PEDIATRICS Vol. 122 No. 6 December 2008, pp. 1252-1257 (doi:10.1542/peds.2007-3162)
ARTICLE |
Elevated Blood Pressure, Race/Ethnicity, and C-Reactive Protein Levels in Children and Adolescents
a Divisions of aPediatric Nephrology
c Pediatric Cardiology
d General Pediatrics, Department of Pediatrics
b Department of Community and Preventive Medicine, University of Rochester Medical Center, Rochester, New York
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Adult hypertension is independently associated with elevated C-reactive protein levels, after controlling for obesity and other cardiovascular risk factors. The objective of this study was to determine, with a nationally representative sample of children, whether the relationship between elevated blood pressure and C-reactive protein levels may be evident before adulthood.
METHODS. Cross-sectional data for children 8 to 17 years of age who participated in the National Health and Nutrition Examination Survey between 1999 and 2004 were analyzed. Bivariate analyses compared children with C-reactive protein levels of >3 mg/L versus 
3 mg/L with respect to blood pressure and other cardiovascular risk factors. Multivariate linear regression was used to evaluate the relationship between elevated blood pressure and C-reactive protein levels.
RESULTS. Among 6112 children, 3% had systolic blood pressure of 
95th percentile and 1.3% had diastolic blood pressure of 95th percentile. Children with C-reactive protein levels of >3 mg/L had higher systolic blood pressure, compared with children with C-reactive protein levels of 3 mg/L (109 vs 105 mm Hg). Obesity, high-density lipoprotein cholesterol levels of <40 mg/dL, and Hispanic ethnicity were independent predictors of elevated C-reactive protein levels. Diastolic blood pressure did not differ between groups. Linear regression analyses showed that systolic blood pressure of 95th percentile was independently associated with C-reactive protein levels in boys but not girls. Subset analyses according to race/ethnicity demonstrated that the independent association of elevated systolic blood pressure with C-reactive protein levels was largely limited to black boys.
CONCLUSIONS. These data indicate that there is interplay between race/ethnicity, elevated systolic blood pressure, obesity, and inflammation in children, a finding that has potential implications for disparities in cardiovascular disease later in life.
Key Words: C-reactive protein • inflammation • ethnicity • hypertension • National Health and Nutrition Examination Survey
Abbreviations: CRP—C-reactive protein • SBP—systolic blood pressure • DBP—diastolic blood pressure • NHANES—National Health and Nutrition Examination Survey • HDL—high-density lipoprotein • BP—blood pressure
C-reactive protein (CRP) is a nonspecific marker of systemic inflammation.1,2 There is evidence that chronic inflammation plays a role in the pathogenesis of atherosclerosis, and modest elevations of high-sensitivity CRP levels (>3 mg/L) may therefore be useful as a marker of increased risk for atherosclerotic diseases.2,3 In adults, elevated CRP levels and elevated blood pressure (BP) are both independent determinants of cardiovascular risk. Furthermore, elevated BP is itself an independent predictor of increased CRP levels, leading to the hypothesis that adult hypertension leads to atherosclerosis in part through chronic inflammation.4–10
Both autopsy studies and clinical studies suggest that atherosclerosis can develop during adolescence and is more prevalent in adolescents with elevated BP.11,12 These findings, together with the potential role of chronic inflammation in the pathogenesis of atherosclerosis, have led investigators to study the relationship between elevated CRP levels, BP, and other cardiovascular risk factors in children and adolescents. Most previous studies did not show an independent association between elevated BP and CRP levels in children, after controlling for adiposity and dyslipidemia.13–17 Two previous studies of cardiovascular risk factors in children in the 1999–2000 National Health and Nutrition Examination Survey (NHANES) reported conflicting results regarding an association between elevated BP and CRP levels.16,18 The objective of the current study was to reexamine the relationship between CRP levels and elevated BP in the larger 1999–2004 NHANES sample of US children and adolescents, with particular emphasis on subjects with BP measurements in the hypertensive range (BP of 95th percentile).19
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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NHANES Study Population, Data Collection, and Laboratory Analyses
The NHANES is a national survey of the civilian, noninstitutionalized, US population. Starting in 1999, the survey has been conducted continuously, evaluating
5000 persons per year with a multistage, stratified, cluster, sampling design.20 Participants complete a detailed home interview, followed by a physical examination and laboratory evaluation in a mobile examination center. Since 1999, BP has been measured in NHANES in subjects 8 years of age.21 The study physician measured the BP 3 times through auscultation using a mercury manometer, after the subject had been sitting quietly for 5 minutes. The first and fifth Korotkoff sounds were determined according to standard recommendations by the American Heart Association. The first reading was discarded and the average of the second and third measurements was recorded as the final BP reading.22 All subjects 8 to 17 years of age who participated in NHANES between 1999 and 2004 were to have CRP, cotinine, homocysteine, total cholesterol, and high-density lipoprotein (HDL) cholesterol levels determined. Triglyceride, insulin, and glycohemoglobin levels were measured only in subsamples and therefore were excluded from the current analysis.21
CRP levels were measured with a high-sensitivity assay using latex-enhanced nephelometry (Nephelometer II analyzer system; Dade Behring Diagnostics, Somerville, NJ), at the University of Washington Medical Center (Seattle, WA). The lower limit of detection of the assay was 0.1 mg/L, and the upper limit of the reference range was 10 mg/L. Homocysteine levels were measured in plasma with an automated fluorescence polarization immunoassay (NHANES 1999–2001, Abbott IMx system homocysteine assay; NHANES 2002–2004, Abbott AxSym system homocysteine assay; Abbott Diagnostics, Abbott Park, IL). Levels of cotinine, a metabolite of nicotine, were measured in serum through isotope dilution-high performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry (Organic Analytical Toxicants Branch, Division of Laboratory Sciences, National Center for Environmental Health, Atlanta, GA). Total cholesterol levels were measured enzymatically (Hitachi 704 analyzer; Lipoprotein Analytical Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD). The method for HDL cholesterol measurement changed during the study period. In NHANES 1999–2002, HDL cholesterol levels were determined after precipitation of other lipoproteins with a polyanion-divalent cation mixture. In NHANES 2003–2004, HDL cholesterol levels were determined directly after the apolipoprotein B-containing lipoproteins were reacted with a blocking agent (Hitachi 704 analyzer; Lipoprotein Analytical Laboratory, Johns Hopkins University School of Medicine).23–25
Analyses
Data sets from NHANES 1999–2000, 2001–2002, and 2003–2004 were merged to create a single data set with subjects from NHANES 1999–2004. Participants 8 to 17 years of age for whom CRP levels and systolic BP (SBP) and/or diastolic BP (DBP) measurements were available were included in the current analysis. Participants with CRP levels of >10 mg/L and those receiving corticosteroids were excluded, to avoid inclusion of children with acute inflammation. Participants receiving estrogens or stimulants were excluded because of the known effects on CRP levels and BP, respectively.26,27
There are currently no guidelines associating CRP levels and cardiovascular risk in children, but adults with CRP levels of >3 mg/L (upper tertile of the population distribution) are considered to be at 1.5- to 2.0-fold increased risk for cardiovascular disease, relative to adults with CRP levels of <1 mg/L (lower tertile of the population distribution).2 In the absence of specific pediatric guidelines, the bivariate analyses compared children and adolescents with CRP levels of >3 mg/L with those with CRP levels of 3 mg/L, with respect to demographic characteristics, BP, and other potential cardiovascular risk factors, including BMI, total cholesterol level, HDL cholesterol level, homocysteine level, and smoking (cotinine level). Mexican American and other Hispanic subjects were analyzed together as Hispanic. Independent associations between elevated BP and CRP levels, as a continuous variable, were then adjusted for covariates through multivariate linear regression analysis. All variables found to be significantly different between subjects with CRP levels of >3 mg/L and those with CRP levels of 3 mg/L were included as independent variables in the regression models. The effect of BP was evaluated both categorically (95th percentile for age, gender, and height19) and continuously (BP index). BP index was defined as the subject's BP divided by the 95th percentile BP for age, gender, and height.19 The effect of BP of 90th percentile was also analyzed for consistency with previous studies.16,28 Multivariate linear regressions were performed separately for boys and girls, because previous studies showed gender differences in associations between CRP levels and cardiovascular risk factors for children.29
Statistical Analyses
Bivariate associations between baseline demographic characteristics, BP, and other cardiovascular risk factors for children with CRP levels of >3 mg/L versus 3 mg/L were analyzed by using 
2 analyses and 2-sided unpaired t tests. Independent associations between CRP levels and BP, controlling for potential confounders, were investigated by using multivariate linear regressions with logarithmically transformed CRP levels as the dependent variable. In regression analyses, CRP levels were logarithmically transformed to improve the distribution of this variable. SUDAAN software (Research Triangle Park Institute, Research Triangle Park, NC) was used to produce weighted national estimates and to adjust SEs, accounting for the complex sampling design of the NHANES. Descriptive data are presented as unweighted counts and weighted proportions. P values of <.05 were considered significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Among the 7458 children 8 to 17 years of age included in NHANES from 1999 to 2004, 301 were missing both SBP and DBP measurements and an additional 688 were missing CRP measurements. Of the remaining 6469 children, 204 had CRP levels of >10 mg/L and were excluded from the current study. Twenty-one children were excluded because of use of estrogens, 122 because of use of stimulants, and 10 because of use of corticosteroids. Of the remaining 6112 children, 3058 (50.7%) were male and 3054 (49.3%) female; 1510 (59.7%) were white, 2391 (18.8%) Hispanic, 1984 (15.5%) black, and 227 (6%) other race/ethnicity. Six hundred ten children (8.8%) had CRP levels of >3 mg/L, and 1183 (17%) had BMI values of
95th percentile. Subjects with CRP levels of 3 mg/L had a median CRP of 0.30 mg/L, with an interquartile range of 0.10 mg/L to 0.80 mg/L. Subjects with CRP levels of >3 mg/L had a median CRP level of 4.6 mg/L, with an interquartile range of 3.8 mg/L to 6.2 mg/L. Four hundred fourteen subjects (6%) had SBP values of 90th percentile. Of those, 219 (53%) had SBP values of 95th percentile (a threefold increase in the available number of subjects with SBP values of 95th percentile, compared with the NHANES 1999–2000 sample). Two hundred forty-nine children had DBP values of 90th percentile and 91 of those children had DBP values of 95th percentile, representing 4% and 1.3% of the total sample, respectively.
Table 1 compares baseline demographic data and laboratory values for subjects with CRP levels of >3 mg/L and subjects with CRP levels of 3 mg/L. Subjects with higher CRP levels were more likely to be slightly older, to be of minority race/ethnicity, to have higher BMI values, to have higher SBP values, and to have low HDL cholesterol levels. The groups were comparable with respect to gender distribution, DBP values, and total cholesterol, homocysteine, and cotinine levels.
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To evaluate the effect of elevated SBP on CRP levels, multivariate linear regression analysis was performed. SBP was analyzed both categorically (
90th percentile and 95th percentile) and continuously (SBP index). On the basis of results of the bivariate analysis, the multivariate regression models were adjusted for age, BMI percentile, race/minority, SBP, and low HDL cholesterol level. Because of limited sample size, children whose race was categorized as other were not included in the regression analysis. The analysis was limited to SBP because DBP did not differ between CRP groups. Table 2 shows the results of regression analysis according to gender. In this adjusted analysis, boys with SBP values of 95th percentile had significantly higher logarithmically transformed CRP levels, compared with boys with lower SBP values (β = .38; P = .018). In contrast, SBP values of 95th percentile did not have an independent effect on logarithmically transformed CRP levels in girls (P = .94). Regardless of gender, BMI percentile was a strong predictor of CRP levels. Hispanic ethnicity and low HDL cholesterol levels were independently associated with logarithmically transformed CRP levels in both boys and girls. SBP was not independently associated with CRP levels when the SBP variable was defined as a SBP value of 90th percentile or when the SBP index was used (data not shown).
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To investigate further the relationship between elevated SBP and CRP levels in boys, multivariate regression analyses were repeated separately according to race/ethnicity categories (Table 3). The regression models included age, BMI percentile, low HDL cholesterol level, and SBP of
95th percentile, with logarithmically transformed CRP levels as the dependent variable. In these adjusted analyses, there was an independent association between SBP values of 95th percentile and logarithmically transformed CRP levels for black boys (β = .46; P = .01) but not white or Hispanic boys. BMI percentile values remained independently associated with CRP levels regardless of race/ethnicity (black boys, β = .015 ± .0014; P < .001; white boys, β = .018 ± .002; P < .001; Hispanic boys, β = .022 ± .0012; P < .001). Age remained independently associated with CRP levels for white boys (β = .0048 ± .002; P = .004) and Hispanic boys (β = .007 ± .001; P = .006) but not black boys (β = .001 ± .001; P = .31). Low HDL levels remained independently associated with CRP levels for black boys (β = .35 ± .10; P = .002) but not white boys (β = .21 ± .12; P = .09) or Hispanic boys (β = .083 ± .11; P = .46).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Cross-sectional studies in adults showed that CRP levels were elevated in subjects with elevated BP, after adjustment for obesity and other cardiovascular risk factors.4–10 In addition, prospective studies showed that elevated CRP levels and hypertension were both independent determinants of cardiovascular risk and their predictive values were additive.2,5,10 An analysis of the Woman's Health Study data showed that participants with both elevated CRP levels and high BP demonstrated the poorest cardiovascular disease event-free survival rates.5 Such findings suggest that inflammation and hypertension may act together to promote atherosclerosis, which emphasizes the importance of any potential relationship between elevated BP and CRP levels.5,10
In contrast to studies in adults, most previous studies of CRP levels and cardiovascular risk factors in children have not found an independent effect of BP on CRP levels, after controlling for the strong influence of BMI on CRP levels.13–17 Two previous reports evaluating the effects of cardiovascular risk factors on high-sensitivity CRP levels in NHANES 1999–2000 both found that adiposity was the best predictor of CRP levels.16,18 In the first report, SBP analyzed as a continuous variable was found to be independently associated with CRP levels in girls 12 to 17 years of age.18 In contrast, a NHANES 1999–2000 study found that high SBP, defined as SBP of 90th percentile, was not associated with increased CRP levels in adjusted analyses.16
The current study evaluated the effect of high SBP on CRP levels in children and adolescents with NHANES 1999–2004 data, a data set with a threefold greater number of children with elevated SBP, compared with NHANES 1999–2000. The larger sample size allowed the current study to focus on children with SBP elevation in the hypertensive range (SBP of 95th percentile).19 Multivariate analysis revealed that SBP of 95th percentile was independently associated with higher CRP levels in male subjects. In subset analyses, the association of high SBP and CRP levels was found to be largely limited to black boys. In contrast to these findings, neither SBP of 90th percentile nor SBP index was independently associated with higher CRP levels, a result that emphasizes the importance of focusing on subjects with the highest elevation of SBP. The current analysis also found that Hispanic ethnicity was independently associated with elevated CRP levels, regardless of gender and BP status. A previous report of the CRP concentration distribution among US children also found that Mexican American children had the highest CRP concentrations among the race/ethnicity groups.30 The propensity of Hispanic youths toward elevated CRP levels (and therefore possibly early atherosclerosis) is particularly notable in light of the greater likelihood of Hispanic adolescents to develop left ventricular hypertrophy in the presence of elevated BP and obesity.31
Similar to previous studies, the current analysis found that BMI was a strong determinant of CRP levels. In addition, low HDL cholesterol levels, a lipid abnormality that is often associated with obesity, was a significant independent predictor of CRP levels in the primary analysis, regardless of gender, SBP, and ethnicity. These findings confirm the importance of obesity and its associated lipid abnormalities as significant cardiovascular risk factors already prevalent in childhood and adolescence. Less than 10% of children had CRP levels of >3 mg/L, a level that represents the upper tertile in adults. In addition, increasing age in the current study was independently associated with higher CRP levels, a finding that was described previously.30 Taken together, these results suggest that inflammation may become more prominent as age increases.
Clinical studies of carotid intima-media thickness suggested that adolescents with primary hypertension are at increased risk for the development of atherosclerosis during youth.12 Autopsy studies confirmed the increased prevalence of early atherosclerotic lesions in the coronary arteries and aorta in adolescents with elevated BP.11 Such findings, along with the recently increased prevalence of obesity-associated hypertension in childhood, demonstrate the importance of understanding the pathogenesis of atherosclerosis in overweight youths with elevated BP.32 The current study results suggest there is interplay between race/ethnicity, elevated BP, and inflammation during childhood and adolescence. The reasons for these findings are unclear, but recent studies in adults also found racial and gender differences in the effects of CRP levels on cardiovascular risk.33–35 Given the potential importance of chronic inflammation in the pathogenesis of atherosclerosis, the current study findings have potential implications for the development of atherosclerosis in youth and subsequent disparities in atherosclerotic cardiovascular disease later in life,36,37 as well as the use of inflammatory markers to identify children and adolescents at risk for the development of hypertension and atherosclerotic diseases later in life.
The current study has several limitations. The cross-sectional study design limits inferences regarding the causal relationship between cardiovascular risk factors and increased CRP levels. NHANES participants had a single CRP determination. For clinical determination of cardiovascular risk in adult patients, the American Heart Association and the Centers for Disease Control and Prevention recommend that CRP levels be measured twice, optimally 2 weeks apart.2 In addition, NHANES participants had BP measured on a single day. Few children with elevated BP measurements in NHANES actually have persistent hypertension, and many children with elevated BP values at a single sitting ultimately are determined to have white-coat hypertension. The focus on SBP of 95th percentile in the current analysis might have lessened this limitation, compared with previous studies, because the likelihood of white-coat hypertension decreases with increased elevation of clinic BP measurements.38 Triglyceride, insulin, and glycohemoglobin levels were not included in the analyses because these tests were performed only for subsamples of the subjects in NHANES. The impact of not having these measures available for the current analysis is not known, but previous studies in children and adults found that insulin resistance and the metabolic syndrome were both associated with elevated CRP levels.28
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This study showed that elevated SBP was independently associated with increased CRP levels in boys, an effect that was most evident for black boys in subset analyses. In addition, Hispanic ethnicity was found to be independently associated with elevated CRP levels, regardless of gender. Obesity was found to be a strong predictor of CRP levels, a result consistent with previous studies. These findings hold potential implications for the future cardiovascular health of minority youths and are particularly notable given the recent increase in the prevalence of pediatric hypertension and obesity. Further studies of racial and ethnic differences in chronic inflammation early in life may lead to a better understanding of differences in cardiovascular outcomes among minority groups of middle-aged and older adults.
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ACKNOWLEDGMENTS |
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Dr Lande was supported in part by grant 5K23HL080068-04 from the National Heart, Lung, and Blood Institute. Dr Pearson was supported in part by grants 5U48 DP000031-02 and 3U48 DP000031-02S1 from the Centers for Disease Control and Prevention, grant R25 CA102618 from the National Cancer Institute, grants UL1 RR024160-1, KL2 RR024136-1, TL1 RR024135-1, and 1R01HL081066-01A2 from the National Institutes of Health, the Rochester Regional Public Health Medicine Education Center Grant, and a Crescendo Clinical Trial grant from Sanofi-Aventis. Dr Fernandez was supported in part by grant 5R01HL079511-04 from the National Heart, Lung, and Blood Institute and a Cardiovascular Health Intervention Network and Coordinating Center grant from the Centers for Disease Control and Prevention.
We thank Dr George Schwartz and Dr Megan Rashid for review of the manuscript.
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FOOTNOTES |
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Accepted Mar 14, 2008.
Address correspondence to Marc B. Lande, MD, Department of Pediatrics, University of Rochester Medical Center, 601 Elmwood Ave, Box 777, Rochester, NY 14642. E-mail: marc_lande{at}urmc.rochester.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject CRP levels are independently associated with adult hypertension, leading to the hypothesis that hypertension causes atherosclerosis at least in part through inflammation. Most studies in children have not demonstrated such a CRP-BP link, after controlling for obesity.
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| What This Study Adds This study demonstrated that systolic BP in the hypertensive range was independently associated with increased CRP levels in boys but not girls. In subset analyses, the association was largely limited to black boys.
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