| | Plasma C-reactive protein levels and their relationship to anthropometric and lipid characteristics among childrenReceived 3 July 2001; received in revised form 16 May 2002; accepted 30 August 2002. Abstract C-reactive protein (CRP), a nonspecific marker of inflammatory status, is associated with cardiovascular disease (CVD) risk factors and the late occurrence of heart disease in adults. However, few studies assess the plasma CRP levels in healthy children. The purpose of this study is to evaluate the relationship between plasma CRP levels and anthropometric and lipid characteristics among children in Taiwan. After a multi-stage sampling of 85 junior high schools in Taipei, we randomly selected 835 children (410 boys and 425 girls) aged 12 to 16 years. Anthropometric and lipid profiles, including total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), and lipoprotein (a) were measured. We also calculated low-density lipoprotein cholesterol levels and the total cholesterol-to-HDL-C ratio as shown on the atherosclerotic index. In both genders, plasma CRP levels were significantly positively correlated with anthropometrics measures and inversely correlated with HDL-C levels. After adjusting for age, cigarette smoking, alcohol consumption, heart rate, and puberty development, children in the fourth quartile CRP subgroups were heavier and had significantly higher body mass index (BMI) and lower HDL-C levels than children with nondetected CRP. In multivariate regression models, CRP was significantly negatively associated with HDL-C levels even after adjusting for BMI in both genders. In this study, anthropometrics measures, especially BMI, were positively associated with plasma CRP levels. Furthermore, elevated CRP levels were associated with adverse lipids profiles. These data suggest that elevated plasma CRP levels might be associated with CVD risk factors that may be related to the late development of CVD in some Taiwanese children.
1. Introduction  C-reactive protein (CRP), a nonspecific marker of inflammation [1], is usually low or undetected in healthy subjects. However, it increases up to 100 times during acute illness or inflammation [1]. In recent years, these acute-phase reactants have been studied as potential markers of systemic diseases, such as cardiovascular diseases 2, 3. In adults, blood CRP levels have been positively correlated with age 4, 5, 6, smoking 5, 7, lipid levels 4, 5, 8, degree of obesity 5, 9, 10, status of cardiovascular disease (CVD) 5, 11, 12, 13, 14, and chronic infection conditions [4]. An increase in age, smoking, body mass index (BMI), and symptoms of chronic infections are all associated with an elevation in CRP levels. Blood CRP levels were positively correlated with total cholesterol, triglyceride, and apolipoprotein B levels and were inversely associated with high-density lipoprotein cholesterol (HDL-C) levels. Moreover, prospective studies have shown that the blood CRP level may be an independent predictor of cardiovascular events in patients with coronary heart disease 3, 4, 5, 8, 12. There are few studies exploring the relationship between blood CRP levels and certain cardiovascular risks among children 14, 15, 16. Whether children with elevated CRP levels may have a higher risk of CVD remains unclear. The purpose of this study is to evaluate the relationship between anthropometric measures and CRP levels. We also examine the association between elevated CRP levels and adverse lipid profiles among children in Taiwan. 2. Materials and methods 2.1. Study sample The Taipei Children Heart Study is an epidemiologic design for collecting the cardiovascular disease risk factors among school children in Taipei during 1995. To obtain a representative distribution of demographic, lifestyle and biochemical characteristics, and cardiovascular disease risk factors, we conducted a cross-sectional survey among junior high school students in Taipei. After a multi-stage sampling of 85 junior high schools, we randomly selected 1500 school children for this survey. The sampling method and results are described elsewhere 17, 18. After considering the study power and sample size, we randomly selected 835 children for this study. 2.2. Data collection All of the participating children completed a structured questionnaire detailing their socio-demographic characteristics, personal history of disease, and lifestyle characteristics including cigarette smoking, alcohol consumption, and puberty development. The Ethical Committee of the Scientific Institute approved this study, and informed consent was obtained from the parents and the children. 2.3. Lifestyles, puberty development, and heart rate measurements Children were divided into never, past, and current smokers based on their responses to a questionnaire. Alcohol drinking status was divided into current and never drinking based on their frequency of alcohol drinking. Puberty development was classified as developed and not based on their pubic hair growth and breast development. Heart rate was measured for 30 seconds by cardiac auscultation during two blood pressure measurements. 2.4. Anthropometric measurements Research technicians measured body weight to an accuracy of 0.1 kg using a standard beam balance scale with subjects barefoot and wearing light indoor clothing. Body height was recorded to the nearest 0.5 cm using a ruler attached to the scale. We calculated BMI as body weight (kg) divided by the square of their height (m). Waist circumferences were measured at the distal third of the line from the xiphoid process to the umbilicus. Hip circumferences were measured 4 cm below the anterior superior process of the iliac spine. We calculated the waist-to-hip ratio (WHR) as the waist circumference divided by the hip circumference. 2.5. Biochemical measurements We collected blood samples after a 12-hour fast and only from students who had followed their usual dietary pattern during the previous 3 days to reduce extraneous between-person variations. Any student who had recently attended a holiday or family party was recontacted several weeks later. We performed the biochemical assays of lipid profiles within 2 weeks of the blood samples being stored at −4°C. The plasma was stored at −70°C before the high sensitive C-reactive protein (CRP) levels were assayed. We measured serum total cholesterol (CHOL) using the esterase oxidase method [19], triglyceride (TG) using an enzymatic procedure [20], and HDL-C by an enzymatic method with magnesium precipitation [21] using the Synchron CX5 analyzer (Beckman Instruments, Palo Alto, CA). Because the subjects' TG did not exceed 400 mg/dL, we used Friedewald's formula [22] to calculate low-density lipoprotein-cholesterol (LDL-C): LDL-C = CHOL – HDL-C – (TG/5). Lipoprotein (a) [Lp(a)] was determined by nephelometric assay [23], which was calibrated using the standard material offered by the manufacturer. Plasma CRP levels were measured using a high sensitivity method with an automated analyzer (Nephelometic 100; Dade Behring Marburg GmbH, Newark, DE) [24]. 2.6. Statistical analyses We used mean and standard deviation to describe the distributions of age, body weight, body height, BMI, and lipid and lipoprotein profiles with gender specification. After excluding children whose plasma CRP levels could not be detected (<0.188 mg/L), we calculated the Spearman correlation coefficient between study variables to evaluate the relationships of plasma CRP on anthropometric measures and lipid profiles with gender specification without the assumption of normality. We further divided the studied children into five subgroups based on their plasma CRP levels (nondetected and the quartile distributions) with gender specification. Because the distributions of TG and Lp(a) were skewed, logarithmic transformation was applied in the statistical analysis. For ease of interpretation, untransformed mean values are presented. We used analysis of covariance to compare the Q4 CRP with nondetected CRP (CRP <0.188 mg/L) children in anthropometric measures and lipid characteristics after adjusting for age, cigarette smoking, alcohol drinking, heart rate, and puberty development. Test-for-trend analyses were performed based on these five CRP subgroups in anthropometric and lipid characteristics after adjusting for the potential confounders. To determine if plasma CRP is a predictor of lipid profiles, we used multivariate regression models to assess the association between CRP and lipid profiles. In separate models, we regressed lipid profiles onto plasma CRP level before and after adjusting for BMI. All regression analyses were adjusted for age, cigarette smoking, alcohol drinking, heart rate, and puberty development. We used the robust variance by PROC MIXED in SAS to insure the validity of inference without the need to involve normal distribution assumptions. A two-tailed P value less than 0.05 was considered statistically significant. All statistical analyses were conducted using the statistical package SAS (SAS Institute, Cary, NC). 3. Results In this study, we included 835 children (410 boys and 425 girls) with a mean age of 13.3 years (range 12–16 years). General characteristics, anthropometric measures, and lipid profiles are presented in Table 1 with gender specification. In general, boys were taller, heavier, and had larger BMI and WHR than girls. However, girls had higher CHOL, TG, HDL-C, LDLC-C, TCHR, and Lp(a) levels than boys. The frequency distributions of plasma CRP levels among all study children are shown in Fig. 1. About 48.9% of the children had plasma CRP levels that could not be detected (<0.188 mg/L), and 17% had relatively high plasma CRP levels (defined as >1.0 mg/L). The median value of CRP was 0.190 mg/L (75th percentile = 0.569 mg/L) for the whole group, 0.301 mg/L (75th percentile = 0.821 mg/L) for boys, and <0.188 mg/L (nondetected levels, 75th percentile = 0.394 mg/L) for girls. There was no statistically significant difference in plasma CRP levels between boys and girls. | | |  | | Boys (n = 410) | Girls(n 5 425) | |
|---|
| | Mean | SD | Mean | SD | |
|---|
| CRP, mg/La | 0.301 | | <0.188 | | |
| Age, y | 13.3 | 0.89 | 13.3 | 0.91 | |
| Heart rate, beats/min | 83.5 | 11.9 | 86.7 | 11.8 | |
| Smoking statusb | | | | | |
| Never | 381 | (92.9) | 419 | (98.6) | |
| Past | 21 | (5.1) | 5 | (1.2) | |
| Current | 8 | (2.0) | 1 | (0.2) | |
| Drinking statusb | | | | | |
| No | 373 | (91.0) | 416 | (97.9) | |
| Yes | 37 | (9.0) | 9 | (2.1) | |
| Puberty developmentb | | | | | |
| No | 103 | (25.1) | 77 | (18.1) | |
| Yes | 307 | (74.9) | 348 | (81.9) | |
| Body height, cm | 161.7 | 8.2 | 156.1 | 5.4 | |
| Body weight, kg | 55.2 | 12.6 | 50.2 | 9.1 | |
| BMI, kg/m2 | 21.0 | 3.8 | 20.6 | 3.3 | |
| Waist circumference, cm | 68.4 | 9.2 | 63.1 | 6.9 | |
| Hip circumference, cm | 87.7 | 8.2 | 88.8 | 6.6 | |
| WHR | 0.78 | 0.05 | 0.71 | 0.04 | |
| CHOL, mg/dL | 153.1 | 26.1 | 161.5 | 28.2 | |
| TG, mg/dL | 74.2 | 36.8 | 77.1 | 33.3 | |
| HDL-C, mg/dL | 54.3 | 13.1 | 55.4 | 12.3 | |
| LDL-C, mg/dL | 84.0 | 23.9 | 90.7 | 24.6 | |
| TCHR | 2.97 | 0.86 | 3.02 | 0.76 | |
| Lp(a), mg/dL | 16.1 | 19.6 | 20.9 | 22.6 | | | | |
|
a
The median values of plasma CRP levels.
b
Using number and percentage. |
Table 2 shows the Spearman correlation of plasma CRP levels on anthropometric measures and lipid profiles among the study children with gender specification. The CRP levels are significantly positively correlated with body weight, BMI, waist circumference, hip circumference, WHR, TG, and TCHR and negatively correlated with HDL-C levels for boys. For girls, the CRP levels are positively correlated with body weight, BMI, waist circumference, hip circumference, and WHR and negatively correlated with HDL-C levels (all P < 0.01). | | | | | Boys (n 5 410) | Girls (n 5 425) | |
|---|
| Body height, cm | 0.030 | 0.016 | |
| Body weight, kg | 0.254* | 0.281* | |
| BMI, kg/m2 | 0.274* | 0.300* | |
| Waist circumference, cm | 0.279* | 0.268* | |
| Hip circumference, cm | 0.257* | 0.264* | |
| WHR | 0.207* | 0.185* | |
| CHOL, mg/dL | 0.015 | −0.076 | |
| TG, mg/dL | 0.158* | 0.029 | |
| HDL-C, mg/dL | −0.199* | −0.151* | |
| LDL-C, mg/dL | 0.062 | 0.049 | |
| TCHR | 0.200* | 0.054 | |
| Lp(a), mg/dL | 0.049 | −0.012 | | | | |
Because there were no clear cut-off points of plasma CRP levels among the study children, we further divided the study children into five subgroups based on their CRP levels (including nondetected and the quartile distributions of plasma CRP levels). We defined children with high CRP if their plasma CRP levels were greater than the 75th percentile on age and gender specification. Table 3 presents the anthropometric measures and lipid profiles among different CRP subgroups. In both genders, children on the fourth quartile CRP subgroups were heavier and had higher BMI, waist circumference, hip circumference, and WHR than children with relatively normal CRP levels (nondetected). Among boys, the children with higher CRP levels had higher TG, LDL-C, and TCHR and lower HDL-C levels than the normal children (all P < 0.05). The fourth quartile CRP subgroup girls had higher CHOL and lower HDL-C levels than the normal girls. There is a significant test for trend of all lipid profiles except LDL-C in boys and CHOL in girls among these five CRP subgroups. | | | | | C-reactive Protein | |
|---|
| | < 0.188 | Q1 | Q2 | Q3 | Q4 | |
|---|
| Boys | (n = 158) | (n = 63) | (n = 63) | (n = 63) | (n = 63) | |
| Age, y | 13.3 ± 0.9 | 13.5 ± 0.8 | 13.4 ± 0.8 | 13.3 ± 0.8 | 13.1 ± 0.9 | |
| Body height, cm | 160.8 ± 8.5 | 163.8 ± 7.9 | 161.9 ± 6.7 | 162.3 ± 8.8 | 161.0 ± 8.1 | |
| Body weight, kg | 50.8 ± 10.0 | 57.4 ± 11.0 | 56.7 ± 13.8 | 59.1 ± 13.5 | 58.3 ± 14.5**,† | |
| BMI, kg/m2 | 19.5 ± 2.7 | 21.3 ± 3.1 | 21.5 ± 4.2 | 22.3 ± 4.1 | 22.4 ± 5.0**,† | |
| Waist circumference, cm | 65.0 ± 6.4 | 69.1 ± 7.1 | 69.7 ± 9.9 | 71.8 ± 9.7 | 71.8 ± 12.3**,† | |
| Hip circumference, cm | 84.9 ± 6.7 | 88.9 ± 7.5 | 88.8 ± 8.9 | 90.5 ± 8.4 | 89.8 ± 9.2**,† | |
| WHR | 0.76 ± 0.04 | 0.77 ± 0.03 | 0.78 ± 0.05 | 0.79 ± 0.05 | 0.80 ± 0.07**,† | |
| CHOL, mg/dL | 153.5 ± 25.0 | 152.3 ± 27.5 | 151.6 ± 21.5 | 148.3 ± 24.0 | 159.2 ± 32.3 | |
| TG, mg/dL | 69.2 ± 37.1 | 72.6 ± 28.8 | 70.0 ± 31.4 | 83.9 ± 34.5 | 82.4 ± 46.9*,† | |
| HDL-C, mg/dL | 56.7 ± 12.4 | 55.3 ± 12.7 | 54.8 ± 15.0 | 50.3 ± 12.1 | 50.7 ± 12.7*,† | |
| LDL-C, mg/dL | 82.9 ± 22.0 | 82.5 ± 25.7 | 82.8 ± 22.2 | 81.3 ± 18.1 | 92.0 ± 31.3* | |
| TCHR | 2.8 ± 0.83 | 2.86 ± 0.69 | 2.97 ± 0.90 | 3.07 ± 0.70 | 3.33 ± 1.07**,† | |
| Lp(a), mg/dL | 16.6 ± 20.9 | 16.8 ± 20.4 | 12.6 ± 14.7 | 16.7 ± 20.0 | 17.1 ± 19.3 | |
| Girls | (n = 250) | (n = 43) | (n = 44) | (n = 44) | (n = 44) | |
| Age, y | 13.2 ± 0.9 | 13.3 ± 0.9 | 13.3 ± 1.0 | 13.4 ± 0.9 | 13.3 ± 0.9 | |
| Body height, cm | 156.1 ± 5.4 | 155.9 ± 6.0 | 157.0 ± 5.5 | 156.5 ± 5.4 | 155.6 ± 5.0 | |
| Body weight, kg | 47.9 ± 7.2 | 51.2 ± 8.1 | 52.2 ± 9.4 | 54.3 ± 9.2 | 56.2 ± 13.8**,† | |
| BMI, kg/m2 | 19.6 ± 2.5 | 21.0 ± 3.0 | 21.1 ± 3.2 | 22.1 ± 3.6 | 23.1 ± 5.2**,† | |
| Waist circumference, cm | 61.5 ± 5.5 | 63.3 ± 6.4 | 64.2 ± 6.9 | 66.1 ± 6.8 | 67.8 ± 10.5**,† | |
| Hip circumference, cm | 87.3 ± 5.5 | 89.8 ± 6.1 | 89.4 ± 6.9 | 91.9 ± 6.7 | 92.8 ± 9.3**,† | |
| WHR | 0.70 ± 0.04 | 0.70 ± 0.04 | 0.72 ± 0.05 | 0.72 ± 0.03 | 0.73 ± 0.05**,† | |
| CHOL, mg/dL | 162.2 ± 24.5 | 164.2 ± 29.4 | 159.0 ± 37.8 | 165.8 ± 36.0 | 153.1 ± 25.9* | |
| TG, mg/dL | 75.9 ± 30.0 | 76.6 ± 27.8 | 74.7 ± 33.5 | 80.9 ± 37.4 | 82.5 ± 48.9 | |
| HDL-C, mg/dL | 56.3 ± 11.5 | 54.7 ± 11.0 | 55.8 ± 15.8 | 54.9 ± 14.1 | 50.5 ± 11.0*,† | |
| LDL-C, mg/dL | 90.7 ± 21.9 | 94.2 ± 25.5 | 88.2 ± 32.2 | 94.7 ± 30.8 | 86.1 ± 22.1 | |
| TCHR | 2.98 ± 0.67 | 3.08 ± 0.68 | 2.96 ± 0.78 | 3.15 ± 0.85 | 3.16 ± 0.87 | |
| Lp(a), mg/dL | 22.1 ± 23.4 | 18.5 ± 20.4 | 14.3 ± 16.7 | 24.8 ± 26.6 | 18.5 ± 19.6 | | | | |
|
*
P < 0.05.
**
P < 0.001, using analysis of covariance to compare the Q4 with nondetected (CRP < 0.188 mg/L) children after adjusting for age, cigarette smoking, alcohol drinking, heart rate, and puberty development; tested using the log-transformed value for TG and Lp(a).
†
Test for trend, P < 0.05. |
Table 4 shows the association of CRP on lipid profiles among the study children. We used multivariate regression analyses to fit the lipid profiles on plasma CRP. In both genders, plasma CRP was significantly inversely associated with HDL-C levels, and these characteristics persisted even after further adjusting for BMI. 4. Discussion In this study, about half of children had nondetected plasma CRP levels (<0.188 mg/L). The median value of plasma CRP level for all study children was 0.19 mg/L (0.301 mg/L for boys and <0.188 mg/L for girls). Plasma CRP levels were positively correlated with body weight, BMI, waist circumference, hip circumference, WHR, and TCHR (boys only) and were negatively correlated with HDL-C levels (boys only). Children with the highest quartile CRP levels were heavier and had higher BMI than those whose levels were relatively normal (CRP nondetected). In both genders, CRP levels were significantly inversely associated with HDL-C levels; these characteristics persisted even after adjusting for BMI. The cross-sectional survey design limits us in evaluating the causal relationships between CRP levels with anthropometric and lipid characteristics. However, a similar study in adults may yield biased or confounded results if the subjects follow a certain lifestyle (such as cigarette smoking) or have infections or tissue damage, which could radically increase CRP levels. Furthermore, fewer children in this age group were undergoing treatment for obesity or were of a dyslipidemic status. They were also less affected by cigarette smoking. Measurement errors are likely to be minimal, and any error would probably be of a random nature and would attenuate our results. The plasma CRP level is a nonspecific marker of inflammatory status and represents the disease activities of a human body. Plasma CRP levels increase significantly in response to trauma and inflammation status; plasma CRP level decreases rapidly with the resolution of those conditions 25, 26, 27, 28. Plasma cytokine levels may elevate and be released from injured tissue during the acute phase of inflammation. This may have resulted from the stimulation of liver that synthesizes acute-phase circulating inflammatory proteins, such as C-reactive protein and interleukin-6 (IL-6) 25, 26, 27, 28. Moreover, the inflammatory properties of IL-6 and tumor necrosis factor (TNF) may play certain roles in the stimulation of acute-phase protein production in the liver, and this may regulate plasma CRP levels 27, 29, 30, 31. In this study, the distribution of plasma CRP levels among all children was positively skewed; this was consistent with other findings 4, 5, 13. The median value of plasma CRP levels was 0.19 mg/L of the all children. These values were similar to children in other studies but were lower than values in adults 4, 13. The plasma CRP levels were elevated with increasing age 4, 5, 6, and boys might be associated with a higher plasma CRP levels 13, 32. However, in our study, there were no differences in plasma CRP levels between genders. Further studies are needed to evaluate the effect of gender on plasma CRP levels among children. Many studies have suggested that obesity may be an inflammatory disorder in humans and that there are several mechanisms linking obesity to elevated CRP levels 5, 9, 10, 33. Among the aforementioned cytokines, particularly IL-6 and TNF-α, some could have a role in the in obesity-inflammatory linkage, which in turn could regulate plasma CRP levels 27, 28, 34, 35, thus explaining the elevation of CRP levels among obese subjects [36]. Obese subjects had higher circulating IL-6 levels, which could have be released from the subcutaneous adipose tissue in humans. Furthermore, IL-6 may be associated with an increase in production of acute-phase protein levels in the liver 30, 31. The release of IL-6 from the adipose tissue may induce low-grade systemic inflammation in subjects with excess body fat. This may explain the association between BMI and CRP levels. TNF-α levels are also associated with CRP levels [37], and they may promote the production of the macrophage migration inhibitory factor [38]. Obese subjects had a higher adipose tissue TNF-α expression, which could be associated with elevated TNF-α levels 39, 40. Finally, plasma CRP levels may be indirectly associated with TNF-α or IL-6 and BMI. These phenomena could also explain why obesity was associated with clinically raised CRP levels in both genders. Similar to BMI, waist circumference is an important clinical indicator of someone who is overweight or obese and is also used as an indicator of overall body fat levels. In our data, girls with higher CRP levels had significantly higher waist measurements. Plasma CRP levels were positively correlated with body weight, waist circumference, and BMI. This was similar to other studies where plasma CRP levels were associated with adiposity in humans 5, 9, 10, 15, 16. In adults, elevation of the CRP level is an independent CVD risk factor and is associated with the development of heart disorders in later life 5, 6, 7, 8, 9, 11, 12, 13, 14. Many studies have shown that CRP level is associated with adverse lipids profiles, such as increases in total cholesterol, triglyceride, and TCHR and decreases in HDL-C levels 4, 5, 8. In our study, plasma CRP levels were inversely associated with HDL-C levels even among school-aged children. In humans, inflammation status, such as elevation plasma CRP levels, might be a predictor for development of atherosclerosis in later life. However, the mechanisms of elevated CRP on adverse lipid metabolism are not clear. Further studies are needed to evaluate the relationships between CRP levels and adverse lipid profiles. In summary, plasma CRP levels are positively correlated with anthropometric measures, such as body weight, BMI, waist circumference, hip circumference, and WHR, among children in Taiwan. Furthermore, plasma CRP levels are inversely associated with HDL-C levels among children, which suggests that plasma CRP level may be a predictor of lipid profiles among children in Taiwan. This may indicate that overweight status and obesity may be states of systemic inflammation and may be associated with the development of atherosclerosis later in life. Further longitudinal studies are needed to evaluate the relationship between an elevation in CRP levels and the development of atherosclerosis in later life. This could provide us with a better strategy for the prevention and treatment of obesity-associated chronic disorders. References 1.
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a Department of Public Health, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China b Department of Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China c Department of Clinical Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China  Corresponding author. Department of Community Medicine, Tri-Service General Hospital, National Defense Medical Center, P.O. Box 90048-509, Nei-Hu, Taipei, Taiwan, ROC, China. Tel: 886-2-8791-0506; fax: 886-2-8791-0590.
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