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(Circulation. 2001;104:145.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

C-Reactive Protein, Insulin Resistance, Central Obesity, and Coronary Heart Disease Risk in Indian Asians From the United Kingdom Compared With European Whites

John C. Chambers, MRCP; Shinichi Eda, PhD; Paul Bassett, PhD; Yusuf Karim, MRCP; Simon G. Thompson, DSc; J. Ruth Gallimore, PhD; Mark B. Pepys, FRS; Jaspal S. Kooner, MD, FRCP

From the National Heart and Lung Institute (J.C.C., Y.K., J.S.K.) and the Department of Medical Statistics and Evaluation (P.B., S.G.T.), Imperial College School of Medicine, Hammersmith Hospital, London, UK; F. Hoffmann-La Roche & Co Ltd, Basel, Switzerland (S.E.); and the Department of Medicine, Royal Free and University College Medical School, London, UK (J.R.G., M.B.P.).

Correspondence to Dr J.S. Kooner, MD, FRCP, Consultant Cardiologist, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. E-mail j.kooner{at}ic.ac.uk

	Abstract

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Background—— Indian Asians in the United Kingdom have increased coronary heart disease (CHD) mortality compared with European whites, but the causes are not well understood. Increased circulating concentrations of C-reactive protein (CRP) are an independent risk factor for CHD. Therefore, we investigated this marker of inflammation in healthy UK Indian Asian and European white men.

Methods and Results—— We measured serum CRP concentrations and conventional CHD risk factors in 1025 healthy male subjects (518 Indian Asians and 507 European whites) aged 35 to 60 years who were recruited at random from general practitioner lists. The geometric mean CRP concentration was 17% higher (95% confidence interval, 3% to 33%) in Indian Asians compared with European whites. CRP values were strongly associated with conventional CHD risk factors, measures of obesity, and metabolic disturbances associated with insulin resistance in both racial groups. The difference in CRP concentrations between Indian Asians and European whites remained after adjustment for conventional CHD risk factors but was eliminated by an adjustment for central obesity and insulin resistance score in Asians. On the basis of these results, we estimate that the processes underlying elevated CRP and/or increased CRP production itself are associated with an 14% increase in population CHD risk among Indian Asians compared with European whites.

Conclusions—— CRP concentrations are higher in healthy Indian Asians than in European whites and are accounted for by greater central obesity and insulin resistance in Indian Asians. Our results suggest that inflammation or other mechanisms underlying elevated CRP values may contribute to the increased CHD risk among Indian Asians.

Key Words: inflammation • population • atherosclerosis

	Introduction

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Coronary heart disease (CHD) mortality is at least 40% higher in UK Indian Asians compared with European whites.^1,2 Conventional coronary risk factors, including smoking, hypercholesterolemia, and hypertension, do not explain their increased CHD risk compared with whites.^3,4 Although diabetes and insulin resistance are more prevalent among Indian Asians,^4,5 the precise mechanisms underlying the increased CHD mortality in Indian Asians are not known.

Inflammation is now widely recognized as a central feature of atherogenesis, and it plays a particularly critical role in the destabilization of the fibrous cap, predisposing to the plaque rupture that triggers most episodes of coronary thrombosis.⁶ C-reactive protein (CRP), the classic acute-phase reactant, is an extremely sensitive systemic marker of inflammation; increased concentrations of CRP have been shown in both clinical and epidemiological studies to be associated with atherothrombotic events. In outpatients with stable or unstable angina,^7,8 inpatients with severe unstable angina,⁹ and healthy asymptomatic individuals in the general population,^10–13 even modestly raised CRP values, within what has hitherto been considered the normal range, are significantly associated with a future risk of myocardial infarction. Thus, among initially healthy subjects whose CRP values are in the upper tertile of the distribution (>2.4 mg/L), the future risk of myocardial infarction is about double that of individuals in the lower tertile. ¹⁴ Although CRP concentrations are positively correlated with important conventional CHD risk factors such as body mass index and smoking ¹⁵ and with other markers of inflammation, ¹⁶ they remain significantly predictive of outcome, even after adjustment for these and all other known confounders.

The purposes of the present study were (1) to test the hypothesis that CRP concentrations are elevated in UK Indian Asians and are associated with their increased CHD risk compared with European whites and (2) to examine the determinants of elevated CRP in the 2 racial groups, who have different coronary risk factor profiles.

	Methods

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Subjects
The study design has been described in detail previously.¹⁷ In brief, we investigated 1025 healthy male subjects (518 Indian Asians and 507 European whites), aged 35 to 60 years, who were identified at random from the age-sex registers of 56 local general practitioners. Subjects were contacted by post, and >50% agreed to take part.¹⁷ Indian Asians were classified as those who had all 4 grandparents of North Indian descent; they had resided in the UK for 27±8 years. European whites were born in the UK. There was little evidence of selection bias in recruitment; specifically, responders and nonresponders had similar ages, body mass indexes, blood pressures, and prevalence of diabetes. Cigarette smoking was more common among nonresponders than responders among Europeans (40% versus 28% respectively, P=0.02) but not Asians. Exclusion criteria included previous myocardial infarction, unstable angina, or coronary revascularization; cardiomyopathy, systemic illness, and serious organ disease; and the presence of pathological Q waves on the ECG. CHD cases recruited as part of the original study¹⁷ were not included in the present analysis because CRP levels change with disease stage and patients were studied at varying time points after diagnosis. The study was approved by the local Ethics Committee, and all participants gave written, informed consent.

Methods
Clinical history, including hypertension, diabetes, habitual smoking, alcohol intake, occupation, and drug therapy, were recorded for all subjects. Three blood pressure readings were taken using a mercury sphygmomanometer with the subject seated for 10 minutes, and the mean was calculated. Anthropometric measurements (height, weight, waist-hip ratio) and ECG were recorded by standardized protocols. Serum samples for estimation of CRP, glucose, total cholesterol, HDL cholesterol, and triglycerides were taken in the morning after an overnight faSt. CRP was measured by automated microparticle-enhanced turbidometric immunoassay run on COBAS MIRA (Roche Diagnostics GMbH).¹⁸ Lipid profiles were determined using an Olympus AU800 multichannel analyzer.

Data Processing and Statistical Analysis
A logarithmic transformation of CRP concentrations was used to reduce the positive skewness of the distribution, and geometric means are therefore presented; approximate SDs are derived from the variance transformation formula. Linear regression was used to estimate the percentage difference in CRP between Indian Asians and European whites, with log CRP as the dependent variable, and adjusting for other explanatory variables. An insulin resistance score was used to provide a summary measure of the insulin resistance syndrome,¹⁹ and it was calculated from SD (z) scores as follows:[z(waist-hip girth ratio)- z(HDL cholesterol)+z(fasting glucose)+z(fasting triglycerides)+z(systolic blood pressure)]. The quantitative relationship between CRP and risk of CHD, independent of conventional CHD risk factors, was calculated by regression of log relative risk against mean log CRP, for the upper and lower tertiles of CRP, using the results of the most recent meta-analysis of prospective studies. ¹⁴ To estimate the increase in CHD risk among Indian Asians associated with elevated CRP, the derived result was applied to the difference in log CRP concentrations between Asians and Europeans.

	Results

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Clinical and Biochemical Characteristics of Subjects
The characteristics of the subjects are summarized in Table 1. Indian Asians had a higher prevalence of hypertension and diabetes and a lower prevalence of cigarette smoking and nonmanual occupation. Waist-hip girth ratio, blood pressure, fasting glucose, triglycerides, and insulin resistance score were higher and HDL cholesterol was lower in Indian Asians compared with European whites.

View this table: [in this window] [in a new window]   Table 1. Clinical and Biochemical Characteristics of European Whites and Indian Asians

CRP Concentrations in Indian Asians and European Whites
CRP concentrations were higher in Indian Asians than in European whites (Table 1). In both racial groups, CRP concentrations were positively associated with age, cigarette smoking, body mass index, waist-hip ratio, blood pressure, glucose, triglycerides, and insulin resistance score and inversely correlated with HDL cholesterol (Tables 2 and 3 and Figure). CRP was most strongly associated with body mass index, waist-hip girth ratio, and insulin resistance score in Indian Asians and Europeans.

View this table: [in this window] [in a new window]   Table 2. Relationships Between CRP and Conventional CHD Risk Factors for European Whites and Indian Asians

View larger version (37K): [in this window] [in a new window]   Geometric mean (95% confidence intervals) CRP concentrations according to quintile of insulin resistance score in Indian Asians (IA) and European whites (EW). Insulin resistance score quintiles are as follows:<-2.66, -2.66 to -0.83, -0.82 to 0.68, 0.69 to 2.58, and >2.58.

View this table: [in this window] [in a new window]   Table 3. Geometric Mean CRP Values Among Indian Asians and European Whites, Stratified by Age, Smoking Habit, and Markers of Obesity

Difference in CRP Concentrations Between Indian Asians and Europeans
Age-adjusted CRP concentrations were 17% (95% confidence interval, 3% to 33%) higher in Indian Asians than in European whites. The increase in CRP concentrations among Asians compared with Europeans remained statistically significant after adjustment for age, cigarette smoking, and body mass index (Table 3) and other conventional CHD risk factors (Table 4). However, the difference in CRP concentrations between the racial groups was abolished by adjustment for waist-hip ratio or insulin resistance score (Tables 3 and 4).

View this table: [in this window] [in a new window]   Table 4. Percentage Difference in CRP Concentrations Between Indian Asians and European Whites

On the basis of the results of a meta-analysis of previous prospective studies,^13,14 we estimate that raised CRP values, or the processes responsible for these, may be associated with an 14% increase in population CHD risk in Indian Asians compared with Europeans. Hence, of the reported 40% excess risk of CHD in Asians compared with Europeans, about two-fifths (that is, log1.14/1og1.40) may be attributable to elevated CRP. However, this figure cannot be considered exact, because there is imprecision in each of the components of the calculation.

	Discussion

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Prospective studies in European and North American populations demonstrate that increased CRP concentrations significantly predict the risk of myocardial infarction. ^7–12 However, CRP values have not previously been investigated in Indian Asians, in whom CHD mortality is 40% higher than among European whites.

In this study, we found that among healthy male subjects from the general population, CRP concentrations were significantly higher in Indian Asians than in European whites. On the basis of the reported relationship between CRP and risk of CHD,¹⁴ we estimate that increased CRP concentrations and/or the processes underlying elevated CRP are associated with an 14% increase in population CHD risk among Indian Asians compared with European whites. The magnitude of this effect on CHD risk is equivalent to a rise in diastolic blood pressure of 5 mm Hg²⁰ or an increase in total cholesterol of 0.5 mmol/L.²¹ Therefore, our results suggest that inflammation or enhanced cytokine production and/or their acute phase consequences may contribute significantly to the increased CHD mortality in Indian Asians.

We examined the reasons underlying the difference in CRP concentrations between the 2 racial groups. We found that CRP concentrations were associated with conventional coronary risk factors in both racial groups, confirming previous findings in European and US studies^11,15 and extending them to Indian Asians. However, the difference in CRP concentrations between Indian Asians and European whites was not reduced by adjustment for conventional CHD risk factors. Instead, elevated CRP concentrations in Indian Asians were accounted for by their greater central obesity compared with Europeans. The association between central adiposity and increased CRP has been noted before in white subjects.^19,22–24 Experimental studies suggest that abdominal adipose tissue is a major source of cytokines, including IL-6, which is an important determinant of hepatic CRP synthesis.^19,25 The central obesity identified in Indian Asians³ may therefore contribute to increased CHD risk in Indian Asians through inflammatory mechanisms. The precise reasons underlying increased central obesity among Indian Asians compared with European whites are not known. Observations that abdominal obesity is increased in the first-degree relatives of Indian Asian CHD patients raise the possibility that central obesity may be determined by major genetic factors in this racial group. ²⁶ This is consistent with recent evidence suggesting that CRP concentrations may be influenced by genetic factors, although the molecular basis remains to be identified.²⁷

Population studies show that diabetes, insulin resistance, and related metabolic abnormalities are more common among Indian Asians than European whites, and they may account for up to 70% of major Q-wave ECG abnormalities in Asians. ^4,5 In the present study, CRP concentrations were also closely associated with levels of HDL cholesterol, triglycerides, glucose, blood pressure, and a composite insulin resistance score in both racial groups. Similar findings have been reported in North American and European populations, which have additionally shown that CRP concentrations and other inflammatory markers, including white cell count and fibrinogen, are strongly associated with plasma insulin and insulin-mediated glucose uptake.^22–24 Although insulin sensitivity was not formally assessed in our subjects, these observations suggest that inflammatory activity is increased among Indian Asian and European white subjects with the insulin resistance syndrome and raise the possibility that inflammatory mechanisms may contribute to the increased risk of CHD among insulin-resistant Indian Asians.

In this study, we investigated CRP concentrations in a representative sample of Indian Asian and European white men living in West London, UK. We found that CRP levels were elevated in Indian Asians and were closely associated with increased central adiposity and markers of insulin resistance in Asians compared with Europeans. Because central adiposity and a high prevalence of insulin resistance are characteristics shared by Indian Asians overseas,^3,28 urban Indian Asians in India,²⁹ and Indian Asian women,³ our findings of elevated CRP among Indian Asian men in West London are likely to be generalizable to other Indian Asian populations. However, additional studies will be needed to confirm this hypothesis. Our cross-sectional study design also does not allow us to confirm that inflammatory mechanisms contribute to the development of atherosclerosis among Indian Asians as in predominantly white populations. A prospective study of CRP and risk of CHD among Indian Asians will be needed to evaluate this possibility.

It is not known whether the increased CRP values associated with CHD reflect the extent and inflammatory activity of atherosclerotic lesions themselves or inflammation elsewhere in the body or both. This question, in turn, focuses attention on the possibility that CRP itself might contribute to atherothrombosis. CRP selectively binds to LDL, especially the modified LDL found within atherosclerotic plaques, ³⁰ and CRP is present almost universally in the plaques,³¹ colocalized with both modified LDL and activated complement.³⁰ The binding of CRP to ligands, including modified LDL, activates complement and could be pro-inflammatory and contribute to atherogenesis.³⁰ CRP can certainly enhance ischemic tissue damage by a complement dependent mechanism. ³² CRP is also reported to increase macrophage production of tissue factor,³³ the coagulation initiator that is clearly implicated in occlusive thrombotic events. ³⁴ It is of interest that statins lower CRP values and cholesterol,³⁵ raising the possibility that some of their protective effects may be mediated through the suppression of inflammation and/or the cytokine cascade.

In conclusion, we have shown that CRP concentrations are higher in Indian Asians compared with European whites and are predominantly explained by the greater central obesity in Indian Asians. Inflammatory and/or cytokine mechanisms may be implicated in the increased CHD risk among Indian Asians.

	Acknowledgments

 
This work was supported in part by MRC Program Grant G97900510 (to M.B.P.) and British Heart Foundation project grant PG/96193. We thank Dr John Danesh for helpful discussions and suggestions.

Received January 26, 2001; revision received April 18, 2001; accepted April 18, 2001.

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				M. T. Schram, N. Chaturvedi, C. Schalkwijk, F. Giorgino, P. Ebeling, J. H. Fuller, and C. D. Stehouwer Vascular Risk Factors and Markers of Endothelial Function as Determinants of Inflammatory Markers in Type 1 Diabetes: The EURODIAB Prospective Complications Study Diabetes Care, July 1, 2003; 26(7): 2165 - 2173. [Abstract] [Full Text] [PDF]

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				E. S. Ford, W. H. Giles, G. L. Myers, and D. M. Mannino Population Distribution of High-Sensitivity C-reactive Protein among US Men: Findings from National Health and Nutrition Examination Survey 1999-2000 Clin. Chem., April 1, 2003; 49(4): 686 - 690. [Full Text] [PDF]

				T. A. Pearson, G. A. Mensah, R. W. Alexander, J. L. Anderson, R. O. Cannon III, M. Criqui, Y. Y. Fadl, S. P. Fortmann, Y. Hong, G. L. Myers, et al. Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association Circulation, January 28, 2003; 107(3): 499 - 511. [Full Text] [PDF]

				B. Thorand, H. Lowel, A. Schneider, H. Kolb, C. Meisinger, M. Frohlich, and W. Koenig C-Reactive Protein as a Predictor for Incident Diabetes Mellitus Among Middle-aged Men: Results From the MONICA Augsburg Cohort Study, 1984-1998 Arch Intern Med, January 13, 2003; 163(1): 93 - 99. [Abstract] [Full Text] [PDF]

				U. N. Das Is Metabolic Syndrome X an Inflammatory Condition? Experimental Biology and Medicine, December 1, 2002; 227(11): 989 - 997. [Abstract] [Full Text]

				L. Mosca C-Reactive Protein -- To Screen or Not to Screen? N. Engl. J. Med., November 14, 2002; 347(20): 1615 - 1617. [Full Text] [PDF]

				S. M. Grundy Obesity, Metabolic Syndrome, and Coronary Atherosclerosis Circulation, June 11, 2002; 105(23): 2696 - 2698. [Full Text] [PDF]

				D. C. Chan, G. F. Watts, P. H. R. Barrett, L. J. Beilin, and T. A. Mori Effect of Atorvastatin and Fish Oil on Plasma High-Sensitivity C-Reactive Protein Concentrations in Individuals with Visceral Obesity Clin. Chem., June 1, 2002; 48(6): 877 - 883. [Abstract] [Full Text] [PDF]

				W. Koenig and M. B. Pepys C-Reactive Protein Risk Prediction: Low Specificity, High Sensitivity Ann Intern Med, April 2, 2002; 136(7): 550 - 552. [Full Text] [PDF]

P. Lopez-Jaramillo, J. P. Casas, and C. A. Morillo C-Reactive Protein and Cardiovascular Diseases in Andean Population Circulation, January 15, 2002; 105 (2): e10 - e10. [Full Text] [PDF]