Metabolic Syndrome and C-Reactive Protein in the General Population

Transcription

1 Circ J 2007; 71: Metabolic Syndrome and C-Reactive Protein in the General Population JMS Cohort Study Shizukiyo Ishikawa, MD; Kazunori Kayaba, MD*; Tadao Gotoh, MD; Yosikazu Nakamura, MD**; Eiji Kajii, MD Background In recent years some studies have shown that metabolic syndrome (MS) is associated with inflammation, indicated by high-sensitivity C-reactive protein (hscrp), but there have been few population-based studies, especially in Japan. Methods and Results The study subjects were 2,191 men and women examined between 1992 and 1995 with the necessary data to ascertain MS as part of the Jichi Medical School Cohort Study. CRP was measured by nephelometry. There were 109 subjects defined as having MS (5.0%), and the proportion of MS cases was higher in men (9.4%) than in women (1.8%). Geometric mean and median CRP in the MS group was higher than that in the non-ms (geometric mean; p<0.001, median: mg/l in MS and mg/l). Proportion of MS increased with CRP, after the subjects were divided by tertile of CRP (odds ratio, 95%confidence interval 1 st tertile as a reference; 2 nd tertile: 2.9, , 3 rd tertile: 5.7, ). Conclusion Inflammation, measured by the concentration of hscrp, was elevated in cases of MS in the general Japanese population. Longitudinal data should be examined in the future. (Circ J 2007; 71: 26 31) Key Words: C-reactive protein; Cardiovascular diseases; General population; Japanese; Metabolic syndrome Metabolic syndrome (MS) comprises obesity, dyslipidemia, diabetes mellitus (DM) or impaired glucose tolerance, and hypertension, and is closely associated with cardiovascular morbidity and mortality in the general population. 1 5 In 1999, MS was defined by the World Health Organization (WHO), 6 and in 2001 another definition was proposed by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on the Detection, Evaluation, and the Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, ATP III). 7 Further definitions have been proposed recently by various organizations or associations; for example, in Japan, the definition of MS was determined in collaboration with 8 scientific associations in Several studies have reported that C-reactive protein (CRP), a representative acute phase reactant, is a marker of cardiovascular diseases (CVD), 9 13 as well as a precursor of diabetes and other metabolic disorders. 14 The relationship between CRP and MS has been examined Ridker et al reported CRP levels were higher among women with MS and that CRP added prognostic information on the risk for CVD in healthy American women. 15 In Japan, there has (Received June 7, 2006; revised manuscript received October 5, 2006; accepted October 19, 2006) Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, Tochigi, *School of Health and Social Services, Saitama Prefectural University, Saitama and **Division of Public Health, Center for Community Medicine, Jichi Medical University, Tochigi, Japan Mailing address: Shizukiyo Ishikawa, MD, Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, Yakushiji, Shimotsuke, Tochigi , Japan. i-shizu@jichi.ac.jp been 1 study of healthy men, 16 and another small-scale study of men and women. 20 In the present study, we examined the relationship between MS and CRP in a large-scale general population of both sexes in Japan. Methods Subjects We conducted the present study as part of the Jichi Medical School (JMS) Cohort Study, which was a prospective population-based cohort study based on a total of 12,490 study subjects, started in 1992 to clarify risk factors of cardiovascular and cerebrovascular diseases in Japanese. Details on the JMS Cohort Study design and some descriptive data have been published previously. 21 Mass screening for CVD has been conducted in Japan since 1983 in accordance with the health and medical service law for the aged, and we used this system to collect the data for this study. In each community, a local government office sent personal invitations to all subjects by mail. Data were obtained in Takasu, Wara and Sakuma between April 1992 and July 1994, and a total of 2,191 subjects were eligible. The participation rate for people invited to the mass screening examination was 56%. Variables Waist circumference was considered an optimal measurement. It was measured at the level of the high point of the iliac crest. Body height was measured in stockinged feet. Body weight was recorded with the subjects clothed, and 0.5kg in summer and 1.0kg in other seasons was subtracted from the recorded weight. Body mass index (BMI) was calculated as weight (kg)/height (m) 2. Systolic and diastolic blood pressures (BP) were measured

2 Metabolic Syndrome and CRP: JMS Cohort Study 27 Table 1 General Characteristics of the Total Study Subjects by Sex Men n=920 Women n=1,271 p value Age (years) NS BMI (kg/m 2 ) NS SBP (mmhg) DBP (mmhg) NS Fasting glucose (mg/dl) <0.001 TC (mg/dl) <0.001 Triglyceride (mg/dl) ( ) 87.4 ( ) <0.001 HDL-C (mg/dl) <0.001 CRP (mg/l) ( ) ( ) <0.001 Physical activity index <0.001 Current smoking (%) <0.001 DM (%) NS Hypertension (%) NS Past history $ Stroke (%) NS Myocardial infarction (%) <0.01 Malignacy (%) Hyperlipidemia (%) NS Data are mean and SD for variables, and percentage for proportions. Triglycerides and CRP: geometric mean (±SD). p values were calculated with unpaired t-test for variables and with chi-square test for proportions. Diabetes mellitus was currently medicated and/or fasting glcose 126 mg/dl. Hypertension was currently medicated and/or SBP 140 mmhg and/or DBP 90 mmhg. $ Data were obtained by questionnaire. BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; HDL-C, high-density lipoprotein-cholesterol; CRP, C-reactive protein; DM, diabetes mellitus. with a fully automated sphygmomanometer, BP203RV-II (Nippon Colin, Komaki, Japan), placed on the right arm of the subject who had rested while seated for 5 mins before measurement. Physical activity index (PAI), which was developed in the Framingham Study, 22 was calculated for 24 h by totaling the weighted sum of hours spent at 5 activity levels: 1.0 for sedation including sleeping; 1.1 for quiet working, such as while seated; 1.5 for a light level of working such as while standing; 2.5 for a moderate level of working, and 5.0 for heavy work, during a normal working day. CRP levels were measured using highly sensitive nephelometry, a latex particle-enhanced immunoassay (NA Latex CRP Kit, Dade Behring, Tokyo, Japan). The value in the calibrator was assigned using certified reference Material 470 (IRMM, Geel, Belgium), and international plasma protein reference material to achieve international standardization for the assay of CRP. The functionality of the assay was found to be satisfactory. 23 The interassay and intraassay coefficients of variation (CV) were 1.18% and 1.36%, respectively. The assay is sufficiently sensitive to detect mg/l of CRP. Undetectable CRP values were recorded as mg/l. Total cholesterol and triglyceride levels were measured by enzymatic methods (Wako, Osaka, Japan; inter assay CV: 1.5% for total cholesterol and 1.7% for triglyceride). High-density lipoprotein-cholesterol (HDL-C) was measured using the phosphotungstate precipitation method (Wako, Osaka, Japan; interassay CV: 1.9%). Blood glucose was measured via an enzymatic method (Kanto Chemistry, Tokyo, Japan; interassay CV: 1.9%. MS According to the 2005 definition and diagnostic criteria of MS in Japanese, subjects had to satisfy the following criteria: waist circumference 85cm for men or 90cm for women as an essential component combined with 2 or more of the following components: triglycerides 150 mg/dl and/or HDL-C <40 mg/dl; systolic BP (SBP) 130 mmhg and/or diastolic BP (DBP) 85 mmhg; fasting blood glucose 110 mg/dl. 8,24 Statistical Analysis Data of variables are expressed as mean ± SD, except CRP. Distribution of CRP was skewed, and CRP was expressed as the geometric means ± SD. P values were calculated with unpaired t-test for variables and with chi-square test for proportions, and p<0.05 was considered significant. We divided the CRP values into tertiles, and the proportion of MS in each tertile was calculated and shown as a percentage in Table 3. Odds ratios (OR) and 95% confidence intervals (CI) were used to evaluate the association between CRP and MS. Statistical analysis was performed using Statistical Analysis System 8.2 edition (SAS Institute, Inc, Cary, NC, USA). Results Table 1 shows the general characteristics of the subjects by sex. Mean age was 57.1±12.2 years in men and 56.3± 12.0 years in women. There were no significant differences in age, BMI or DBP between men and women. Fasting glucose, triglycerides, CRP, and PAI were higher in men than in women, and SBP, total cholesterol and HDL-C were higher in women than in men. The subjects were from the general population, and only a few had major past histories: stroke, 1.2% in men and 0.6% in women; myocardial infarction, 1.4% in men and 0.3% in women; malignancy, 0.7% in men and 1.8% in women. Regarding hyperlipidemia, we did not have specific data about statin use, but few subjects were medicated (2.1% in men, 1.3% in women). The distributions of all subjects and subjects with MS

3 28 ISHIKAWA S et al. A 900 Men Women B 40 Men Women Number Number s 40s 50s 60s 70s Age 0 30s 40s 50s 60s 70s Age Fig 1. Distribution of all participants (A) and participants with metabolic syndrome (B) classified into 10-year age groups. Table 2 General Characteristics of Subjects With or Without MS MS Non-MS n % n % p value Men Age (years) NS BMI (kg/m 2 ) <0.001 SBP (mmhg) <0.001 DBP (mmhg) <0.001 Fasting glucose (mg/dl) <0.001 TC (mg/dl) NS Physical activity index NS CRP (mg/l) ( ) ( ) <0.001 Women , Age (years) BMI (kg/m 2 ) <0.001 SBP (mmhg) <0.001 DBP (mmhg) <0.001 Fasting glucose (mg/dl) <0.001 TC (mg/dl) Physical activity index NS CRP (mg/l) ( ) ( ) <0.001 Total , Age (years) NS BMI (kg/m 2 ) <0.001 SBP (mmhg) <0.001 DBP (mmhg) <0.001 Fasting glucose (mg/dl) <0.001 TC (mg/dl) NS Physical activity index NS CRP (mg/l) ( ) ( ) <0.001 Data are mean and SD. CRP, geometric mean (±SD). p value was calculated with unpaired t-test. NS, not significant: p>0.05. MS, metabolic syndrome. Other abbreviations see in Table 1. classified into 10-year age groups are shown in Fig 1. Those aged in their 60 s comprised the greatest numbers for all subjects of each sex across the age groups. Although the 50 s age group had the most men, the 60s age group had the most women. Table2 shows the data for subjects with or without MS. The MS group consisted of 109 men and women (5.0%), and had a higher proportion of men (9.4%) than women (1.8%). Geometric mean levels of CRP were similar in both men (0.308mg/L) and women (0.327mg/L). There was a similar tendency among other variables between the with and without MS group. Overall, mean age was 59.4±12.1 years in the MS group and 56.5±12.1 years in the non-ms group and there was no significant difference between the 2 groups. Mean value of total cholesterol was 197.7±31.1 mg/dl in the MS group and 191.8±33.8mg/dl in the non-ms group, and mean PAI was 33.3±8.9 in the MS group and 32.9±7.8 in the non-ms group; there were no significant differences

4 Metabolic Syndrome and CRP: JMS Cohort Study Table 3 Effect of Diabetes on CRP With or Without MS MS Non-MS DM (+) DM ( ) DM (+) DM ( ) Men Women Data of CRP were shown in geometric mean. Abbreviations see in Tables 1,2. Table 4 Proportion of MS Divided by Tertile of CRP Tertile 1st 2nd 3rd Total MS Non-MS ,082 MS (%) All subjects were divided by tertiles; cutoff points were mg/l and mg/l. 1st: first tertile, the lowest group; 2nd: second tertile, the next group; 3rd: third tertile, the highest group. Abbreviations see in Tables 1,2. Odds ratio of Metabolic syndrome st 2nd 3rd CRP 29 Fig 2. Odds ratios of metabolic syndrome for the 2nd and 3rd tertiles of C-reactive protein (CRP) were analyzed using the 1st tertile of CRP as a reference. 1st: first tertile (the lowest group); 2nd: second tertile (the next group); 3rd: third tertile (the highest group). Odds ratios (95% confidence interval) of 2nd and 3rd tertiles: 2.9 ( ) and 5.7 ( ). in total cholesterol or PAI between the 2 groups. Mean values of BMI, SBP, DBP, fasting blood glucose in the MS group were significantly higher than those in the non-ms group (BMI: 26.7±2.8 kg/m 2 in MS and 22.6±2.8 kg/m 2 in non-ms, p<0.0001; SBP: 144.7±18.6 mmhg in MS and 129.4±22.0 mmhg in non-ms, p<0.0001; DBP: 85.8± 11.2 mmhg in MS and 76.9±12.8 mmhg in non-ms, p<0.0001; fasting glucose: 109.4±28.6 mg/dl in MS and 93.2±15.5 mg/dl in non-ms, p<0.0001). Geometric means (± SD) of CRP were 0.312mg/L ( mg/l) in MS and mg/l ( mg/l) and CRP in the MS group was significantly higher than that in the non-ms (p<0.0001). As for the effect of DM on CRP values in those with or without MS, the difference between CRP values among subjects with and without MS was larger than the difference between CRP values among those with and without DM (Table 3). The total subjects were divided into tertiles according to the CRP values, and the cutoff points were 0.057mg/L and mg/l. The proportion of MS cases divided by tertile of CRP was 1.7% in the 1st tertile, 4.6% in the 2nd tertile and 8.7% in the 3rd tertile, and in total, MS was 5.0% (Table 4). Using the 1st tertile of CRP as a reference, the OR of MS were significantly higher in the 2nd tertile (OR, 95%CI: 2.9, ) and 3rd tertile (5.7, ), and a dose response relationship was seen between CRP and the prevalence of MS (Fig 2). These results were almost identical after exclusion of subjects with major past histories or with hyperlipidemia. Discussion We examined the relationship between MS and CRP in the 1990s in the general population of Japan as part of the analysis of baseline data in the JMS Cohort Study. The participation rate of eligible subjects among people invited to the mass screening examination was 56%. The Japanese criteria for MS were defined in 2005, and 2,191 subjects in 3 of the 12 areas of the JMS Cohort Study were analyzed to determine who had MS. The MS group had a higher proportion of men (9.4%) than women (1.8%). There were less subjects with MS because the study subjects were residents in rural areas, general population-based, and there were very few subjects with major past histories, such as stroke, myocardial infarction or malignancy. We did not have detailed data on status or medication for hyperlipidemia, but only a few subjects were being medicated for hyperlipidemia, so the influence of the statin use was thought to be negligible. In fact, after exclusion of the subjects with major past histories or with medication for hyperlipidemia, the results remained almost identical. In this analysis, CRP was closely related to MS, and the mean concentration of CRP values was higher in the MS group than in the non-ms group. The inflammatory process is known to play an important role in the pathogenesis of atherosclerosis, and CRP is a not only a strong marker of CVD 9 13 and ischemic stroke, 25,26 but also may be involved in initiating atherosclerosis. 27 Our colleagues have reported lower levels of CRP in Japanese compared with studies conducted in other Western countries, 28 as well as intra-individual stability of CRP levels over an interval of 5 years. 29 In Western countries, MS is associated with mortality in older women, 3 and with CVD in middle-aged 1,4 and elderly people. 2,5 In diabetic patients, the new definition of MS in Japan was not predictive for CVD in either male or female patients in a prospective study, but a positive relationship according to WHO or NCEP-ATP III criteria was documented. 30 In a case control study, there was a positive association between MS and ischemic stroke in Japanese patients according to NCEP-ATP III criteria. 31 Furthermore, Ridker et al reviewed CRP in relation to MS and CVD in a prospective study. 32 Several studies have reported a relationship between components of MS and CRP. A population-based study in the UK showed that CRP correlated with BMI and smoking, but not with other risk factors. 11 In cohort studies using random sampling of the general population in the MONICA Augsburg Cohort Study, CRP predicted future myocardial infarction, and also correlated positively with BMI, BP and DM, but negatively with HDL-C. 10 In the Cardiovascular Health Study, CRP correlated positively with BMI, waist circumference and triglyceride, and negatively with HDL-C. 33 CRP was related to obesity in mono-

5 30 ISHIKAWA S et al. zygotic twins independent of genetic influence, 34 and in cross-sectional studies, MS was related to CRP. Laaksonen et al showed that CRP was a predictor of future MS in a population-based cohort study. 35 In Asia, Lee et al reported that CRP correlated with BMI, waist circumference, triglyceride, SBP, DBP and serum glucose, but negatively with HDL-C, and the mean concentration of CRP was approximately 2-fold that of those without MS, according to the criteria defined by NCEP-ATP III. In our study, the mean concentration of CRP was much lower than in other countries, even Korea; however, the mean concentration of CRP in the MS group was approximately 2-fold higher than that in the non-ms group. 17 Nakanishi et al reported that CRP levels increased continuously with the level of fasting glucose in both sexes in the Japanese population. 36 In a cohort study, the risk of developing cardiac disease was 2.2-fold greater in the MS group than in the non-ms group, according to NCEP-ATP III criteria. 37 There are only 2 studies that have examined the relationship between MS and CRP in Japanese. Tamakoshi et al reported that the components of MS were associated with elevated CRP in healthy working men, 16 and Oda et al tried to develop a cut-off level for CRP to indicate MS in outpatient men and women. 20 We did not have detailed drug information among subjects medicated for DM, hypertension or hyperlipidemia, which might have affected some data and is a study limitation. However, the strengths of the present study are: (1) that we examined the relationship between MS and CRP just after the Japanese criteria for MS were defined in 2005; (2) that the study samples came from a large general population in a multicenter study; and (3) that the data were obtained in the first half of the 1990s when there were very few studies of hscrp, especially in Japan. In the new Japanese definition of MS, waist circumferences were 85 cm for men and 90 cm for women, but there were no thresholds associated with risk for CVD in Japanese diabetic patients. 30 Miyatake et al reported briefly that the prevalence of MS using the new Japanese definition was 30.7% in Japanese men and only 3.6% in Japanese women. 38 We also thought that waist circumference as a necessary component of MS was too strict, and we intend to investigate the risk for CVD in a future cohort study. 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