  the anatomic and pathophysiological genesis of atherosclerosis is in childhood [ 15 ] . the traditional framingham risk factors ( hyperlipidemias , blood pressure , obesity , diabetes , and cigarette smoking ) have been used as the starting point for evaluating individual risk to vascular disease , and each factor is strongly associated with increased risk to coronary heart disease ( chd ) in adults and , in children , associated with family history of chd [ 69 ] .
it has been estimated that the traditional chd risk factors may explain about 50% of chd morbidity and mortality , eliciting efforts to identify additional predictive factors , such as high - sensitivity c reactive protein ( hscrp ) .
biomarkers predictive of inflammatory processes in acute clinical settings ( e.g. , during infection or after traumas ) have become valuable predictors of future vascular events .
this primal organism response to invading pathogens , trauma , or chronic inflammation presumably represents a protective mechanism and involves a cascade of thrombotic and inflammatory factors of variable expression . in the chronic state ,
acute phase reactants have become important predictors of future vascular events : thus , baseline serum high - sensitivity c - reactive protein ( hscrp ) values have been correlated with the development of chd in healthy men [ 11 , 12 ] and women   in the harvard study population , corroborated by other groups [ 13 , 14 ] . in a prospective study of 506 men who had fatal chd or had
a nonfatal myocardial infarction compared to 1025 men free of chd , men in the top third for entry hscrp had an odds ratio for chd of 2.13 ( 95% confidence interval 1.383.28 ) after age , town , smoking , vascular risk factors , and indicators of socioeconmic status were adjusted for . the cascade of tnf- and il-6 elevation leads to increments in hscrp and fibrinogen , with resulting adhesion molecule expression , and may facilitate development of type 2 diabetes mellitus ( t2 dm ) as well as chd .
cross - sectional studies in children have shown a strong association between hscrp and obesity , triglycerides , hdl cholesterol , diastolic blood pressure , and fibrinogen [ 1720 ] .
longitudinal data from the young finns study   showed that hscrp tracked significantly from ages 318 years ( at entry ) to ages 2439 years .
analysis , adult carotid artery intimal medial thickness ( cimt ) was associated with childhood elevated systolic blood pressure , high ldl cholesterol , and smoking , but not with childhood hscrp .
, however , showed that elevated hscrp levels in children are associated with increased cimt as well as with decreased brachial artery flow - mediated dilatation , and zieske et al .   reported that serum hscrp is independently associated with advanced atherosclerosis in youth
thus , in aggregate , these studies suggest that measurement of hscrp in childhood [ 2123 ] might predict adult cardiovascular risk .  
the national growth and health study ( nghs ) , its ancillary studies , and the extension of the followup of the cincinnati clinic cohort by investigator - initiated research projects , provide an opportunity to assess hscrp tracking in black and white females from mid - adolescence to young adulthood and to identify factors associated with high concentrations of hscrp and with its tracking .
briefly , nghs was a 10-year ( 19871997 ) multicenter cohort study to explicate origins of black - white disparities in obesity and its effects on cardiovascular ( cvd ) risk factors in women .
race was self - declared and enrollment was restricted to 9- and 10-year old girls from racially concordant households , that is , to girls who said they were black or white and whose parents or guardians said that they were black or white , respectively . in ancillary projects ,
the cincinnati clinic measured fasting insulin at visit 7 ( mean  sd age 16  1 ) , in addition to the nghs variables  lipid profiles , apo a1 , systolic and diastolic blood pressure . at age 16
after completion of nghs , the cincinnati clinic extended followup with measurement of insulin to age 25 and collected hscrp at ages 24 , 25 , and 26 .   in the nghs , and its extension , procedures followed were in accordance with the ethical standards of the institutional review boards of the centers , who approved the study .
signed informed consent was obtained from the girls ' parents or guardians and assent from the girls .
methods for measurement of lipids , fasting serum insulin , glucose , height , weight , waist circumference , and systolic and diastolic blood pressure have been previously described [ 24 , 25 ] .
fasting glucose was measured at ages 10 and 1924 , insulin at ages 10 , 16 , and 1925 . at each visit
, girls were asked whether they were taking a birth control pill , since hscrp may be elevated by estrogen - progestin oral contraceptives .
the nghs used bmi to assess overweight annually according to a standard protocol , as recommended by several expert panels [ 2729 ] and waist circumference as an indicator of fat patterning .    using criteria previously described , nghs subjects having fasting blood glucose 126  mg / dl   at age 10 or type 1 dm at any time from age 10 through age 25 were excluded ( n = 7 ) from the analysis sample for this report . diagnosis of diabetes was based on who criteria , fasting glucose 126  mg / dl , and self - reported diabetes with treatment by a physician .
we did not have measurement of c - peptides as well as diabetes autoantibody levels , gold standard methods   to distinguish type 1 from type 2 diabetes .   fasting serum insulin levels ( competitive protein - binding radioimmunoassay ) were measured after an overnight fast ( 8  hr ) using the michigan diabetes research and training center ( ann arbor ) at age , and using the endocrine lab at the university of cincinnati / children 's medical center at ages 16 , 19 , and 2025 .  
hscrp was measured using the n high - sensitivity latex - enhanced immunonephelometric ( bn 100 nephelometer , dade behring ) assay .
since hscrp was not normally distributed , black - white differences in hscrp and differences between birth control pill users and nonusers were assessed by wilcoxon rank sum tests . for assessment of changes in hscrp and for regression analyses ,
spearman correlations were used to assess the tracking of hscrp from age 16 to 26 years , table 1 . after adjusting for age , race , bmi , waist circumference , insulin , maximum glucose , total cholesterol , hdl cholesterol , ldl cholesterol , triglyceride , and systolic and diastolic blood pressure , spearman partial correlations
were also calculated to assess the tracking of hscrp from ages 24 to 26 , and 25 to 26 , table 1 .
spearman correlations were used to assess the associations of hscrp with cardiovascular risk factors at ages 16 , 24 , 25 , and 26 years including age , race , bmi , waist circumference , insulin , total cholesterol , triglyceride , hdl cholesterol , ldl cholesterol , systolic blood pressure , diastolic blood pressure , and maximum glucose , table 2 .
the hochberg - benjamini   false discovery rate ( fdr ) for multiple comparisons was used , table 2 .
after log transformation of hscrp , all of the variables from table 2 were incorporated as candidate explanatory variables into stepwise regression models with hscrp as the dependent variable at ages 16 , 24 , 25 , and 26 , table 3 .
spearman correlations were used to assess relationships of change in hscrp ( in logarithm scale ) from ages 24 to 26 and from 25 to 26 with changes in cardiovascular disease variables : age , bmi , total cholesterol , triglyceride , hdl cholesterol , ldl cholesterol , systolic blood pressure , and diastolic blood pressure during the same period , table 4 .
all of the variables from table 4 were incorporated as candidate explanatory variables into stepwise regression models with change in hscrp ( in logarithm scale ) from age 24 to 26 and from 25 to 26 as dependent variables , table 5 .
hscrp did not differ between birth control pill users versus nonusers , p  .28 and did not differ by race , p  .09 .
hence , data are presented for the total cohort without subcategorization by birth control pill use or race .
there were no differences ( p > .05 ) in hscrp or cvd risk factors between girls with 2 sequential hscrp measurements and those with only 1 measurement .
median and interquartile range for hscrp at age 16 were 1.5 ( 0.75.6 ) , at age 24 , 2.0 ( 0.74.0 ) , at 25 , 1.7 ( 0.64.2 ) , and at 26 , 1.7 ( 0.64.6 )  mg / l .  
subsets of the cohort had hscrp measured at different ages , 1 , 2 , 9 , and 10 years apart , making possible studies of hscrp tracking and factors associated with it , table 1 .
thus , there were 37 girls having hscrp measured at age 16 ( 18 black , 19 white ) with subsequent measurements at age 24 ( n = 6 ) , 25 ( n = 22 ) and 26 ( n = 21 ) , table 1 .
in addition , 172 girls ( 91 black , 81 white ) had hscrp measured at age 24 , with subsequent measures at age 25 ( n = 3 ) and at age 26 ( n = 147 ) , table 1 . additionally , hscrp was measured at age 25 in 391 girls ( 217 black , 174 white ) and subsequently at age 26 in 225 of these girls , table 1 .
hscrp was measured at age 26 in 392 girls ( 215 black , 177 white ) , table 1 .  
age 16 hscrp correlated with subsequent measures at ages 25 ( r = 0.77 , p < .0001 ) and 26 ( r = 0.50 , p = .02 ) , table 1 .
age 24 hscrp correlated with levels at age 26 ( r = 0.66 , p < .0001 ) and age 25 hscrp correlated with levels at age 26 ( r = 0.71 , p < .0001 ) , table 1 .
after adjusting for age , race , bmi , insulin , maximum glucose , total cholesterol , triglyceride , hdl cholesterol , ldl cholesterol , and systolic and diastolic blood pressure , hscrp at age 24 remained highly correlated with levels at age 26 ( partial r = 0.63 , p < .0001 ) , as did hscrp at age 25 with levels at age 26 ( partial r = 0.54 , p <
the top 30% of the distribution , 24 ( 56% ) remained in the top 30% at age 26 , while 26 of 41 ( 63% ) with hscrp at age 24 in the bottom 30% of the distribution remained in the bottom 30% at age 26 .
of 62 girls in the hscrp top 30% at age 25 , 42 ( 68% ) remained in the top 30% at age 26 , while 49 of 72 ( 68% ) originally in the bottom 30% at age 25 remained there at age 26 .
of the 37 girls at age 16 , significant positive bivariate correlates with hscrp included bmi , waist circumference , insulin , and maximum glucose , table 2 .   at ages 24 , 25 , and 26
, significant bivariate correlates with hscrp included bmi , waist circumference , insulin , total cholesterol , triglyceride , hdl cholesterol , ldl cholesterol , systolic blood pressure , diastolic blood pressure , and maximum glucose , table 2 .
waist circumference ( age 16 , partial r = 44.8% ) and bmi ( ages 24 , 25 , and 26 , partial r = 33.1% , 34.4% , 31.1% ) were the major significant ( p < .0001 ) explanatory variables for hscrp , table 3 . at ages 24 and 25 ,
total cholesterol levels were significant explanatory variables , accounting for 2.5% and 1.9% of hscrp variance , table 3 . at age 26
, triglyceride accounted for 3.5% of hscrp variance , table 3 . with the exception of inclusion of race as a significant explanatory variable at age 26 ,
the results in table 3 were identical to results if only those variables which had significant bivariate correlations in table 2 were included as candidate explanatory variables ( data not shown ) .
race was unrelated to change in hscrp from age 24 to 26 , and from age 25 to 26 , table 4 .
changes in bmi , waist circumference , total cholesterol , triglyceride , and ldl cholesterol were positively and significantly related to changes in hscrp from ages 24 to 26 , table 4 .
changes in bmi , waist circumference , total cholesterol , and triglyceride were positively and significantly related to changes in hscrp from age 25 to 26 , table 4 .   after including all of the candidate explanatory variables of table 4 into a stepwise regression model , change in total cholesterol and change in bmi were significant explanatory variables for change in hscrp from age 24 to 26 ( partial r = 12.3% , 6.6% ) , table 5 .
changes in bmi ( partial r = 8.5% ) and change in tg ( partial r = 3.3% ) were significant explanatory variables for change in hscrp from age 25 to 26 , table 5 .
the results in table 5 were identical to results if only those variables which had significant bivariate correlations in table 4 were included as explanatory variables ( data not shown ) .
the chronic expression of acute phase proteins , in the stable , ostensibly nonacute setting , is of unclear etiology .
such proteins could be present in excess due to ( a ) incomplete resolution of a previous acute episode , ( b ) ongoing monocyte / macrophage activation , and/or ( c ) enhanced baseline production determined by coordinate genetic control .
activation of the monocyte / macrophage in the acute setting may be among the first dominoes in the inevitable cascade of expressed cytokines and growth factors [ 34 , 35 ] .
activated monocytes produce tnf and il-1-like cytokines , which lead to the full acute phase reaction , including hscrp ( 17 ) .   in adults ,
statins lower hscrp concurrently with ldl cholesterol , and hscrp levels achieved on statin therapy are predictive of cvd event rates irrespective of the lipid endpoint used . to test the hypothesis
whether or not subjects with normal ldl cholesterol but elevated hscrp represent a population at increased risk that might benefit from statin treatment , the jupiter trial   randomized 17,802 apparently healthy persons with elevated hscrp to 20  mg rosuvastatin daily or placebo .
the rates of the primary endpoint ( composite of nonfatal myocardial infarction , nonfatal stroke , hospitalization for unstable angina , revascularization , and confirmed death from cardiovascular causes ) were 0.77 and 1.36 per 100 person - years of followup in the rosuvastatin and placebo groups , respectively .
it was postulated that hscrp more accurately selected high - risk subjects than ldl cholesterol due to hscrp 's association with multiple cvd risk factors , thus representing an aggregate - integrated marker of the total inflammatory burden of an individual .
while inflammation is a crucial component of atherothrombosis   and patients with elevated hscrp and low or intermediate ldl cholesterol levels [ 10 , 37 ] are at increased vascular risk , it is not known whether inhibition of inflammation per se will lower vascular event rates . a direct test of the inflammatory hypothesis of atherothrombosis requires an agent that inhibits inflammation without affecting other components of the atherothrombotic process , particularly ldl cholesterol .
the forthcoming cardiovascular inflammation reduction trial ( cirt ) will randomize 7000 stable coronary artery disease patients with persistent elevations of hscrp to placebo or very low - dose methotrexate ( 10  mg weekly ) , a proven anti - inflammatory regimen that reduces tnf - alpha , il-6 , and crp levels and is in wide use among rheumatoid arthritis patients .
the cirt trial , if successful , would help confirm the inflammatory hypothesis of atherothrombosis and open innovative , anti - inflammatory approaches to the treatment and prevention of cardiovascular disorders .
it is not yet known whether hscrp is a risk factor for cardiovascular disease independent of other known risk factors [ 10 , 37 ] , nor is it well understood how long hscrp would need to be normalized independent of changes in other cvd risk factors to reduce cvd events .
moreover , it is not yet known whether hscrp , a $ 43 test , is useful in assessing childhood antecedents of young adult cardiovascular risk above and beyond conventional childhood cvd risk factors , and whether high hscrp is reversible with childhood therapeutic interventions .
although karakas and koenig reported that birth control pill use elevated hscrp , it had no significant effect on hscrp in our current study .
reported significant 21-year tracking of hscrp from childhood and adolescence into the fourth decade , but hscrp was not independently associated with young adulthood carotid intimal - medial thickness ( cimt ) .
, however , showed that elevated hscrp levels in children were associated with increased cimt and decreased brachial artery flow - mediated dilatation , a marker of the loss of vascular flexibility .
in addition , zieske et al .   reported that serum hscrp is independently associated with advanced atherosclerosis in youth . in the current study , there was significant tracking of hscrp across several years from age 24 to 26 ( r = 0.66 , p < .0001 ) and from age 25 to 26 ( r = 0.71 , p < .0001 )
. similarly strong long - term correlations were found from age 16 to ages 25 ( r = 0.77 , p < .0001 ) and 26 ( r = 0.50 , p = .02 ) .
these tracking coefficients remained significant after adjusting for multiple cvd risk factors ; hscrp at age 24 remained highly correlated with levels at age 26 ( partial r = 0.63 , p < .0001 ) , as did hscrp at age 25 with levels at age 26 ( partial r = 0.54 , p < .0001 ) .
exemplifying this strong tracking of hscrp , 24 of 43 girls ( 56% ) with top 30% hscrp at age 24 remained in the top 30% at age 26 , while 26 of 41 girls ( 63% ) with bottom 30% hscrp at age 24 remained in the bottom 30% at age 26 .
of 62 girls in the top 30% of the hscrp distribution at age 25 , 42 ( 68% ) remained in the top 30% at age 26 , while 49 of 72 ( 68% ) originally in the bottom 30% at age 25 remained there at age 26 .  
with exception of the report by juonala et al . , tracking of hscrp during childhood and into young adulthood has not yet been reported . with 21-year followup from childhood to young adulthood , juonala et al .   reported significant tracking between childhood and adult hscrp levels , highest in 18 years olds at study entry , r = 0.47 in females , 0.32 in males , and p < .0001 for both .
congruent with the findings of the current study , the association between childhood and adult hscrp levels in finns   was independent of serum lipids , blood pressure , smoking , obesity indices , and insulin .  
significant tracking of hscrp from childhood into young adulthood speculatively raises the issue whether childhood hscrp can predict adult atherosclerosis or cvd events independent of traditional cardiovascular risk factors ( hdl and ldl cholesterol , triglyceride , blood pressure , and obesity ) . in the study by juonala et al .
, however , childhood hscrp was not independently associated with young adulthood carotid imt . in 8091 ,
subjects with hscrp  2  mg / l randomized to placebo in the jupiter ( rosuvastatin ) trial , over a 4-year period , the intraclass correlation for repeated hscrp measurements was 0.54 ( 95% ci 0.530.55 ) without adjustment and 0.50 ( 95% ci 0.490.51 ) after adjustment for demographic , lifestyle , and comorbidity determinants , glynn et al .   concluded that  
concentrations of hscrp show strong tracking , even after selection of individuals with initially high values . without statin therapy , increased concentrations of hscrp generally remain high over time .   
, in the current study , at age 16 , hscrp was significantly positively correlated with bmi , waist circumference , and insulin . by stepwise regression , waist circumference and bmi were the major significant ( p < .0001 ) explanatory variables for hscrp , with waist circumference accounting for 44.8% of the variance of hscrp at age 16 , and bmi accounting for 33.1% of variance of hscrp at age 24 , 34.4% at age 25 , and 31.1% at age 26 .
the consistent , independent , and significant association of bmi with hscrp from age 16 to 26 in our current study emphasizes the pediatric and young adult cardiovascular ramifications of obesity . in a recently reported 23.9 year followup study from age
11.3 years of 4857 american indian children without diabetes , endogenous death rates among children with the highest quartile of bmi were more than double those among children in the lowest bmi quartile ( incidence - rate ratio , 2.30 , 95% confidence interval 1.46 to 3.62 ) .
our report is limited by the small number of girls ( n = 37 ) that had hscrp measurements at age 16 and then again at ages 25 and 26 , thus limiting the information on tracking from adolescence into young adulthood . however , tracking data from age 24 to 26 was available in 147 girls and in 225 from age 25 to 26 . in adults , hscrp levels
have been correlated with the development of chd in healthy men   and women [ 11 , 13 , 14 ] . in adults , hscrp levels
are associated with the traditional chd risk factors , but also confer independent information about chd status and future risk [ 10 , 40 ] .
high childhood hscrp might be viewed as a useful index of childhood obesity that would affect progression to future premature death from endogenous causes   and to atherosclerotic disease [ 18 , 41 ] .
 
 objective . we assessed adolescent anthropometry , lipids , insulin , glucose , and blood pressures to identify factors associated with high - sensitivity c - reactive protein ( hscrp ) and its tracking in young adults . 
 methods . 
 ten - year prospective study of 589 schoolgirls , 321 black , 268 white . results . 
 hscrp did not differ ( p > .08 ) by race or oral contraceptive use . 
 hscrp tracked from age 16 to 25 ( r = 0.77 ) , 16 to 26 ( r = 0.50 ) , 24 to 26 ( r = 0.66 ) , and 25 to 26 ( r = 0.71 ) , all p  .02 . by stepwise regression , at age 16 , waist circumference accounted for 44.8% of hscrp variance ; bmi accounted for 33.1% , 34.4% , and 31.1% at ages 24 , 25 , and 26 , p < .0001 for all . 
 changes in cholesterol and bmi were associated with change in hscrp from age 2426 ( partial r2 = 12.3%  p < .0001 , 6.6%  
 p = .0012 ) . 
 changes in bmi and triglyceride ( partial r2 = 8.5%  p = .0001 , 3.3% , p = .0045 ) were associated with change in hscrp from age 25 to 26 . 
 conclusions . 
 hscrp tracks from age 16 to 26 , with bmi , waist circumference , and cholesterol as major determinants . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion