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Technical Briefs |
Divisions of
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Environmental Hazards and Health Effects and
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Laboratory Sciences, National Center for Environmental Health, and
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Division of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30341
aaddress correspondence to this author at: Centers for Disease Control and Prevention, 4770 Buford Hwy., MS K66, Atlanta, GA 30341; fax 770-488-8150, e-mail esf2{at}cdc.gov
C-reactive protein, an acute-phase reactant, is produced in the liver and belongs to the pentraxin family of proteins (1). This protein is very sensitive to inflammation, and its concentration can increase rapidly in response to a wide range of stimuli. Originally described in 1930 (2), C-reactive protein measurements served mostly in a diagnostic, albeit a nonspecific one, and in a monitoring role in such fields as infectious diseases and rheumatology. In the past decade, as the role of inflammation in cardiovascular disease became appreciated, interest turned to C-reactive protein as a possible risk marker for cardiovascular disease. Since then, studies have shown that the C-reactive protein concentration is positively associated with cardiovascular disease incidence and mortality (3) even when the concentration is <3.0 mg/L, which was previously thought to be "normal" (4).
As these research findings have reached the medical community, the use of C-reactive protein measurements has increased, but guidelines addressing the role of C-reactive protein testing in the primary and secondary prevention of cardiovascular disease have not been developed. To facilitate the development of such guidelines, several issues must be addressed, including population distributions of C-reactive protein concentrations and thresholds for interventions.
A key piece of missing information has been the population distribution of C-reactive protein in the US, especially the distribution of C-reactive protein concentrations <3.0 mg/L. This information is helpful in calculating the fraction of cardiovascular disease attributable to increased C-reactive protein concentrations. The National Health and Nutrition Examination Survey (NHANES) III provided information only on the upper ranges of the C-reactive protein distribution (5)(6) because the C-reactive protein test used in that survey had a lower detection limit of 3.0 mg/L.
Another missing piece of information is whether Creactive protein concentration distributions differ among major population groups. Previous research on the association between C-reactive protein and cardiovascular disease has been conducted overwhelmingly among white study participants. New data from NHANES 1999 and 2000, which used a high-sensitivity C-reactive protein test, allowed us to (a) provide the distribution of Creactive protein concentrations for US men across the full range of this analyte and (b) examine C-reactive protein distributions among several racial or ethnic groups.
This analysis uses data from NHANES obtained during 1999–2000 (7). A representative sample of the noninstitutionalized civilian US population was selected by use of a stratified multistage sampling design. The four stages of selection were the selections of primary sampling units (counties or groups of adjacent counties), segments within primary sampling units, households within segments, and one or more participants within households. Trained interviewers, using a computer-assisted personal interview system, interviewed participants at home. Participants were asked to attend the mobile examination center, where they were asked to complete additional questionnaires, undergo various examinations, and provide a blood sample. Persons with low incomes, African Americans, and Mexican Americans were oversampled. The study received human subjects’ approval, and participants were asked to sign an informed consent form.
Blood samples were centrifuged within 1 h of phlebotomy. Serum samples were frozen at -10 °C in the mobile examination center and shipped weekly to the University of Washington Medical Center (Seattle, WA), where they were analyzed within 3 weeks of arrival. C-reactive protein concentrations were measured by latex-enhanced nephelometry (N High Sensitivity CRP assay) on a BNII nephelometer (Dade Behring). Two levels of control materials from Bio-Rad Laboratories were used for quality-control purposes, and day-to-day CVs ranged from 4.9% to 7.8%. The means for the control materials were 1.67 and 3.82 mg/L for samples analyzed during an initial 9-month period and 1.84 and 3.95 mg/L for a subsequent 12-month period.
We limited our analyses to men 
20 years of age who attended the mobile examination center. We examined the C-reactive protein concentration distribution by age and race or ethnicity (white, African American, Mexican American, and other). To examine whether C-reactive protein concentrations differed by race or ethnicity, we performed linear regression analyses after log-transforming C-reactive protein concentrations. We ran models that were unadjusted, age-adjusted, and adjusted for age, education, smoking status, body mass index, and alcohol intake. We used SAS 6.12 to generate percentiles of the C-reactive protein concentration distribution, using the mobile examination center sampling weight to account for the oversampling. We used SUDAAN (Software for the Statistical Analysis of Correlated Data) to do regression analyses.
Of the 2269 men 20 years of age who were interviewed, 2074 attended the examination. The 195 men who did not attend the examination tended to be 3.1 years older than those who did attend (P = 0.070). The percentages who were white or had completed at least high school did not differ significantly between the two groups.
A total of 1940 men 20 years of age had a C-reactive protein value and form the basis of the analyses. C-reactive protein concentrations ranged from 0.1 to 156.0 mg/L. The distribution was highly skewed. The median C-reactive protein concentrations were 1.6 mg/L for all men, 1.6 mg/L for white men, 1.7 mg/L for African-American men, 1.5 mg/L for Mexican-American men, and 1.8 mg/L for other men (Fig. 1
). C-reactive protein concentration increased steadily with age. Detailed information about the C-reactive protein distribution may be found in a supplemental table that accompanies the online version of this Technical Brief at Clinical Chemistry Online (http://www.clinchem.org/content/vol49/issue4/).
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Although the upper boundary for the fourth quintile was a little higher among African-American men and men of other races or ethnicities, the quintile boundaries were similar enough to suggest that no major racial or ethnic differences exist. The sample sizes of African-American men and men of other races or ethnicities were smaller than those for the other two groups of men; therefore, the C-reactive protein concentration distributions for African-American men and men of other races or ethnicities were subject to more sampling variability.
Linear regression analyses indicated that log-transformed C-reactive protein concentrations did not differ among the four race or ethnic groups either in unadjusted analyses or analyses adjusted for age, smoking status, body mass index, and alcohol intake (Table 1
). Age and body mass index were positively associated with log-transformed C-reactive protein concentrations, and current smokers had higher C-reactive protein concentrations than participants who had never smoked. Alcohol intake was not significantly associated with C-reactive protein concentrations. Among the variables included in the regression model, the Wald 
2 was largest for body mass index.
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This study is the first to describe the C-reactive protein concentration distribution using a high-sensitivity Creactive protein assay in a representative sample of US men. As such, these data may serve as reference intervals for US men. The results from NHANES 1999–2000 fill important gaps in our understanding of the distributions of C-reactive protein concentrations among various races or ethnicities and in the range <3.0 mg/L.
The use of C-reactive protein concentration and total cholesterol:HDL-cholesterol quintiles has been proposed as a cardiovascular risk assessment tool (8). Because population-based data based on a high-sensitivity assay were not available for the US population, the question of whether C-reactive protein quintiles needed to be established for each sex and for each race or ethnic group remained unanswered. By showing that C-reactive protein concentration did not differ statistically among white, African-American, Mexican-American, and other men, the data from NHANES 1999–2000 suggest that race- or ethnicity-specific C-reactive protein quintiles are not needed for men.
Wener et al. (5) previously presented the 95th percentiles of the C-reactive protein concentration, measured using a low-sensitivity assay, of NHANES III. Like these authors, we found that C-reactive protein concentration for NHANES 1999–2000 increased with age. They also described some race differences but did not discuss whether these differences were statistically significant. In the NHANES 1999–2000 data, however, the median concentrations were similar among the four racial or ethnic groups, as were the log-transformed concentrations. A previous review of determinants of C-reactive protein concentrations suggested that C-reactive protein concentration varied with age and race or ethnicity (9).
The distribution of C-reactive protein in the population is known to be highly skewed (10)(11)(12)(13), and the C-reactive protein data from NHANES 1999–2000 are no exception. In addition, many other studies have presented some statistics about C-reactive protein concentration in their samples (12)(14)(15)(16)(17)(18)(19)(20).
C-reactive protein is a very nonspecific marker for inflammation. Many diseases and conditions can produce increases in C-reactive protein concentrations. To preserve the generalizability of our findings, we did not exclude participants with various conditions. For example, body mass index is strongly associated with C-reactive protein concentration (21). Excluding overweight or obese participants would have led to the loss of more than one-half of the sample. Excluding other participants with cardiovascular disease, diabetes mellitus, and a myriad of other conditions would have led to additional sizeable exclusions, thus calling into question the generalizability of our findings.
In conclusion, we describe for the first time the full distribution of C-reactive protein concentration among US men. Because of the current interest in the possible use of C-reactive protein measurements to assess cardiovascular risk, these results could be helpful to researchers and clinicians alike.
References
The following articles in journals at HighWire Press have cited this article:
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  S-S. Lee, S. Singh, L. Magder, and M. Petri Predictors of high sensitivity C-reactive protein levels in patients with systemic lupus erythematosus Lupus, February 1, 2008; 17(2): 114 - 123. [Abstract] [PDF]
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 J. Ishikawa, Y. Tamura, S. Hoshide, K. Eguchi, S. Ishikawa, K. Shimada, and K. Kario Low-Grade Inflammation Is a Risk Factor for Clinical Stroke Events in Addition to Silent Cerebral Infarcts in Japanese Older Hypertensives: The Jichi Medical School ABPM Study, Wave 1 Stroke, March 1, 2007; 38(3): 911 - 917. [Abstract] [Full Text] [PDF]
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 D. C. Crawford, C. L. Sanders, X. Qin, J. D. Smith, C. Shephard, M. Wong, L. Witrak, M. J. Rieder, and D. A. Nickerson Genetic Variation Is Associated With C-Reactive Protein Levels in the Third National Health and Nutrition Examination Survey Circulation, December 5, 2006; 114(23): 2458 - 2465. [Abstract] [Full Text] [PDF]
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 D. E. Laaksonen, L. Niskanen, K. Nyyssonen, K. Punnonen, T.-P. Tuomainen, and J. T. Salonen C-reactive protein in the prediction of cardiovascular and overall mortality in middle-aged men: a population-based cohort study Eur. Heart J., September 1, 2005; 26(17): 1783 - 1789. [Abstract] [Full Text] [PDF]
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 A. Khera, D. K. McGuire, S. A. Murphy, H. G. Stanek, S. R. Das, W. Vongpatanasin, F. H. Wians Jr, S. M. Grundy, and J. A. de Lemos Race and Gender Differences in C-Reactive Protein Levels J. Am. Coll. Cardiol., August 2, 2005; 46(3): 464 - 469. [Abstract] [Full Text] [PDF]
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M. Di Napoli, M. Schwaninger, R. Cappelli, E. Ceccarelli, G. Di Gianfilippo, C. Donati, H. C.A. Emsley, S. Forconi, S. J. Hopkins, L. Masotti, et al. Evaluation of C-Reactive Protein Measurement for Assessing the Risk and Prognosis in Ischemic Stroke: A Statement for Health Care Professionals From the CRP Pooling Project Members Stroke, June 1, 2005; 36(6): 1316 - 1329. [Abstract] [Full Text] [PDF]
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 B. J. Nicklas, T. You, and M. Pahor Behavioural treatments for chronic systemic inflammation: effects of dietary weight loss and exercise training Can. Med. Assoc. J., April 26, 2005; 172(9): 1199 - 1209. [Abstract] [Full Text] [PDF]
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G. L. Myers, N. Rifai, R. P. Tracy, W. L. Roberts, R. W. Alexander, L. M. Biasucci, J. D. Catravas, T. G. Cole, G. R. Cooper, B. V. Khan, et al. CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Report From the Laboratory Science Discussion Group Circulation, December 21, 2004; 110(25): e545 - e549. [Full Text] [PDF]
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 E. S. Ford, W. H. Giles, A. H. Mokdad, and G. L. Myers Distribution and Correlates of C-Reactive Protein Concentrations among Adult US Women Clin. Chem., March 1, 2004; 50(3): 574 - 581. [Abstract] [Full Text] [PDF]
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T. B. Ledue and N. Rifai Preanalytic and Analytic Sources of Variations in C-reactive Protein Measurement: Implications for Cardiovascular Disease Risk Assessment Clin. Chem., August 1, 2003; 49(8): 1258 - 1271. [Abstract] [Full Text] [PDF]
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