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From the Department of Medicine (S.S.A., E.L., K.T., S.Y.), McMaster University, and Population Health Research Institute (S.S.A., F.R., Q.Y., E.L., K.T., S.Y.), Hamilton Health Sciences and McMaster University, Hamilton, Canada; Six Nations Health Services (B.D., R.J.), Ohsweken, Canada; University of Toronto (V.V.), Toronto, Canada; and the Department of Pathology and Molecular Medicine (M.M.), McMaster University, Hamilton, Canada; for the SHARE and SHARE-AP investigators.
ABSTRACT
Background— Small increases in the inflammatory marker C-reactive protein (CRP) are predictive of vascular events among asymptomatic individuals. There are few data supporting the use of CRP as a risk marker among nonwhite individuals.
Methods and Results— 1250 adults of South Asian, Chinese, European, and Aboriginal ancestry were randomly sampled from 4 communities in Canada. Participants provided fasting blood samples for CRP, glucose, lipids, and coagulation factors, and they had undergone a carotid B-mode ultrasound. Cardiovascular disease was determined by history and electrocardiogram. The age- and sex-adjusted mean CRP was 3.74 mg/L (standard error, 0.14) among Aboriginals, 2.59 mg/L (0.12) among South Asians, and 1.18 mg/L (0.13) among Chinese compared with 2.06 mg/L (0.12) among Europeans (overall P<0.0001). Differences in the CRP concentration between ethnic groups were substantially diminished, but not abolished, after adjustment for metabolic factors. CRP was independently associated with CVD after adjusting for the Framingham risk factors, atherosclerosis, anthropometric measurements, and ethnicity (OR=1.03 for a 0.1-increase in CRP; P=0.02).
Conclusions— CRP varies substantially between people of different ethnic origin and is influenced by their differences in metabolic factors. Prospective validation of CRP as a risk predictor for cardiovascular disease among nonwhite ethnic groups is required.
CRP varies substantially between people of different ethnic origin. Compared with Europeans, Aboriginals, South Asians, and Chinese have significantly different CRP distributions, which are influenced by metabolic factors including abdominal adiposity, body weight, and HbA1c. CRP is independently associated with CVD across all populations.
Key Words: C-reactive protein ? ethnicity ? risk ? cardiovascular disease ? metabolic syndrome
Introduction
Inflammation is integrally associated with all stages of initiation, growth, and complications of the atherosclerotic plaque.1 The major conventional vascular risk factors include elevated blood pressure, exposure to tobacco, atherogenic lipoproteins, and elevated glucose.2 These factors promote the release of inflammatory mediators that attract a host of inflammatory cells into the growing atherosclerotic lesion.1,3 These processes lead to plaque instability and make plaque prone to rupture, resulting in clinical events such as acute coronary syndromes, stroke, and peripheral arterial occlusion.4
Several, but not all, prospective studies have reported a relationship between elevated concentrations of inflammatory markers and incident clinical cardiovascular events.5,6 One of these markers, C-reactive protein (CRP), is an acute phase reactant that increases dramatically in response to tissue injury or infection, is synthesized primarily in the liver, and is stimulated by interleukin (IL)-6 and other pro-inflammatory cytokines.1,3 Recently, prospective studies among asymptomatic individuals suggest that even small increases of CRP within the conventional "normal range" are predictive of vascular events.7 A meta-analysis of 22 prospective studies reported that the risk ratio of the top tertile of baseline CRP compared with the bottom tertile of baseline CRP was 1.58 (95% CI, 1.48 to 1.68) for future coronary heart disease.6 This relationship persisted after adjustment for age, sex, smoking, and the other major conventional cardiovascular risk factors. CRP is also strongly correlated with factors associated with the metabolic syndrome such as body fat, visceral fat, and fasting insulin, and is a predictor of type 2 diabetes.8 Recently, elevated CRP levels were reported to be predictive of cardiovascular events among women with various stages of the metabolic syndrome and the development of type 2 diabetes.8,9 Therefore, CRP appears to play an important role as a marker of inflammation associated with atherosclerosis and the metabolic syndrome among asymptomatic men and women.
Although CRP appears to be a useful predictor of vascular disease in apparently healthy people, its general applicability to screening populations at risk for cardiovascular disease (CVD) is currently debated.10 The potential advantage of CRP as a screening test over conventional risk factors and other markers of inflammation is that its assay is well-validated, relatively inexpensive, and widely available.10 However, to date the majority of evaluations of CRP have been conducted among individuals of European origin. Before advocating the widespread use of CRP as a screening test for individuals who are at risk for CVD, the American Heart Association (AHA) and Centers for Disease Control (CDC) in their recent AHA/CDC Scientific statement called for information on population-based high-sensitivity (hs)-CRP information to be generated among blacks, Hispanics, Native Americans, and people of Asian and South Asian heritage.10 This is because current "reference intervals" have been derived almost exclusively from European or European American reference populations, and the applicability of these intervals to other populations is unclear.
We sought to determine whether the distribution of CRP differs substantially between people of Aboriginal, South Asian, Chinese, and European origin, between men and women, and, if observed, differences in CRP distribution could be explained by known anthropometric and biochemical correlates of CRP. We also examined the independent association between CRP and CVD in addition to known predictors of CVD. To do this, we analyzed data from a random population-based sample of 1250 subjects comprising people of European, Chinese, South Asian, and Aboriginal origin living in Canada.
Design and Methods
Recruitment of Participants
People of South Asian, Chinese, European, and Aboriginal ancestry were randomly sampled from 3 cities (Hamilton, Toronto, Edmonton), and the Six Nations Reservation (Ohsweken, Ontario) in Canada as previously described.11,12 To be eligible, individuals must have lived in Canada for at least 5 years and be between the ages of 35 and 75 years. Individuals with chronic debilitating illnesses such as terminal cancer and renal failure were excluded.11,12
Assessment of Risk Factors, Atherosclerosis, and CVD
After providing informed consent, fasting blood samples were collected in the morning from all participants, and all nondiabetic participants drank a 75-gram glucose solution, after which blood samples were repeated 2 hours later. Blood samples were collected and processed according to a standard protocol and were shipped to the core laboratory in Hamilton for analysis.11,12 All participants completed a general health questionnaire and had undergone a 12-lead electrocardiogram as previously described.11,12
CRP Assay
All blood samples were assayed using serum or plasma that had been continuously frozen at –70°C since blood collection and processing. Serum hs-CRP was measured using a high-sensitivity automated-rate nephelometric immunoassay (Dade Behring hs-CRP; BNII Nephelometer System, Marburg, Del). The intra-assay imprecision is 2.3% to 4.4% and the interassay imprecision is 2.1% to 5.7%.
Atherosclerosis and CVD
Atherosclerosis was measured using the standardized quantitative B-mode carotid ultrasound scanning, which consisted of a transverse scan followed by a full-circumferential longitudinal scan in which images from 6 well-defined carotid artery segments of the right and left carotid arteries (12 segments/patient) were obtained. The maximal intimal medial thickness for each segment was identified, and the mean of the maximum intimal medial thickness readings for the 12 segments was calculated for each participant.11,12 Using this technique, the intraclass correlation coefficients for between and within ultrasonographer (0.91, 0.90) and reader (0.88, 0.92) reliabilities were high. Prevalent CVD was classified as: coronary artery disease, defined as angina (Rose questionnaire), a self-reported hospitalization for myocardial infarction, silent myocardial infarction (major Q waves by Minnesota criteria), percutaneous coronary angioplasty, or coronary artery bypass graft surgery; or. cerebrovascular disease, defined by self-report of a previous stroke confirmed by a physician.11,12
Framingham Risk Score, Metabolic Syndrome, and CRP Risk Classification
The Framingham Global risk score was calculated using the risk equations developed by Wilson et al.13 This combined the variables of age, sex, low-density lipoprotein (LDL), high-density lipoprotein cholesterol, blood pressure, and smoking to generate a 10-year prediction of fatal and nonfatal coronary heart disease events. Participants were classified as being at low risk if their risk score was <10%, at intermediate risk if score was between 10% and 20%, and at high risk if score was >20%.10,13 The metabolic syndrome was defined using the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) criteria.14 Individuals who had 3 of the following abnormalities: waist circumference >102 cm in men and >88 cm in women; serum triglycerides level of at least 1.69 mmol/L; high-density lipoprotein cholesterol level of <1.04 mmol/L in men and <1.29 mmol/L in women; blood pressure of at least 130/85 mm|Hg; or serum glucose level of at least 6.1 mmol/L were classified as having the metabolic syndrome. Based on the AHA/CDC Scientific Statement for health care professionals, the CRP risk criteria (developed for use among whites) were used to classify participants as being at low risk (CRP <1.0 mg/L), at average risk (CRP 1.0 to 3.0 mg/L), or at high risk (CRP >3.0 mg/L).10
Statistical Analysis
All analyses were computed using SAS (version 8.2). Comparisons of continuous variables were performed using ANCOVA, with adjustment for age and sex when indicated. Post-hoc pair-wise comparisons were performed using Bonferonni principle to adjust for multiple comparisons.15 Spearman correlation coefficients were used to assess the association between continuous variables. For statistical comparisons of discrete variables between groups, logistic regression was performed, with age and sex as covariates. To determine the independent predictive value of CRP on CVD, stepwise multivariable logistic regression was performed using conventional CVD risk factors, atherosclerosis, ethnicity, body mass index (BMI), and waist circumference as independent variables.
Results
Between October 1996 and April 2000, 1250 (323 South Asians, 306 Chinese, 322 Europeans, 299 Aboriginal) men and women completed the clinic visit and had CRP measured; 9.6% had established CVD, 25.8% had metabolic syndrome, and 23% were cigarette smokers. The average age of participants was 50.4 (10.3) years and 51.1% were women.
CRP Distribution
The distribution of CRP varied significantly between ethnic groups. The mean CRP was the highest among Aboriginals, followed by South Asians, intermediate among people of European origin, and lowest among the Chinese. (Table 1). Significantly more Aboriginals had CRP levels >10 mg/L (15.7%) compared with the other groups. Even after exclusion of these individuals with extreme values, the mean and median concentrations of CRP remained significantly elevated among Aboriginals and South Asians, compared with the Europeans and Chinese (Figure 1). Using the AHA/CDC criteria, 55% of Aboriginals, 28% of South Asians, and 25% of Europeans, compared with only 6.0% of Chinese, were classified as being at high risk (CRP >3.0 mg/L). Overall, CRP values were higher among women compared with men, although this sex difference was only separately significant among people of South Asian and Aboriginal origin, and not among the Chinese or Europeans (Figure 2).
TABLE 1. Demographics and CRP Distribution
Figure 1. CRP distribution by ethnic group. *Percentage of individuals within each ethnic group who have CRP values above 3 mg/L.
Figure 2. Sex and ethnic comparisons of CRP. Bars above the histogram represent SEM.
Correlates of CRP
The distribution of anthropometric, inflammatory, and biochemical correlates of hs-CRP were examined overall and by ethnic group. BMI, waist circumference, HbA1c, insulin, white blood cell count, and fibrinogen were strongly correlated with CRP, and this association was consistent across ethnic groups (Table 2). The ethnic differences in CRP concentration paralleled the differences in the prevalence of the metabolic syndrome and CVD, and diminished markedly after adjustment for metabolic factors including BMI, waist circumference, triglycerides, systolic blood pressure, and HbA1c. The mean hs-CRP changed from 3.83 to 2.85 (SE, 0.15) mg/L among Aboriginals, 2.55 to 2.72 (0.12) mg/L among South Asians, 2.09 to 2.13 (0.12) mg/L among Europeans, and from 1.11 to 1.72 (0.13) mg/L among the Chinese (Table 2).
TABLE 2. Correlates of CRP and Ethnic Differences in Anthropometric, Biochemical, and Inflammatory Markers
CRP by Increasing Criteria of Metabolic Syndrome
The median CRP concentration for people defined as having the metabolic syndrome (3.0 metabolic syndrome criteria) varied markedly between the subgroups, being 2.59 mg/L overall, 1.50 mg/L among the Chinese, 1.95 mg/L among the Europeans, and 2.47 mg/L among the South Asians, compared with 4.25 mg/L among Aboriginals.
CRP Association With CVD
To determine whether an independent association between CRP and prevalent CVD existed, we developed a multivariate logistic regression model with prevalent CVD as the dependent variable. CRP remained independently associated with CVD after adjustment for the Framingham risk factors (age, sex, systolic blood pressure, LDL cholesterol, high-density lipoprotein cholesterol, smoking status, and diabetes), atherosclerosis, anthropometric parameters (waist circumference and BMI), triglycerides, and ethnicity (for a 0.1-increase in CRP, the odds of CVD increased by 3%) (Table 3).
TABLE 3. Association of CRP and CVD
Framingham Risk Score, Metabolic Syndrome, and CRP
Participants were classified as being at low, moderate, or high risk for CHD over the next 10 years using the Framingham risk equation after removing 173 participants with CRP values >10 mg/L or prevalent CVD. Within each category, the percentage of people classified as being at low (CRP <1 mg/L), moderate risk (1 to 3 mg/L), and high risk (>3 mg/L) by the CRP risk criteria was determined; 731 people were classified as being at low risk by Framingham score, and 29% (212/731) had intermediate CRP levels, and 22% (164/731) had high CRP levels (Table 4). More than half of this group were people of Aboriginal and South Asian origin (202/537).
TABLE 4. CRP Concentration by Framingham Risk Categories*
Discussion
Our results demonstrate marked differences in the distribution of CRP between people of varying ethnic origin, and between women and men. Compared with Europeans, Aboriginals, South Asians, and Chinese have significantly different CRP distributions, and these are influenced by differences in abdominal adiposity, body weight, and glucose metabolism. Adjustment for these differences substantially reduces, but does not eliminate, the ethnic differences in CRP distribution.
Previous investigators have reported CRP to be higher among South Asians, blacks, Hispanics, Mexicans, and Aboriginals when compared with whites.16–19 However, with the exception of the NHANES III cohort, which reported data among non-Hispanic blacks and Mexicans,17 these reports were derived from samples of convenience and included relatively few subjects. In our study, in which individuals from 4 ethnic groups were randomly sampled and assessed in a standardized manner, CRP was significantly elevated among Aboriginals and South Asians and significantly lower among the Chinese population compared with the Europeans. Thus, together with the increased white blood cell count observed among Aboriginals and South Asians, this provides evidence that these ethnic groups at high risk have a heightened pro-inflammatory state. Ethnic differences in CRP were reduced but not eliminated after adjustment for metabolic factors, including waist circumference, which is a surrogate measurement of visceral adiposity. Visceral adiposity is strongly correlated with insulin resistance and CRP, and it appears to be an important explanatory variable linking abnormalities in inflammatory cytokines with the future development of diabetes and possibly CVD.8,20 IL-6 is the primary cytokine involved in CRP synthesis and is released from visceral and subcutaneous fat stores.3,8 Thus, the markedly elevated CRP concentrations observed among Aboriginals and South Asians (in contrast to the Chinese) may be partly explained by their greater abdominal adiposity. However, a recent report suggests that people of South Asian origin have an underlying pro-inflammatory state that is not explained by their greater adiposity or insulin resistance, which may contribute to their increased propensity for type 2 diabetes and CVD development.21 Although this is supported by our observations, we recognize that adjustment for "surrogate measures" of visceral adiposity may incompletely account for differences in inflammatory markers attributable to the presence of visceral fat. Future prospective investigations are needed to determine whether the increased inflammatory state observed among high-risk ethnic groups, as well as among women within these groups, is associated with a higher incidence of cardiovascular events.
We have demonstrated that the distribution of CRP is significantly different between ethnic groups. Fifty-five percent of Aboriginal people were classified as "high-risk" compared with only 6% of Chinese by using the AHA/CDC consensus panel CRP cutoff values.10 Therefore, use of uniform CRP cut-points to define vascular risk are likely not appropriate across diverse populations. Further, when participants were stratified by the Framingham risk score and when the CRP risk classification was applied, a large proportion of participants who were classified as being at "low risk" for CHD by Framingham (n=731) had intermediate (29.0%) or high CRP risk levels (22.4%). This contrasts with the AHA/CDC statement that individuals who have a 10-year Framingham risk score <10% will be unlikely to be at high risk, as identified by hs-CRP testing.10
Our results emphasize the need for prospective investigations of CV risk factors among nonwhite ethnic groups.22 Although the Framingham risk score reasonably predicts CHD events among whites and blacks in the US, it has been shown to overestimate the CHD risk among Americans of Japanese, Hispanic, and Aboriginal origin,23 as well as among men from the United Kingdom.24 Furthermore, consideration of metabolic factors in risk prediction algorithms may be especially important among certain ethnic groups. We have previously reported that the relative risk of prevalent CVD among people with the metabolic syndrome versus those without was 2.46 (17.2% versus 7.0%, P=0.0001),25 which is consistent with findings from Sweden, Finland, and Italy.26–27 Furthermore, the metabolic syndrome is associated with at least a 2-fold increased incidence of CVD death among men and women, even after adjustment for conventional risk factors such as age, LDL cholesterol, smoking, and family history.9,28 Therefore, to reduce the underidentification or overidentification of "at-risk" individuals among nonwhite populations, prospective assessment of conventional cardiovascular risk factors such as those included in the Framingham risk score, metabolic factors such as abdominal adiposity, BMI, and glucose, as well as the independent contribution of the hs-CRP, is required.
Our study has several strengths. First, to minimize bias in our comparisons, participants were selected at random from the community. Second, a uniform protocol was used, including questionnaires, physical measurements, and analysis of laboratory measurements in a centralized core laboratory. The potential limitations to our study include our modest sample size and the way in which atherosclerosis was measured. However, our assumption that carotid atherosclerosis is a reasonable surrogate for generalized atherosclerosis is supported by several large studies,29–31and the reproducibility of our technique is high.12 Furthermore, although our analyses allow us to highlight the impact of metabolic syndrome on CRP, the lack of prospective follow-up does not permit us to confirm the validity of the CRP risk ranges among nonwhite ethnic groups. Therefore, the question of whether CRP is additive to conventional risk stratification, or the metabolic syndrome, in predicting future vascular risk among nonwhite populations must be addressed in future studies, some of which are underway.
Conclusions
CRP varies substantially between people of different ethnic origin and is heavily influenced by the differences in metabolic factors they possess. CRP is independently associated with CVD over conventional cardiovascular risk factors, atherosclerosis, and anthropometric parameters across all populations. Prospective validation of CRP as a risk predictor for CVD among nonwhite ethnic groups is required.
Acknowledgments
Dr Anand is a recipient of a Canadian Institutes of Health Research Clinician Scientist Award. Mr Razak is a recipient of an Ontario Graduate Scholarship. Dr Yusuf is a recipient of a Canadian Institutes of Health Research Career Scientist Award and holds a Heart and Stroke Foundation of Ontario Research Chair.
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