A novel indicator, relative children’s lipid accumulation product (RCLAP) for metabolic syndrome


 BackgroundThe children’s lipid accumulation product (CLAP) was associated with MS in Chinese children and adolescents. The study was to develop a more effective indicator, relative children’s lipid accumulation product （RCLAP）associated with MS reflect the density of lipid accumulation among Chinese children and adolescents. MethodsA stratified cluster sampling method was used to recruit 683 students aged 8-15 years in this study. The presence of MS was defined according to the NCEP-ATP III criteria. The t-test, chi-square test, logistic regression models were used to analyze the associations of SBMI, SWHtR, SlnCLAP, SRCLAP-H, SRCLAP-SH, RCLAP-W with MS. Receiver Operating Characteristic (ROC) curves was used to evaluate the predictive efficiency of above indexes for predicting MS. ResultsThe overall prevalence of MS was 4.8% (boys 6.6%, girls 2.8%). In girls, after adjusting for sedentary activity time, WHtR, BMI, CLAP, RCLAP-H, RCLAP-SH and RCLAP-W significantly increased risk of MS (OR(95%CI):15.79 (3.15-79.21), 3.73 (0.87-15.95), Null, 96.13 (11.11-831.97), 96.13 (11.11-831.97), 18.28 (4.24-78.87), respectively). In boys, after adjusting for ages and moderate-to-vigorous physical activity time, WHtR, BMI, CLAP, RCLAP-H, RCLAP-SH and SRCLAP-W significantly increased risk of MS (OR(95%CI): 37.43(11.67-120.10), 68.33(18.51-252.20), 105.86(21.99-509.68), 171.75(33.60-878.00), 133.18(27.65-641.39), 50.13(15.48-162.37, respectively). The AUCs of RCLAP-H and RCLAP-SH for predicting MS were 0.950, 0.948 in girls, and 0.952, 0.952 in boys, which were higher than these of BMI, WHtR, CLAP and RCLAP-W.ConclusionThe relative children，s lipid accumulation products（RCLAP-H and RCLAP-SH ) were more effective indicators for predicting MS than BMI, WHtR and CLAP in Chinese children and adolescents.


Introduction
Over the past two decades, there has been a striking increase in the number of people with metabolic syndrome (MS) [1]. In 2009, the overall age-standardized estimates prevalence of the MS was 21.3% based on the criteria of revised National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) [2]. A meta-analysis showed that the MS increased the risk of type 2 diabetes and cardiovascular diseases (CVD) [3]. Concomitantly with the increasing prevalence of childhood obesity, the prevalence of metabolic syndrome is rising among children and adolescents [4]. According to the International Diabetes Federation (IDF), NCEP-ATPIII and Chinese children metabolic syndrome righteousness and prevention advice (CHN2012) criteria, the prevalence of MS among Chinese children was 1.8%, 2.6% and 2.0%, respectively. In addition, the MS prevalence in children with overweight and obese was 4.7% and 17.3% based on IDF criteria in 2004-2014, respectively [5]. Childhood MS are associated with hypertension, hyperlipidemia, insulin resistance and type 2 diabetes, which can also lead to cardiometabolic diseases during adulthood. The MS was de ned as the presence of ≥ 3 components: central obesity, hypertriglyceridemia, high fasting glucose, low high-density lipoprotein (HDL) and hypertension [6]. Many factors may induce MS, including unhealthy eating habits and lack of exercise [7,8], the etiology and pathogenesis of MS are very complex [9,10]. Thus, the more effective indicators to predict MS are very important in children and adolescents.
Some researches had reported that body mass index (BMI), waist circumference (WC), abdominal skinfold thickness (AST), Waist-to-height ratio (WHtR) and triglycerides (TG) were effectively related with MS [11][12][13][14]. However, the above indicator is limited to distinguishing adipose tissue from lean mass and showing circulating lipid accumulation. The lipid excess is along with expansion of visceral adipocytes and elevating blood concentrations of certain lipids, which was referred to as lipid overaccumulation and could lead to ectopic deposition of lipids in non-adipose tissues, insulin resistance and other metabolic dysfunctions [15][16][17]. Kahn et al [15] proposed a new marker the lipid accumulation product (LAP), re ected the total lipid accumulation in the body to predict MS in adults. The LAP that was product of waist circumference (WC) and fasting triglycerides(TG)concentration. The studies had showed LAP was a powerful marker for predicting MS and was better than BMI, WC and WHtR in adults. However, LAP may not directly re ect lipid accumulation in children and adolescents. Zhang et al [18] developed a novel indicator, the children's lipid accumulation product (CLAP), associated with MS in Chinese children and adolescents. The CLAP that was product of WC, AST, and TG concentration (CLAP = WC (cm) × AST (mm) × TG (mmol/L)/100). They reported that CLAP was an effective indicator associated with MS and was better than BMI and WHtR. Wang et al [19] showed that CLAP was signi cantly associated with hypertension in children and adolescents, and can more effectively predict childhood hypertension than WC, WHtR, BMI, AST, and TG. Yuan et al [20] showed that the CLAP was signi cantly associated with impaired fasting glucose (IFG) in Chinese boys, and it performed better than WC, WHtR, AST and TG.
From the formula of CLAP, we know that AST shows the accumulation of skin fat at a point on the abdomen, multiplying by WC shows the accumulation of whole abdominal fat and then multiplying by TG to a certain extent shows the accumulation of body lipid. However, CLAP could not re ect the density of lipid accumulation in body.
It was well known that there are multifarious types of obesity, different obesity types have different locations where fat accumulates. The relative CLAP at per unit body height, sitting height and weight may re ect the density of lipid accumulation among children and adolescents. However, it has been not cleared whether the relative CLAP at per unit body height, sitting height and weight were more effective indicators related to MS than CLAP, BMI and WHtR. The purpose of this study was to develop more effective relative CLAP indicators for predicting MS.

Subjects
In this study, a total of 683 students aged 8-15 years were selected from two nine-year schools via the strati ed cluster sampling methods, including 317 girls (46.4%) aged at (10.98±1.83 years and 366 boys (53.6%) aged at (10.77±1.80 years).

Measurement
The medical staff who received standardized training measured the participants' body weight, height, sitting height (SH), Diastolic blood pressure (DBP), Systolic blood pressure (SBP), WC and AST. The participants kept have an empty stomach when they were measured, and were requested barefoot, dressed in light clothes and stood straight. An electronic scale was used to measure weight, and the reading was accurate to 0.1 kg. Height and SH were measured using Mechanical height measure, and the readings were accurate to 0.1 cm. Blood pressure was measured on the right arm with an appropriately sized cuff using mercury sphygmomanometer after having a rest for at least 10 min. DBP was de ned as the fth Korotkoff sound (K5), SBP was de ned as the onset of the Korotkoff sound (K1). The blood pressure was measured twice at interval of 2 min. Waist circumference (WC) was measured along a horizontal line at 1 cm above the belly button using a Nylon tapes, the reading was accurate to 0.1cm. Abdominal skinfold thickness (AST) was measured at the intersection of the horizontal umbilicus and the right midclavicular line, the reading was accurate to 0.1 mm.
The children and adolescents after at least 8 h of overnight fasting were collected 3 mL venous blood samples by nurses received standardized training. The enzyme-linked immunoassay method was used to detect HDL-C. Enzymatic methods were used to detected TG and FBG levels.

De nition of Metabolic Syndrome (MS)
In this study, MS was diagnosed according to the amended NCEP-ATP III criteria [21]. high fasting blood glucose(FBG)≥110mg/dL; abdominal obesity: WC≥ 90th age-and sex-speci c percentile for Chinese children [22]; high blood pressure: SBP and/or DBP ≥90th percentile for gender and age [23]; low highdensity lipoprotein cholesterol (HDL-C)≤40 mg/dL; high triglycerides TG ≥110mg/dL; when three or more of the five components were present that MS was identified.

Surveys of Behavioral Indexes
We investigated dietary behaviors which included the frequency of breakfast, milk, fresh vegetables, fruits, nuts, fried foods, carbonated drinks, eating out, western-style fast food, high-energy snacks. Each of the dietary behavior items was assigned 6 grades including never (0 points), 1 time per month (0.25 points), 2 time per month (0.5 points), 1-3 times per week (2 points), 4-6 times per week (5 points), and 1 time per day (7 points). The total scores of healthy dietary behaviors (including breakfast, milk, fruits, nuts, fresh vegetables) and risk dietary behaviors (including fried foods, eating out, carbonated drinks, high-energy snacks, western-style fast food) were de ned as ≥the 75th percentile (P75) and < 75th percentile (P75) two grades. Children's Leisure Activities Study Survey (CLASS) questionnaire was used to investigate Physical activities [24]. The moderate-to-vigorous physical activity was de ned as <60min and ≥60min two grades, and sedentary activity time was de ned as <120min and ≥120min two grades [25].

Results
A total of 683 children aged 8-15 years (366 boys and 317 girls) were included in this study. The overall prevalence of MS was 4.8%, 2.8% for girls and 6.6% for boys. As shown in Table 1. The results showed that weight, WC, AST, BMI, WHtR, CLAP, RCLAP-H, RCLAP-SH, RCLAP-W, SBP, DBP, TG among girls with MS were signi cantly higher than those without MS; the boys with MS had higher values of height, siting height, weight, WC, AST, BMI, WHtR, CLAP, RCLAP-H, RCLAP-SH, RCLAP-W, SBP, DBP, TG, compared to those without MS (P < 0.05). On the contrary, girls and boys with MS had lower values of HDL-C than those without MS, respectively (P < 0.05). The prevalence of MS among boys aged 12-15 years was signi cantly higher than that aged 8-11 years (P < 0.05). The proportion of moderate-to-vigorous physical activity time (≥ 60 min) among boys with MS was signi cantly lower than those without MS (P < 0.05).   As shown in Table 4 and Fig. 1

Discussion
Metabolic syndrome (MS) has become a major public health issue worldwide [26]. This study showed that the overall prevalence of MS was 4.8% (boys 6.6%, girls 2.8%) in children and adolescents aged 8-15 years. The similar prevalence of MS was reported among Indian studies aged 12-17 years (4.2%) [27] and US adolescents (4.5%) [28]. Rodríguezmorán et al [29] reported that there was higher prevalence of MS among Mexico adolescents (6.5%) and Esmaillzadeh et al [30] reported that there was 10.1% of Iranian adolescents with MS. The present study showed that prevalence of MS among girls (2.8%) was lower than that in boys (6.6%), which was consistent with the results of most previous studies [21,31,32]. The reasons might be due to the fact that the boys had lower levels of moderate-to-vigorous physical activity and higher levels of risk dietary behaviors, so there has higher prevalence of overweight or obesity among boys than girls. However, other studies had also reported there was no signi cant difference of prevalence of MS between sex [9]. The current study showed that the prevalence of MS among boys aged 12-15 years was signi cantly higher than that aged 8-11 years, which was in line with the result of study from Gooty et al [33]. This may be associated with an increased exposure of risk factors for MS as boys age [34]. It was reported that the ability to regulate glucose was progressively lost with age [35]. Moreover, in the present study we found that moderate-to-vigorous physical activity time < 60 min was a risk factor for MS in boys, which was consistent with previous studies [36,37]. Styne et al [38] also showed that at least 20 min of vigorous short bursts of physical activity a day, for 3 to 5 days per week can improve metabolic measures in children and adolescents. Physical activity is helpful in improving lipid pro le by increasing HDL concentration and decreasing both LDL and triglycerides concentrations [39].
The additional ndings of this cross-sectional study were that the children with MS demonstrated higher BMI, WHtR, and CLAP levels compared to children without MS, which was in line with previous studies [11,13,14,18]. However, these indexes were limited to showing the accumulation of lipids. BMI can't show indication of body fat distribution, and it is not only related to fat mass, but also related to fat-free mass [40].  [41,42]. In our study population, the effect of SRCLAP-W was not obvious, which may be that WC and AST re ect weight to some extent, so the effect of CLAP divided by weight will be weakened.
We all know that excess lipid material will increasingly be deposited in nonadipose tissues (e.g. liver, kidneys, skeletal muscle, heart, blood vessels and pancreas) where it may adversely modify cellular metabolism, accelerate apoptosis [43,44]. Commonly adopted predictive indicators of abdominal obesity include WC and related indices such as the waist-to-height and waist-to-hip ratios [45,46]. Ectopic lipid deposition is di cult to quantify directly in children and adolescents, but an increased RCLAP value may indicate that various tissues or organs have become more vulnerable to injury from lipid overaccumulation. The metabolically obese normal-weight (MONW) [47] individuals who having normal body weight but with obesity, are characterized by the presence of a cluster of cardiovascular risk factors.
Janssen [48] proposed who also ful ll the criteria for the MS be classi ed as MONW. Du et al [49] had showed LAP and visceral adiposity index (VAI) are effective markers for identifying the Chinese adults with MONW phenotype, we speculate that that RCLAP-H or RCLAP-SH may be applicable to identifying MONW in children and adolescents.
There were also some limitations in this study. Firstly, it was a cross sectional study, the causality between RCLAP and MS cannot be inferred. Secondly, we only studied Chinese children and adolescents, the generalizability to other ethnic groups is limited. Finally, the sample size in our study is limited, so we cannot provide a representative cut-off values in different ages and gender for the time being. Therefore, the results need to be con rmed by other studies.

Conclusion
The present study developed relative children ' s lipid accumulation products (RCLAP

Availability of data and materials
All data generated or analysed during this study are included in this published article.

Competing interests
The authors declare that they have no competing interests.

Funding
The study was supported by grants from National Natural Science Foundation of China (81502823)