creactive protein ( crp ) is an acutephase protein of the family of the pentraxins and is widely used in clinical settings to monitor chronic and acute inflammatory conditions.1 the positive association between crp levels and the risk of future coronary heart disease ( chd ) has been studied extensively.2 , 3 the metabolic syndrome ( ms ) represents a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus , which coexist more often than by chance alone . it is widely accepted that the spectrum of ms includes abdominal obesity , hypertension , hypertriglyceridemia , low highdensity lipoprotein cholesterol ( hdlc ) , and glucose intolerance , although the exact cutoff values are debated.4 , 5 two large metaanalyses have shown that the presence of ms raises chd risk 2fold.6 , 7 experimental and observational evidence suggests that inflammation may play a central role in the pathogenesis of cardiovascular disease.8 crp is associated with all parameters of the ms9 and has been acknowledged to be an independent but not causal2 , 10 risk factor for incident chd and to add prognostic value for chd risk on top of the ms criteria.3 , 9 , 11 , 12 , 13 , 14 
  the presence of obesityrelated metabolic disturbances varies widely among obese persons . metabolically healthy obese persons are characterized by having excessive body fat while displaying a favorable metabolic profile characterized by high levels of insulin sensitivity ; no hypertension ; and a favorable lipid , inflammation , hormonal , liver enzyme , and immune profile.15 recent studies have indicated that this healthier metabolic profile may not translate into a lower risk for mortality,16 , 17 whereas other studies suggested that this population might have cardiovascular risk comparable to metabolically healthy nonobese persons.18 , 19 to the best of our knowledge , the role of crp in the assessment of chd risk has not been described previously in metabolically healthy obese persons . we set out to determine the associations between crp levels and the risk of chd in this group . we tested the following hypotheses : metabolically healthy obese persons with low levels of crp ( 1 ) have lower cardiovascular risk than metabolically unhealthy obese persons with elevated levels of crp and ( 2 ) have comparable risk of cardiovascular events compared with metabolically healthy nonobese persons . we examined these hypotheses in the european prospective investigation of cancer  norfolk ( epicnorfolk ) prospective population study . epicnorfolk is a prospective population study of 25  639 male and female inhabitants of norfolk , united kingdom , aged 39 to 79  years . briefly , epicnorfolk is part of the 10country collaborative epic study designed to investigate determinants of cancer . additional data were obtained to enable assessment of determinants of other diseases such as chd . at the baseline survey between 1993 and 1997 , participants completed a detailed health and lifestyle questionnaire with additional data collection performed by trained nurses at a clinic visit . the study cohort was similar to uk population samples with regard to many characteristics including anthropometry , blood pressure , and lipids but with a lower proportion of smokers . full details of the population were reported elsewhere.20 
  ms criteria were defined as described previously , with minor modifications.4 abdominal obesity , obese persons , and obesity were all defined as an elevated waist circumference 102  cm ( 40  in ) in men and 89  cm ( 35  in ) in women . hypertension was defined as systolic blood pressure 130  mm  hg , diastolic blood pressure 85  mm  hg , or use of antihypertensive medication.2 hypertriglyceridemia was defined as triglyceride levels 150  mg / dl ( 1.7  mmol / l ) , whereas low hdlc was defined as hdlc < 40  mg / dl ( 1.03  mmol / l ) in men or hdlc < 50  mg / dl ( 1.30  mmol / l ) in women . hyperglycemia was defined as glycated hemoglobin hba1c 6% or being on antidiabetic medication at inclusion . metabolically healthy abdominally obese persons were defined as having an elevated waist circumference 102  cm ( 40  in ) in men and 89  cm ( 35  in ) in women without the presence of any of the other ms criteria . all participants were flagged for mortality at the uk office of national statistics , with vital status ascertained for the entire cohort . the death certificates were coded by trained nosologists according to the international classification of diseases , 10th revision ( icd10 ) . in addition , participants were identified using their unique national health service numbers through data linkage with the east norfolk health authority ( encore ) database , which identifies all hospital contacts throughout england and wales for residents of norfolk . participants were identified as having a chd event if the corresponding icd10 code ( i20i25 ) was recorded as the underlying cause of that hospitalization or mortality . the norwich district health authority ethics committee approved the study , and all participants gave signed informed consent . blood samples were processed directly at the department of clinical biochemistry , university of cambridge , or stored at 80c . serum levels of total cholesterol , hdlc , and triglycerides were measured in fresh samples with ra 1000 ( bayer diagnostics ) . because of limited funding , hba1c levels were measured for participants from 1995 only ; this approximates a random subset of the cohort . hba1c was measured on fresh edta blood samples using highperformance liquid chromatography ( diamat automated glycated hemoglobin analyzer ; biorad laboratories ltd ) . when additional funding became available in 2010 , serum concentrations of crp were measured for all participants with available frozen baseline serum samples using a fullrange , highsensitivity assay on an olympus au640 clinical chemistry analyzer ( olympus uk ltd ) . for the current analysis , study participants with missing data for crp , waist circumference , lipids , blood pressure , hba1c , or use of antihypertensive or antidiabetic medication were excluded . summary data are presented as meansd for continuous variables with a normal distribution , as median and interquartile range ( iqr ) for continuous variables with a nonnormal distribution , and as percentage ( number ) for categorical variables . because triglycerides and crp were not normally distributed , these parameters were logtransformed before analysis . a 2sided t test was used to test differences between groups for continuous variables , and a chisquare test was used for categorical variables . a cox proportional hazards model was used to assess the association between crp levels and chd . associations were expressed as hazard ratios ( hrs ) and corresponding 95% cis per 1sd increment in ( logtransformed ) crp . participants were censored at the time of the first occurrence of the cardiovascular event analyzed , the time of death , or the end of followup , which was march 31 , 2008 , whichever came first . three cox regression models were performed to investigate the relation of chd event rates , crp , and ( 1 ) metabolically healthy or unhealthy persons , ( 2 ) persons with or without abdominal obesity , or ( 3 ) metabolically healthy or unhealthy persons with or without abdominal obesity . all models were adjusted for sex and age or for sex , age , smoking status , the use of lipidlowering medication at baseline , and lowdensity lipoprotein cholesterol . subgroup analyses to test for a possible interaction between sex and crp was performed by the inclusion of an interaction term in the multivariable corrected model . the proportional hazards assumption was met for each variable in the model applied . the predefined level of significance was set at 0.05 . epicnorfolk is a prospective population study of 25  639 male and female inhabitants of norfolk , united kingdom , aged 39 to 79  years . briefly , epicnorfolk is part of the 10country collaborative epic study designed to investigate determinants of cancer . additional data were obtained to enable assessment of determinants of other diseases such as chd . at the baseline survey between 1993 and 1997 , participants completed a detailed health and lifestyle questionnaire with additional data collection performed by trained nurses at a clinic visit . the study cohort was similar to uk population samples with regard to many characteristics including anthropometry , blood pressure , and lipids but with a lower proportion of smokers . full details of the population were reported elsewhere.20 
  ms criteria were defined as described previously , with minor modifications.4 abdominal obesity , obese persons , and obesity were all defined as an elevated waist circumference 102  cm ( 40  in ) in men and 89  cm ( 35  in ) in women . hypertension was defined as systolic blood pressure 130  mm  hg , diastolic blood pressure 85  mm  hg , or use of antihypertensive medication.2 hypertriglyceridemia was defined as triglyceride levels 150  mg / dl ( 1.7  mmol / l ) , whereas low hdlc was defined as hdlc < 40  mg / dl ( 1.03  mmol / l ) in men or hdlc < 50  mg / dl ( 1.30  mmol / l ) in women . hyperglycemia was defined as glycated hemoglobin hba1c 6% or being on antidiabetic medication at inclusion . metabolically healthy abdominally obese persons were defined as having an elevated waist circumference 102  cm ( 40  in ) in men and 89  cm ( 35  in ) in women without the presence of any of the other ms criteria . all participants were flagged for mortality at the uk office of national statistics , with vital status ascertained for the entire cohort . the death certificates were coded by trained nosologists according to the international classification of diseases , 10th revision ( icd10 ) . in addition , participants were identified using their unique national health service numbers through data linkage with the east norfolk health authority ( encore ) database , which identifies all hospital contacts throughout england and wales for residents of norfolk . participants were identified as having a chd event if the corresponding icd10 code ( i20i25 ) was recorded as the underlying cause of that hospitalization or mortality . the norwich district health authority ethics committee approved the study , and all participants gave signed informed consent . blood samples were processed directly at the department of clinical biochemistry , university of cambridge , or stored at 80c . serum levels of total cholesterol , hdlc , and triglycerides were measured in fresh samples with ra 1000 ( bayer diagnostics ) . because of limited funding , hba1c levels were measured for participants from 1995 only ; this approximates a random subset of the cohort . hba1c was measured on fresh edta blood samples using highperformance liquid chromatography ( diamat automated glycated hemoglobin analyzer ; biorad laboratories ltd ) . when additional funding became available in 2010 , serum concentrations of crp were measured for all participants with available frozen baseline serum samples using a fullrange , highsensitivity assay on an olympus au640 clinical chemistry analyzer ( olympus uk ltd ) . for the current analysis , study participants with missing data for crp , waist circumference , lipids , blood pressure , hba1c , or use of antihypertensive or antidiabetic medication were excluded . summary data are presented as meansd for continuous variables with a normal distribution , as median and interquartile range ( iqr ) for continuous variables with a nonnormal distribution , and as percentage ( number ) for categorical variables . because triglycerides and crp were not normally distributed , these parameters were logtransformed before analysis . a 2sided t test was used to test differences between groups for continuous variables , and a chisquare test was used for categorical variables . a cox proportional hazards model was used to assess the association between crp levels and chd . associations were expressed as hazard ratios ( hrs ) and corresponding 95% cis per 1sd increment in ( logtransformed ) crp . participants were censored at the time of the first occurrence of the cardiovascular event analyzed , the time of death , or the end of followup , which was march 31 , 2008 , whichever came first . three cox regression models were performed to investigate the relation of chd event rates , crp , and ( 1 ) metabolically healthy or unhealthy persons , ( 2 ) persons with or without abdominal obesity , or ( 3 ) metabolically healthy or unhealthy persons with or without abdominal obesity . all models were adjusted for sex and age or for sex , age , smoking status , the use of lipidlowering medication at baseline , and lowdensity lipoprotein cholesterol . subgroup analyses to test for a possible interaction between sex and crp was performed by the inclusion of an interaction term in the multivariable corrected model . a complete data set on crp levels , abdominal obesity , hypertension , hypertriglyceridemia , hdlc , and hba1c was available for 7279 participants . table  1 shows the baseline characteristics according to metabolic phenotype and crp level for the study participants . the mean age was 58  years , and 57% of participants were women . during followup , 825 ( 11% ) chd events occurred . crp levels for those with 0 , 1 , 2 , 3 , or 4 ms criteria were 0.8  mg / l ( iqr 0.41.7  mg / l ) , 1.2  mg / l ( iqr 0.62.4  mg / l ) , 1.5  mg / l ( iqr 0.83.1  mg / l ) , 2.2  mg / l ( iqr 1.24.3 likewise , crp levels were significantly higher in participants with versus without abdominal obesity independent of ms criteria ( p for trend < 0.001 ) . figure  1 displays the median and the 25th and 75th percentiles of the crp distribution according to the number of ms criteria and the presence of abdominal obesity . crp indicates creactive protein ; hba1c , glycated hemoglobin a1c ; hdlc , highdensity lipoprotein cholesterol ; ldlc , lowdensity lipoprotein cholesterol . distribution of crp levels according to the number of ms criteria and the presence of abdominal obesity . a mann  whitney u test was used to test for significant differences in crp level within the number of ms criteria groups . * * * p<0.01 . hrs for chd according to the presence or absence of metabolic health , abdominal obesity , and crp level are shown in table  2 . among metabolically unhealthy participants , those with crp 2 mg / l had significantly higher chd risk than those with crp < 2  mg / l ( hr 1.37 , 95% ci 1.161.63 , p<0.001 ) . < 2  mg / l had a significantly lower risk than metabolically unhealthy participants with crp levels < 2  mg / l ( hr 0.53 , 95% ci 0.430.65 , p<0.001 ) . compared with sex and ageadjusted hrs , additional adjustment for smoking status , the use of lipidlowering medication at baseline , and lowdensity lipoprotein cholesterol did not change these results importantly ( hr 1.31 , 95% ci 1.101.56 , p=0.002 , and hr 0.60 , 95% ci 0.480.73 , p<0.001 , respectively ) . hazard ratios of coronary heart disease depending on metabolic phenotype or the presence of abdominal obesity stratified by creactive protein levels data presented as hazard ratios and corresponding 95% cis . model 2 is corrected for age , sex , smoking , the use of lipidlowering medication at baseline , and lowdensity lipoprotein cholesterol . crp indicates creactive protein . among participants with abdominal obesity , those with crp 2  mg / l had significantly higher chd risk compared with those with a crp level < 2  mg / l ( hr 1.45 , 95% ci 1.141.85 , p=0.002 ) . nonobese participants with crp levels < 2  mg / l had a significantly lower risk than those with abdominal obesity and crp levels < 2  mg / l ( hr 0.73 , 95% ci 0.580.92 , p=0.008 ) . compared with sex and ageadjusted hrs , additional adjustment for smoking status , lipidlowering medication at baseline , and lowdensity lipoprotein cholesterol did not change the results importantly ( hr 1.38 , 95% ci 1.081.75 , p=0.010 , and hr 0.75 , 95% ci 0.590.94 ; p=0.013 , respectively ) . the risk of chd for metabolically unhealthy obese participants with crp < 2  mg / l was significantly higher compared with metabolically healthy obese participants with crp < 2  mg / l ( hr 1.88 , 95% ci 1.202.94 , p=0.006 ) . < 2  mg / l ( hr 1.59 , 95% ci 0.972.62 , p=0.066 ) , although this trend did not reach statistical significance . importantly , metabolically healthy participants without abdominal obesity had chd risk comparable to metabolically healthy obese participants with crp levels < 2  mg / l ( hr 0.91 , 95% ci 0.601.39 , p=0.674 , for crp < 2  mg / l ; hr 1.22 , 0.781.91 , p=0.387 , for crp > because sex is known to influence both crp levels and chd risk , we performed a subgroup analysis by sex to investigate a possible interaction between sex and crp levels for risk of chd . we did not find a statistical difference for the interaction of sex and crp in the multivariable adjusted model ( p=0.511 ) . figure  2 displays chd event rates according to the number of ms criteria and the presence of abdominal obesity in participants with either high or low crp levels . chd event rates according to the number of ms criteria and the presence of abdominal obesity and the presence or absence of an elevated crp level . a chisquare test was used to test for differences between event rates between and within the specified groups . to compare differences between the groups with no abdominal obesity and with abdominal obesity , chd indicates coronary heart disease ; crp , creactive protein ; ms , metabolic syndrome ; ns , not significant . a complete data set on crp levels , abdominal obesity , hypertension , hypertriglyceridemia , hdlc , and hba1c was available for 7279 participants . table  1 shows the baseline characteristics according to metabolic phenotype and crp level for the study participants . the mean age was 58  years , and 57% of participants were women . during followup , 825 ( 11% ) chd events occurred . crp levels for those with 0 , 1 , 2 , 3 , or 4 ms criteria were 0.8  mg / l ( iqr 0.41.7  mg / l ) , 1.2  mg / l ( iqr 0.62.4  mg / l ) , 1.5  mg / l ( iqr 0.83.1  mg / l ) , 2.2  mg / l ( iqr 1.24.3 likewise , crp levels were significantly higher in participants with versus without abdominal obesity independent of ms criteria ( p for trend < 0.001 ) . figure  1 displays the median and the 25th and 75th percentiles of the crp distribution according to the number of ms criteria and the presence of abdominal obesity . crp indicates creactive protein ; hba1c , glycated hemoglobin a1c ; hdlc , highdensity lipoprotein cholesterol ; ldlc , lowdensity lipoprotein cholesterol . distribution of crp levels according to the number of ms criteria and the presence of abdominal obesity . a mann  whitney u test was used to test for significant differences in crp level within the number of ms criteria groups . * * * p<0.01 . hrs for chd according to the presence or absence of metabolic health , abdominal obesity , and crp level are shown in table  2 . among metabolically unhealthy participants , those with crp 2 mg / l had significantly higher chd risk than those with crp < 2  mg / l ( hr 1.37 , 95% ci 1.161.63 , p<0.001 ) . < 2  mg / l had a significantly lower risk than metabolically unhealthy participants with crp levels < 2  mg / l ( hr 0.53 , 95% ci 0.430.65 , p<0.001 ) . compared with sex and ageadjusted hrs , additional adjustment for smoking status , the use of lipidlowering medication at baseline , and lowdensity lipoprotein cholesterol did not change these results importantly ( hr 1.31 , 95% ci 1.101.56 , p=0.002 , and hr 0.60 , 95% ci 0.480.73 , p<0.001 , respectively ) . hazard ratios of coronary heart disease depending on metabolic phenotype or the presence of abdominal obesity stratified by creactive protein levels data presented as hazard ratios and corresponding 95% cis . model 2 is corrected for age , sex , smoking , the use of lipidlowering medication at baseline , and lowdensity lipoprotein cholesterol . among participants with abdominal obesity , those with crp 2  mg / l had significantly higher chd risk compared with those with a crp level < 2  mg / l ( hr 1.45 , 95% ci 1.141.85 , p=0.002 ) . nonobese participants with crp levels < 2  mg / l had a significantly lower risk than those with abdominal obesity and crp levels < 2  mg / l ( hr 0.73 , 95% ci 0.580.92 , p=0.008 ) . compared with sex and ageadjusted hrs , additional adjustment for smoking status , lipidlowering medication at baseline , and lowdensity lipoprotein cholesterol did not change the results importantly ( hr 1.38 , 95% ci 1.081.75 , p=0.010 , and hr 0.75 , 95% ci 0.590.94 ; p=0.013 , respectively ) . the risk of chd for metabolically unhealthy obese participants with crp < 2  mg / l was significantly higher compared with metabolically healthy obese participants with crp < 2  mg / l ( hr 1.88 , 95% ci 1.202.94 , p=0.006 ) . the risk of chd for metabolically healthy obese participants with crp 2  mg / l was higher than that for metabolically healthy participants with crp < 2  mg / l ( hr 1.59 , 95% ci 0.972.62 , p=0.066 ) , although this trend did not reach statistical significance . importantly , metabolically healthy participants without abdominal obesity had chd risk comparable to metabolically healthy obese participants with crp levels < 2  mg / l ( hr 0.91 , 95% ci 0.601.39 , p=0.674 , for crp < 2  mg / l ; hr 1.22 , 0.781.91 , p=0.387 , for crp > 2 mg / l ) . because sex is known to influence both crp levels and chd risk , we performed a subgroup analysis by sex to investigate a possible interaction between sex and crp levels for risk of chd . we did not find a statistical difference for the interaction of sex and crp in the multivariable adjusted model ( p=0.511 ) . figure  2 displays chd event rates according to the number of ms criteria and the presence of abdominal obesity in participants with either high or low crp levels . chd event rates according to the number of ms criteria and the presence of abdominal obesity and the presence or absence of an elevated crp level . a chisquare test was used to test for differences between event rates between and within the specified groups . to compare differences between the groups with no abdominal obesity and with abdominal obesity , all patients of each ms group chd indicates coronary heart disease ; crp , creactive protein ; ms , metabolic syndrome ; ns , not significant . the results of the present study indicated that metabolically healthy obese persons with low crp levels had a trend toward lower risk than metabolically healthy obese persons with elevated levels of crp . more important , we observed that metabolically healthy obese persons with low crp levels had a chd risk similar to that of healthy nonobese persons . these data suggest that among metabolically healthy obese persons , low crp levels are associated with low chd risk . the positive association between crp levels and the ms and between the ms and chd have been studied extensively . previous studies suggest that those with the ms or with elevated levels of crp have an increased risk of chd9 , 21 ; however , 2 large recently published metaanalyses assessing the associations of crp concentration with risk of vascular outcomes did not include the ms in their subgroup analyses.2 , 3 our data indicate that metabolically unhealthy persons with elevated crp levels have a significantly higher risk of future chd compared with metabolically unhealthy persons with crp levels < 2  mg / dl . ridker et  al previously reported an ageadjusted hr of 2.3 ( 95% ci 1.63.3 ) for women with the ms if crp levels <3  mg / l were present in contrast to the hr of 4.0 ( 95% ci 3.05.4 ) if crp levels > 3  mg / l were present.9 rutter et  al similarly observed that crp independently predicted chd above the presence of the ms in the framingham prospective cohort study.12 we found similar associations for abdominally obese participants with elevated crp levels showing an increased risk for chd compared with abdominally obese participants with low crp levels . previous studies linking crp levels to chd were performed largely in populations with a lower prevalence of obesity than that of the current us population.22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 in the 2 largest published studies of crp and chd disease,25 , 27 the mean body mass index ( in  kg / m ) of participants ranged from 25 to 26 , lower than the recently reported mean of 28.7 in us adults,33 indicating the clinical need for data regarding crp in obese populations . the strong heart study examined the relationship between crp levels and chd in an obese population with a mean body mass index > 30.34 after multivariable adjustment for traditional risk factors , no significant association was observed between elevated crp levels ( > 3  mg / l ) and chd events ; however , subgroup analyses examining these relationships in obese and nonobese participants were not performed.32 similarly , gupta et  al reported that the association between crp and atherosclerosis is diminished in obese persons aged 30 to 65  years.35 the role of interleukin 6 was recently corroborated by 3 mendelianbased association studies.36 , 37 , 38 singlenucleotide polymorphisms associated with decreased interleukin 6 signaling were found to correlate with lower values of acutephase reactants , such as crp and fibrinogen , with a concomitant proportional reduction in cardiovascular risk . this lower predictive accuracy of crp in obese participants may be affected by the close correlation between crp and adiposity . interleukin 6 is the principle cytokine that stimulates crp release from the liver , and up to onethird of circulating interleukin 6 is released from adipose tissue.39 , 40 despite these data suggesting a weakened association in obese versus nonobese persons , our data showed that obese participants with elevated levels of crp have a higher risk of future chd than obese participants with crp levels < 2  mg / dl , suggesting that crp adds prognostic information for the obese population , although the presence or absence of cardiometabolic risk factors may influence the predictive value of crp in abdominally obese persons ( figure  2 ) . this study focused primarily on crp and the risk of future cardiovascular events among participants recently characterized by primeau et  al : metabolically healthy obese persons . despite having excessive body fat , these participants displayed a favorable metabolic profile characterized by high levels of insulin sensitivity ; no hypertension ; and a favorable lipid , inflammation , hormonal , liver enzyme , and immune profile.15 previous prospective studies provided mixed findings with regard to the prognosis of future chd events in the metabolically healthy obese population . three prospective studies observed that metabolically healthy obese persons have a risk of cardiovascular disease , mortality , and allcause mortality similar to that of metabolically healthy nonobese persons.18 , 41 , 42 in contrast , 2 other studies suggested that , compared with metabolically healthy nonobese persons , metabolically healthy obese persons have a higher risk of cardiovascular mortality and allcause mortality.16 , 17 more recently , ortega et  al showed that when accounting for fitness , cardiovascular risk was lower for metabolically healthy obese persons compared with metabolically unhealthy obese persons.19 this study suggested that metabolically healthy obese persons might have decreased cardiovascular risk compared with their metabolically unhealthy peers because the metabolically healthy group is usually more physically fit . our study showed that metabolically healthy obese participants with low crp levels had a risk of future chd similar to that of metabolically healthy nonobese participants as well as that of metabolically healthy nonobese participants with elevated crp . these data suggest that crp could help identify those metabolically healthy obese persons who are at low chd risk . when interpreting the results of our study , several aspects need to be taken into account . an important strength of this study is the relatively large number of chd events occurring during followup ( n=825 ) . crp levels and hrs for chd were similar to those observed in previous publications.3 the prevalence of metabolic risk criteria was in agreement with other large observational cohort studies , whereas the prevalence of the metabolically healthy but obese phenotype was somewhat higher in our population compared with previous studies,19 probably because we defined abdominal obesity by waist circumference , whereas other studies used other measures to determine obesity ( eg , body mass index).12 it must be noted that in view of the subgroups used in our analyses , differences in our population did not always reach our predefined significance level . this study was not designed and powered for the current analyses ; therefore , the results should be considered as hypothesis generating and in need of confirmation in larger populations . in this prospective cohort study , the use of such medication or changes in diet could have altered crp levels and the inherent cardiovascular risk.43 , 44 the positive association between crp levels and the ms and between the ms and chd have been studied extensively . previous studies suggest that those with the ms or with elevated levels of crp have an increased risk of chd9 , 21 ; however , 2 large recently published metaanalyses assessing the associations of crp concentration with risk of vascular outcomes did not include the ms in their subgroup analyses.2 , 3 our data indicate that metabolically unhealthy persons with elevated crp levels have a significantly higher risk of future chd compared with metabolically unhealthy persons with crp levels < 2  mg / dl . ridker et  al previously reported an ageadjusted hr of 2.3 ( 95% ci 1.63.3 ) for women with the ms if crp levels <3  mg / l were present in contrast to the hr of 4.0 ( 95% ci 3.05.4 ) if crp levels > 3  mg / l were present.9 rutter et  al similarly observed that crp independently predicted chd above the presence of the ms in the framingham prospective cohort study.12 we found similar associations for abdominally obese participants with elevated crp levels showing an increased risk for chd compared with abdominally obese participants with low crp levels . previous studies linking crp levels to chd were performed largely in populations with a lower prevalence of obesity than that of the current us population.22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 in the 2 largest published studies of crp and chd disease,25 , 27 the mean body mass index ( in  kg / m ) of participants ranged from 25 to 26 , lower than the recently reported mean of 28.7 in us adults,33 indicating the clinical need for data regarding crp in obese populations . the strong heart study examined the relationship between crp levels and chd in an obese population with a mean body mass index > 30.34 after multivariable adjustment for traditional risk factors , no significant association was observed between elevated crp levels ( > 3  mg / l ) and chd events ; however , subgroup analyses examining these relationships in obese and nonobese participants were not performed.32 similarly , gupta et  al reported that the association between crp and atherosclerosis is diminished in obese persons aged 30 to 65  years.35 the role of interleukin 6 was recently corroborated by 3 mendelianbased association studies.36 , 37 , 38 singlenucleotide polymorphisms associated with decreased interleukin 6 signaling were found to correlate with lower values of acutephase reactants , such as crp and fibrinogen , with a concomitant proportional reduction in cardiovascular risk . this lower predictive accuracy of crp in obese participants may be affected by the close correlation between crp and adiposity . interleukin 6 is the principle cytokine that stimulates crp release from the liver , and up to onethird of circulating interleukin 6 is released from adipose tissue.39 , 40 despite these data suggesting a weakened association in obese versus nonobese persons , our data showed that obese participants with elevated levels of crp have a higher risk of future chd than obese participants with crp levels < 2  mg / dl , suggesting that crp adds prognostic information for the obese population , although the presence or absence of cardiometabolic risk factors may influence the predictive value of crp in abdominally obese persons ( figure  2 ) . this study focused primarily on crp and the risk of future cardiovascular events among participants recently characterized by primeau et  al : metabolically healthy obese persons . despite having excessive body fat , these participants displayed a favorable metabolic profile characterized by high levels of insulin sensitivity ; no hypertension ; and a favorable lipid , inflammation , hormonal , liver enzyme , and immune profile.15 previous prospective studies provided mixed findings with regard to the prognosis of future chd events in the metabolically healthy obese population . three prospective studies observed that metabolically healthy obese persons have a risk of cardiovascular disease , mortality , and allcause mortality similar to that of metabolically healthy nonobese persons.18 , 41 , 42 in contrast , 2 other studies suggested that , compared with metabolically healthy nonobese persons , metabolically healthy obese persons have a higher risk of cardiovascular mortality and allcause mortality.16 , 17 more recently , ortega et  al showed that when accounting for fitness , cardiovascular risk was lower for metabolically healthy obese persons compared with metabolically unhealthy obese persons.19 this study suggested that metabolically healthy obese persons might have decreased cardiovascular risk compared with their metabolically unhealthy peers because the metabolically healthy group is usually more physically fit . our study showed that metabolically healthy obese participants with low crp levels had a risk of future chd similar to that of metabolically healthy nonobese participants as well as that of metabolically healthy nonobese participants with elevated crp . these data suggest that crp could help identify those metabolically healthy obese persons who are at low chd risk . when interpreting the results of our study , several aspects need to be taken into account . an important strength of this study is the relatively large number of chd events occurring during followup ( n=825 ) . crp levels and hrs for chd were similar to those observed in previous publications.3 the prevalence of metabolic risk criteria was in agreement with other large observational cohort studies , whereas the prevalence of the metabolically healthy but obese phenotype was somewhat higher in our population compared with previous studies,19 probably because we defined abdominal obesity by waist circumference , whereas other studies used other measures to determine obesity ( eg , body mass index).12 it must be noted that in view of the subgroups used in our analyses , differences in our population did not always reach our predefined significance level . this study was not designed and powered for the current analyses ; therefore , the results should be considered as hypothesis generating and in need of confirmation in larger populations . in this prospective cohort study , the use of such medication or changes in diet could have altered crp levels and the inherent cardiovascular risk.43 , 44 we confirmed a strong association between elevated crp levels and an increased risk of chd in abdominally obese or metabolically unhealthy persons . importantly , our data indicated that among metabolically healthy obese persons , low crp levels appeared to be associated with chd risk comparable to that of healthy nonobese persons . epicnorfolk is supported by program grants from the medical research council uk and cancer research uk . the crp measurements in the full cohort were supported by a grant from the medical research council to the medical research council epidemiology unit , cambridge , united kingdom ( mrc g0701863 ) . the funding sources had no role in the study design , the conduct of the analysis , or the decision to submit the manuscript for publication .
backgroundconflicting data exist about the cardiovascular risk of metabolically healthy obese persons . 
 the prognostic value of creactive protein ( crp ) in this intriguing group is unknown . 
 we assessed the association between crp levels and the risk of coronary heart disease ( chd ) in metabolically healthy persons with abdominal obesity.methods and resultsin the european prospective investigation of cancer  norfolk prospective cohort , crp levels and information on metabolic syndrome criteria were available for 7279 participants , of whom 825 ( 11% ) developed chd during a followup period of 10.91.8  years . 
 there was a trend toward a higher multivariableadjusted hazard ratio for chd in metabolically healthy obese participants with crp levels > 2  mg / l compared with < 2  mg / l ( hazard ratio 1.59 , 95% ci 0.972.62 , p=0.066 ) . 
 metabolically unhealthy obese participants had significantly higher chd risk compared with metabolically healthy obese participants with crp levels 
 < 2  mg / l ( hazard ratio 1.88 , 95% ci 1.202.94 , p=0.006 ) . 
 most important , we found that the risk of chd among metabolically healthy obese persons with crp levels < 2  mg / l was comparable to that of metabolically healthy nonobese persons ( hazard ratio 0.91 , 95% ci 0.601.39 , p=0.674).conclusionsamong metabolically healthy obese persons , low crp levels were associated with a chd risk comparable to that of metabolically healthy nonobese persons . 
 crp appears to be an easy and widely available method for identifying a lowrisk subpopulation among metabolically healthy obese persons .