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Dietary long-chain n–3 fatty acids of marine origin and serum C-reactive protein concentrations are associated in a population with a diet rich in marine products^1,2,3

¹ From the Departments of Medicine and Science in Sports and Exercise (KN and RN) and Public Health and Forensic Medicine (AH, SK, KO-M, TS, NN, and IT), Tohoku University Graduate School of Medicine, Sendai, Japan; the Division of Epidemiology and Community Health School of Public Health, University of Minnesota, Minneapolis, MN (AH); and the Center for Preventive Medicine and Salutogenesis, Tohoku Fukushi University, Sendai, Japan (KF)

² Supported by a Grant-in-Aid for Scientific Research (13557031); a Grant for Research Conducted by the Japanese Society for Promotion of Science (14010301) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; research grants 2002 and 2003 from the Japanese Atherosclerosis Prevention Fund; and a Health Science Grant on Health Services (H16-seisaku-023) and a Grant for Comprehensive Research on Aging and health (H16-choju-016) from the Ministry of Health, Labor and Welfare of Japan.

³ Reprints not available. Address correspondence to K Niu, Department of Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail: ggg{at}mail.tains.tohoku.ac.jp.

	ABSTRACT

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Background: Several studies have reported that the intake of n–3 polyunsaturated fatty acids (PUFAs) or fish is inversely associated with serum C-reactive protein (CRP) concentrations, but few studies have evaluated the relations between serum CRP concentrations and consumption of n–3 PUFAs derived from marine products in populations with a diet rich in marine products. Therefore, it is still unclear whether a greater consumption of n–3 PUFAs is associated with lower serum CRP concentrations.

Objective: The aim of this study was to investigate the relations between n–3 PUFA intake and serum CRP concentration in the Japanese, who have a diet rich in marine products.

Design: We designed a cross-sectional survey of 401 men and 570 women aged 70 y who were living in Japan. CRP concentrations were measured, and subjects whose serum CRP concentrations were 10.0 mg/L were excluded. Dietary intake was assessed with a self-administered diet-history questionnaire.

Results: After adjustment for several predictors of inflammation, the odds ratio of high CRP (1.0 mg/L) for increasing quartiles of total n–3 PUFA and eicosapentaenoic acid + docosahexaenoic acid were 1.0, 0.72, 0.57, and 0.44 (P for trend = 0.01) and 1.0, 0.91, 0.76, and 0.54 (P for trend = 0.03), respectively.

Conclusions: Greater intake of n–3 PUFAs derived from marine products, as measured with a self-administered questionnaire, was independently related to a lower prevalence of high CRP concentrations in this older Japanese population with a diet rich in marine products. Our findings suggest that even very high intakes of n–3 PUFAs may lower serum CRP concentrations.

Key Words: C-reactive protein • n–3 fatty acids • eicosapentaenoic acid • EPA • docosahexaenoic acid • DHA • inflammation • Japanese fish

	INTRODUCTION

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Low-grade inflammation, as indicated by moderately elevated C-reactive protein (CRP) concentrations, is a strong independent risk factor for the development of cardiovascular events (1). Recent data suggest that high CRP concentrations may contribute directly to atherogenesis (1, 2).

Epidemiologic studies suggest a lower incidence of coronary heart disease (CHD) in populations with a diet rich in fish (3). The active components of fish that reduce CHD risk are believed to be the long-chain n–3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA; 20:5n–3) and docosahexaenoic acid (DHA; 22:6n–3) (3).

Mechanisms that may link n–3 PUFA intakes and a lower incidence of cardiovascular disease (CVD) include decreases in serum triacylglycerol and platelet aggregation and antiarrhythmic effects (4). Antiinflammatory properties of n–3 PUFAs may also help reduce CVD (5). Experimental studies also provided support for an antiinflammatory role of n–3 PUFAs, including an inhibition of cytokine release from endothelial cells and improved endothelial dysfunction (6, 7). These endothelial abnormalities are early events in the development of atherosclerosis (8).

Several epidemiologic studies have assessed the relation between CRP concentrations and n–3 PUFA intakes in Western countries, such as the United States, Denmark, Spain, Sweden, and Greece (9-14). These observational studies showed inverse associations of fish and its components with serum CRP concentrations. However, the amount of fish or fish foods consumed is remarkably lower in these study populations than in the Japanese (15), and serum CRP concentrations in the Japanese are lower than those in Western populations (16-21). Therefore, it is conceivable that a higher consumption of fish may contribute to the lower serum concentrations of CRP in Japan. However, few studies have reported the relation between serum concentrations of CRP and consumption of n–3 PUFAs derived from marine products in population with a diet rich in marine products. Therefore, it is still unclear whether a greater consumption of n–3 PUFAs is associated with lower serum CRP concentrations. Thus, we designed a cross-sectional study to investigate the relations between n–3 PUFA intakes and serum CRP concentrations in the Japanese, who have a diet rich in marine products.

	SUBJECTS AND METHODS

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Study participants
Our study population comprised subjects aged 70 y who were living in the Tsurugaya area of Sendai, one of the major cities in the Tohoku area of Japan. At the time of the study in 2002, there were 2730 persons aged 70 y living in Tsurugaya. We invited all of these persons to participate in a comprehensive geriatric assessment of medical status, physical function, cognitive function, and dental status; 1178 gave their informed consent. The protocol of this study was approved by the Institutional Review Board of the Tohoku University Graduate School of Medicine.

We excluded subjects whose high-sensitivity CRP concentration had not been measured (n = 29). We also excluded those subjects whose serum CRP concentrations were 10.0 mg/L (n = 35), because people with acute inflammatory conditions frequently have serum CRP concentrations 10.0 mg/L (22). Furthermore, those who did not have any information on diet were excluded (n = 91). Finally, the highest and lowest 2.5% of total energy intake from all subjects (n = 52) was excluded. As a result of these exclusions, the final study population comprised 971 subjects (41.3% men) with a mean (±SD) age of 76.0 ± 4.7 y.

Measurement of serum CRP
CRP concentrations were determined by using an immunotechnique with a Behring BN II analyzer (Dade Behring, Tokyo, Japan). The BN II high sensitivity assay utilizes a monoclonal antibody coated on polystyrene particles and fixed-time kinetic nephelometric measurements (23).

Assessment of dietary intake
A brief self-administered diet-history questionnaire (BDHQ) included 75 food items with specified serving sizes that were described by natural portions or standard weight and volume measures of the servings commonly consumed in this study population. For each food item, the participants indicated their mean frequency of consumption over the past year in terms of the specified serving size by checking 1 of the 7 frequency categories ranging from "almost never" to "2 or more times/d". The mean daily intake of nutrients was calculated using an ad hoc computer program developed to analyze the questionnaire. Japanese food-composition tables, 4th edition (24), and assessments of dietary fatty acid intake (25) were used as the nutrient database. The reproducibility and validity of the BDHQ were described in detail elsewhere (26). The energy-adjusted intake of EPA + DHA from the BDHQ was significantly correlated with serum EPA + DHA concentrations (men: r = 0.37; women: r = 0.33) (26). The energy-adjusted intake of n–3 PUFAs from the BDHQ was also significantly correlated with the intake of n–3 PUFA measured by 16 d of diet recording (men: r = 0.42; women: r = 0.45) (26).

Assessment of other variables
Anthropometric measurements (height and body weight) were recorded by using a standardized protocol. Body mass index (BMI) was calculated as weight (kg)/height² (m). Blood pressure (BP) was measured at home with an HEM747IC device (Omron Life Science Co Ltd, Tokyo, Japan), which uses the cuff-oscillometric method to generate a digital display of systolic and diastolic BPs. The mean of 15.6 ± 10.5 (± SD) BP measurements was used as the BP value. Participants who did not measure home BP on 3 d were treated as having missing information on hypertension.

Blood samples were drawn from the antecubital vein, with minimal tourniquet use, while the subjects were seated. Specimens were collected in siliconized vacuum glass tubes containing sodium fluoride for blood glucose and no additives for lipids and CRP analyses.

Total cholesterol, HDL-cholesterol, and blood glucose concentrations were measured by using enzymatic methods (total cholesterol: Denka Seiken, Tokyo, Japan; HDL cholesterol: Daiichi Pure Chemicals, Tokyo, Japan; blood glucose: Shino-Test, Tokyo, Japan). Information on smoking status, use of aspirin, drinking status, and history of prior CVD were obtained from the questionnaire survey. Current drinkers were further asked about drinking frequency, beverage types usually consumed, and amount consumed on a single occasion. From these responses, we calculated the average daily alcohol consumption in grams. We also treated statin agents as independent confounding factors because they have been reported to lower CRP concentrations (27). The drug information was confirmed by a well-trained pharmacist.

Definitions of variables
We categorized the study participants, on the basis of recently proposed cutoffs for CRP, as having low concentrations (<1.0 mg/L) or high concentrations (1.0 mg/L) (28, 29). When we calculated log-transformed CRP, 1.0 was added [CRP value (mg/L) + 1] before transformation.

Hypertension was defined as a home systolic BP of 135 mm Hg or a home diastolic BP of 85 mm Hg or the use of antihypertensive agents (30). Diabetes was defined as a casual blood glucose concentration of 200 mg/dL or the current use of antidiabetic medication. Hypercholesterolemia was defined as a total cholesterol concentration of 220 mg/dL or the current use of nonstatin lipid-lowering agents.

Leisure time physical activity (LTPA) was assessed first with a self-reported single-item question on whether the participant obtained any LTPA in the past year. If the subjects responded "yes," questions were asked about the frequency and duration of walking, brisk walking, and sports. LTPA was then classified into 3 categories on the basis of frequency and duration in the participant: 1) high, at least 3–4 times/wk for 30 min each time, 2) low, some activity in the past year but not enough to meet high levels, and 3) none, no LTPA. We further classified LTPA into 6 categories on the basis of the above 3 categories and each physical activity, such as walking, brisk walking, and sports: 1) level 1, no walking, no brisk walking, no sports; 2) level 2, low walking, no brisk walking, no sports; 3) level 3, high walking, no brisk walking, no sports; 4) level 4, any walking, low brisk walking, no sports; 5) level 5, any walking, high brisk walking, no sports; 6) level 6, any walking, any brisk walking, low or high sports. Detailed information was provided in our previous reports (31).

Statistical analysis
Descriptive, biochemical, and nutritional data are presented as means ± SE or percentages. We used log-transformed CRP as the dependent variable and the consumption of EPA + DHA per 2000 kcal of energy intake categorized in quartiles as the independent variable. Differences in variables between the EPA + DHA groups were examined by for continuous variables or by multiple logistic regression analysis for variables of proportion after adjustment for age and sex. Multiple logistic regression analysis and analysis of covariance were used to examine the relation of n–3 PUFA with high CRP (1.0 mg/L), log-transformed CRP after adjustment for age, sex, BMI, hypercholesterolemia (nonstatin drugs), HDL cholesterol, hypertension, history of CVD, diabetes, smoking habits and history, LTPA, alcohol consumption, use of statin drugs, use of aspirin, energy intake, and intakes (per 2000 kcal of energy intake) of cis-linoleic acid (cis-LA), -linolenic acid (ALA), protein, saturated fat, monounsaturated fat and cholesterol. P values for linear trend were calculated by using the median (g/d x 2000 kcal) of the n–3 PUFA groups. The odds ratios (ORs) and 95% CIs of high CRP concentrations for increasing n–3 PUFA concentrations, with the lowest concentration as the reference, was also calculated by using multiple logistic regression analysis. The population attributable fraction of high CRP was calculated as the sum of the proportion of high CRP in the each n–3 PUFA intake group x (relative hazard of high CRP in each category –relative hazard of high CRP in the highest quartile)/relative hazard of high CRP in each category (32). A significant difference was defined as P < 0.05. All statistical analyses were performed by using the Statistical Analysis System 9.1 edition for WINDOWS (SAS Institute Inc, Cary, NC).

	RESULTS

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In this study population, the mean (±SD) EPA + DHA intake was 1.38 ± 0.82 g/d in men and 1.17 ± 0.67 g/d in women. The mean (±SD) EPA + DHA intake in the lowest quartile of EPA + DHA (per 2000 kcal of energy intake) were 0.55 ± 0.19 g/d in men and 0.48 ± 0.14 g/d in women. In this study, the subjects whose serum CRP concentrations were 10.0 mg/L were excluded. The mean (±SD) and median CRP concentrations were 1.14 ± 1.52 and 0.58 mg/L, respectively. Correlations of total n–3 PUFAs (EPA + DHA + ALA) with EPA, DHA, and EPA + DHA were 0.76, 0.76, and 0.76, respectively. The correlation of EPA and DHA was extremely high (r = 0.98). Age- and sex-adjusted baseline characteristics and CRP concentrations according to quartiles of EPA + DHA per 2000 kcal of energy intake are presented in Table 1. Mean age did not differ significantly between the EPA + DHA groups (P for trend = 0.39). Sex did not differ significantly between the EPA + DHA groups (P for trend = 0.28). Mean BMI also did not differ significantly between the EPA + DHA groups (P for trend = 0.88). Mean HDL cholesterol was significantly higher across EPA + DHA quartiles (P for trend = 0.03). The prevalence of a history of CVD and hypercholesterolemia was significantly greater in the highest EPA + DHA quartile (P for trend = 0.04 and <0.01, respectively). The percentage of subjects with hypertension, with diabetes, who used statin drugs, and who were current smokers, exsmokers, and nonsmokers did not differ significantly between the EPA + DHA groups (P for trend = 0.27, 0.54, 0.39, 0.12, 0.08, and 0.81, respectively). Mean alcohol consumption also did not differ significantly between the EPA + DHA quartiles (P for trend = 0.48). Mean total energy intake and intakes per 2000 kcal of energy intake as total fat, saturated fat, monounsaturated fat, polyunsaturated fat, cholesterol, protein, and vitamin E were significantly higher across EPA + DHA quartiles (P for trend < 0.01). Mean intakes per 2000 kcal of energy intake as carbohydrate were significantly lower across EPA + DHA quartiles (P for trend < 0.01). Mean intakes of fiber, ALA, and cis-LA per 2000 kcal of energy intake did not significantly differ in the highest EPA + DHA quartiles (P for trend = 0.95, 0.32, and 0.23, respectively). Although the difference was not statistically significant (P for trend = 0.26), the proportion of subjects with high CRP concentrations was lowest in the highest EPA + DHA quartile.

Table 2

Table 3

	DISCUSSION

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In this cross-sectional study, we examined the relation between the consumption of n–3 PUFAs derived from marine products and the serum CRP concentrations of the Japanese population with a diet rich in marine products. These results suggested that the intake of n–3 PUFAs derived from marine products was independently related to a lower prevalence of high CRP concentrations (1 mg/L) in the Japanese population with a diet rich in marine products. If we assumed a causal relation between n–3 PUFA intakes and high CRP concentrations, 30% of the high CRP concentrations was explained by a lower intake of n–3 PUFAs.

The n–3 PUFAs possess antiinflammatory properties, such as the ability to inhibit inflammatory cytokine production (5, 6). James et al (5) concluded that EPA could act as a competitive inhibitor of arachidonic acid conversion to inflammatory mediators, such as prostaglandin E₂ and leukotriene B₄. Decreased synthesis of these eicosanoids has been observed after inclusion of fish oil in the diet. These mechanisms may contribute to the inverse association of n–3 PUFA intake with CRP concentration.

Serum CRP concentration is higher in Westerners than in the Japanese. Median serum CRP concentrations in 1999–2002 were 1.6 mg/L in American males and 2.7 mg/L in American females (16). Moreover, Khera et al (20) reported that the median serum CRP concentrations were 3.0 mg/L in American blacks and 2.3 mg/L in American whites. In Canadians of various ethnic origins, mean serum CRP concentrations were 2.49 mg/L in Europeans, 1.50 mg/L in the Chinese, 3.22 in South Asians, and 6.21 mg/L in Aboriginals (21). In contrast, Yamada et al (19) reported that, in their population-based study of the Japanese, the median serum CRP concentrations were 0.16 mg/L in males and 0.09 mg/L in females aged 30 y. Consistent with these studies, the median CRP value of 0.58 mg/L in our participants was lower than the National Health and Nutrition Examination Survey (NHANES) medians of 2.8 and 2.7 mg/L for those aged 70–79 and 80 y, respectively (16).

Several epidemiologic studies assessed the relation between CRP concentrations and n–3 PUFA intakes in Western countries (9-14). Most of these studies reported an inverse relation between CRP and n–3 PUFA. However, the amount of n–3 PUFA consumption was remarkably lower in these studies than in ours. Pischon et al (11) reported that the median EPA + DHA consumption in the highest percentile (90–100% of EPA + DHA consumption per percentage energy intake) was 1.12g/d in men and 0.47 g/d in women. Lopez-Garcia et al (9) reported that the median EPA + DHA consumption in the highest quintile was 0.45g/d. Zampelas et al (14) reported that 88% of men and 91% of women reported that they consumed at least one unit of fish per week in their study, and mean consumption of n–3 PUFAs was 0.40 ± 0.31 g/d in men and 0.52 ± 0.29 g/d in women. These values are comparable with the lowest quartile of our study (median EPA + DHA intake: 0.55 g/d in men and 0.47 g/d in women). Therefore, our study indicated that higher amounts of fish consumption may be associated with a lower prevalence of high CRP. It appears that the greater consumption of fish may explain the lower serum CRP concentration in the Japanese than in Westerners. However, as shown in Table 1, even participants in the lowest quartile of n–3 PUFA intake had a lower CRP concentration and a lower prevalence of high CRP values than did Western populations. Therefore, although n–3 PUFA intake might be one of the factors that explains the lower CRP concentrations in the Japanese than in Westerners, n–3 PUFA intake cannot fully explain the between-population difference observed. Further exploration is required to clarify other factors that explain the lower CRP concentrations in the Japanese population.

A recent study provided information that even when traditional risk factor profiles for CHD were worse in Japan than in the United States (33), the prevalence of coronary atherosclerosis and CHD mortality in Japan is still considerably lower than in the United States (17, 34). Therefore, there may be some other important protective factors against atherosclerosis and CHD in Japan. Differences in genetic factors are unlikely to fully explain the difference because studies of Japanese migrants to the United States clearly illustrated an increase in CHD morbidity and mortality in Japanese men in the United States (35). An elevated CRP concentration is a strong independent risk factor for the development of cardiovascular events (1). Moreover, recent data suggest that CRP plays an important role in atherogenesis (1, 2). Thus, the present study suggests that one possible pathway by which marine n–3 PUFAs may reduce the risk of CHD in the Japanese is by decreasing serum CRP concentrations. Although they did not assess CRP concentrations, parallel findings (ie, fish intake is inversely associated with inflammatory markers) were reported by Iso et al (36).

A previous study reported that the relation between fish intake and CRP was observed only in women (10). Therefore, we examined the relation separately for men and women. However, we observed no significant interaction between sex and fish intake for CRP concentrations or the prevalence of high CRP. Although the interaction was not significant and the number of diabetic patients was small (n = 91), we found that the inverse relation between n–3 PUFA intake and CRP concentration was stronger in diabetic patients than in nondiabetic patients. To our knowledge, no previous study reported the relation between n–3 PUFA intake and CRP concentrations in diabetic patients. Further study is required to clarify the relation between n–3 PUFA intake and CRP concentrations in diabetic patients.

This study had several limitations. First, the participants were sufficiently active and healthy to participate in the survey; therefore, it is possible that our results do not apply to subjects at higher risk. Second, because this study population was aged 70 y, the results may not be generalizable to younger populations. Third, because this study was cross-sectional, we cannot infer causality from our results. Therefore, a prospective study or trial should be undertaken to confirm the relation between serum CRP concentration and n–3 PUFA consumption. Moreover, although we adjusted for a considerable number of confounding factors, we cannot exclude the possibility that CRP is affected by other dietary habits correlated with habitual dietary intake of fish. Therefore, an intervention study is necessity to establish a causal relation between fish consumption and serum CRP concentrations. Several randomized controlled trials examined whether fish-oil supplementation or fish intake can reduce CRP concentrations (37-39). However, these trials did not yield consistent findings. These topics should be further examined. Finally, a BDHQ was used to assess habitual dietary intake in the present study. The BDHQ was adapted for a large-scale epidemiologic study from a full-version diet-history questionnaire (DHQ), for which the reproducibility and validity was well documented (40). Although the validity of the BDHQ is slightly inferior to the validity of the DHQ (26), the reproducibility and validity of the BDHQ has been well examined (26).

In conclusion, this is the first study to show that intake of n–3 PUFAs derived from marine products, as measured with a self-administered questionnaire, is independently and continuously related to a lower likelihood of serum CRP concentrations 1.0 mg/L in an older Japanese population. Furthermore, our findings suggest that even high (by Western standards) intakes of n–3 PUFAs might lower CRP concentrations.

	ACKNOWLEDGMENTS

 
We thank Aaron R Folsom for his valuable comments on this paper.

KN and AH were responsible for the study concept and design, acquisition of subjects and data, analysis and interpretation of data, and preparation of manuscript. SK, KO-M, and KF were responsible for the acquisition of subjects and data and analysis and interpretation of data. TS and NN were responsible for the analysis and interpretation of data. IT was responsible for the acquisition of subjects and data, for obtaining funding, and for supervision. RN was responsible for the acquisition of subjects and data, for the analysis and interpretation of data, and for supervision. None of the authors had a conflict of interest to disclose.

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