term monitoring of PTX3 levels in obese andMS children will help in the treatment, complications andprognosis of obesity.

The limitations of this study include the relatively smallnumber of subjects and its cross-sectional design, which doesnot allow establihsment of a causal relationship between

Table 1 Clinical and laboratory characteristics of patients according tometabolic syndrome status

MS (+) MS (−) P value

Female/male (n) 12/19 26/20 ns

Age (y) 13.0±2.1 12.5±1.8 ns

Height (m) 155.4±12.3 154.2±11.3 ns

Pubertal (%) 25.4 37.6 ns

Weight (kg) 72.3±16.2 67.0±14.8 ns

BMI (kg/m2) 29.7±3.2 27.9±3.2 0.021

Fat mass index (%) 34.9±4.4 33.3±4.7 ns

Waist circumference (cm) 77.7±5.5 73.9±4.3 0.002

Systolic BP (mmHg) 131.1±8.8 108.3±12.3 0.000

Diastolic BP (mmHg) 83.7±6.4 72.8±7.7 0.000

Triglycerides (mg/dl) 202.9±58.4 100.5±45.9 0.000

HDL - C (mg/dl) 34.3±4.5 49.9±8.9 0.000

LDL - C (mg/dl) 93.4±26.4 91.9±25.6 ns

T - C (mg/dl) 169.9±27.4 153.6±3.1 0.027

Glucose (mg/dl) 85.3±7.3 84.9±7.5 ns

Insulin (mIU/ml) 42.4±33.3 23.3±18.1 0.006

HOMA-IR 9.1±7.5 4.9±3.8 0.005

PTX3 (ng/ml) 2.1±1.2 1.4±0.9 0.024

NS No significance; BMI Body mass index; HDL - C High densitylipoprotein cholesterol; T – C Total cholesterol; LDL – C Low densitylipoprotein cholesterol; BP Blood pressure; MS Metabolic syndrome;HOMA – IR Homeostasis model assessment of insulin resistance; PTX3Pentraxin 3

Table 2 Correlations between PTX3 levels and HDL - C or waistcircumference after adjustment for age and gender

r P value

HDL – C −0.23 0.04

Waist circumference 0.29 0.01

HDL-C High density lipoprotein cholesterol

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PTX3 and MS. Another limitation is that the PTX3 levels in ahealthy population were not measured.

Conclusions

To the authors’ knowledge, this is the first report to show anassociation between elevated PTX3 levels and cardiovascularrisk factors in children withMS. It is propose that PTX3 levelsshould be considered as a potential biomarker of MS in obesechildren and adolescents. Nevertheless, further studies onlarger number of patients (with and without MS) as well ashealthy controls will shed further light on the usefulness ofPTX3 as a marker for MS.

Acknowledgments The authors thank Prof. Dr. Sebahattin Muhtaroglufor performing analyses in the biochemistry laboratory of Erciyes Uni-versity, Medical Faculty.

Conflict of Interest None.

Source of Funding Health Goverment of Turkey provided financialhelp to conduct the study.

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