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Nutritional Epidemiology

Polymorphisms Cyclooxygenase-2 -765G>C and Interleukin-6 -174G>C Are Associated with Serum Inflammation Markers in a High Cardiovascular Risk Population and Do Not Modify the Response to a Mediterranean Diet Supplemented with Virgin Olive Oil or Nuts^1–3,

⁴ Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain; ⁵ CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain; ⁶ Human Nutrition Unit, Faculty of Medicine, University Rovira i Virgili, 43201 Reus, Spain; ⁷ Department of Preventive Medicine and Public Health, School of Medicine, University of Navarra, 31080 Navarra, Spain; ⁸ Cardiovascular Epidemiology Unit, Municipal Institut for Medical Research, 08003 Barcelona, Spain; ⁹ Instituto de la Grasa, Consejo Superior de Investigaciones Cientificas, 41012 Sevilla, Spain; ¹⁰ Department of Epidemiology, School of Medicine, University of Malaga, 29071 Malaga, Spain; ¹¹ Department of Cardiology, Hospital Txagorritxu, 01009 Vitoria, Spain; ¹² University Institute for Health Sciences Investigation, Hospital Son Dureta, 07014 Palma de Mallorca, Spain; ¹³ Department of Epidemiology and Public Health, Hospitales Universitarios Virgen del Rocío, 41013 Sevilla, Spain; ¹⁴ Department of Family Medicine, San Pablo Health Center, Primary Care Division of Sevilla, 41007 Sevilla, Spain; ¹⁵ Department of Biochemistry and Molecular Biology, University of Valencia, 46010 Valencia, Spain; ¹⁶ Department of Nutrition and Bromatology, School of Pharmacy, 08007 Barcelona, Spain; ¹⁷ Arteriosclerosis Unit, Hospital Carlos III, 28029 Madrid, Spain; ¹⁸ Primary Health Care Division, 08036 Barcelona, Spain; and ¹⁹ Lipid Clinic, Endocrinology and Nutrition Service, and ²⁰ Department of Internal Medicine, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi Sunyer, 08036 Barcelona, Spain

^* To whom correspondence should be addressed. E-mail: dolores.corella{at}uv.es.

	ABSTRACT

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Inflammation is involved in cardiovascular diseases. Some studies have found that the Mediterranean diet (MD) can reduce serum concentrations of inflammation markers. However, none of these studies have analyzed the influence of genetic variability in such a response. Our objective was to study the effect of the -765G>C polymorphism in the cyclooxygenase-2 (COX-2) gene and the -174G>C polymorphism in the interleukin-6 (IL-6) gene on serum concentrations of IL-6, C-reactive protein, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 as well as their influence on the response to a nutritional intervention with MD. An intervention study in a high cardiovascular risk Mediterranean population (314 men and 407 women) was undertaken. Participants were randomly assigned to consume a low-fat control diet or a MD supplemented with virgin olive oil or nuts. Measures were obtained at baseline and after a 3-mo intervention period. At baseline, the COX-2 -765G>C polymorphism was associated with lower serum IL-6 (5.85 ± 4.82 in GG vs. 4.74 ± 4.14 ng/L in C-allele carriers; P = 0.002) and ICAM-1 (265.8 ± 114.8 in GG vs. 243.0 ± 107.1 µg/L in C-carriers; P = 0.018) concentrations. These differences remained significant after multivariate adjustment. The IL-6 -174G>C polymorphism was associated with higher (CC vs. G-carriers) serum ICAM-1 concentrations in both men and women and with higher serum IL-6 concentrations in men. Following the dietary intervention, no significant gene x diet interactions were found. In conclusion, although COX-2 -765G>C and IL-6 -174G>C polymorphisms were associated with inflammation, consuming a MD (either supplemented with virgin olive oil or nuts) reduced the concentration of inflammation markers regardless of these polymorphisms.

	Introduction

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	Materials and Methods

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    Study design and participants. The Prevención con Dieta Mediterránea study is a parallel-group, multicenter, controlled, randomized clinical trial (ISRCTN35739639) aimed at assessing the effects of the MD on the primary prevention of cardiovascular disease (main outcome). It is currently taking place (anticipated completion date, December 2010). Here, we included data from the first evaluation study designed to assess the 3-mo effects of the dietary interventions (3 groups) on inflammation markers and other intermediate phenotypes (6). Briefly, from October 2003 to March 2004, potential high cardiovascular risk participants (n = 930) were selected by physicians in Primary Care Centers in Spain. Eligible participants were community-dwelling people (55–80 y of age for men; 60–80 y of age for women) who fulfilled at least 1 of 2 criteria: type 2 diabetes; 3 cardiovascular risk factors (current smoking, hypertension, hypercholesterolemia, BMI 25 kg/m², or a family history of premature cardiovascular disease). Exclusion criteria were cardiovascular disease, any severe chronic illness, drug or alcohol addiction, history of allergy, or intolerance to olive oil or nuts. We excluded 158 participants before randomization. Of the 772 participants who entered the study, we analyzed 721 Caucasian participants (314 men and 407 women) who completed the 3-mo intervention trial and had both the COX-2 -765G>C and the IL-6 -174G>C polymorphisms determined. All participants provided written informed consent to participate in the study. The Institutional Review Board of each participating center approved the study protocol.

    Dietary intervention. After the screening visit, each center randomly assigned the high cardiovascular risk participants to 1 of 3 diet groups using a computer-generated, random number sequence. The groups were: 1) MD supplemented with extra virgin olive oil (MD+VOO); 2) MD supplemented with 30 g/d of mixed nuts (MD+NUTS); and 3) a control group (intervention with a low-fat diet) (CTRL). A registered dietitian gave personalized dietary advice to each participant, with recommendations on the desired frequency of specific food intake. Informative group talks and provision of written material with descriptions of the MD and typical foods were conducted [Supplemental document 1 (in English) and 2 (in Spanish)]. The general guidelines to the 2 MD groups were for abundant use of virgin olive oil for cooking and dressing of dishes; consumption of 2 servings/d of vegetables (at least 1 of them as salad); 3 servings/d of fresh fruits (including natural juices); 3 servings/wk of legumes; 3 servings/wk of fish or seafood (at least 1 of fatty fish); 3 servings/wk of nuts or seeds; selected white meats (i.e. poultry without skin or rabbit) instead of red meats or processed meats (i.e. burgers and sausages); and regularly cooking with salsa made with minced tomato, garlic, and onion simmered in olive oil, adding other aromatic herbs or not, for dressing different dishes. Negative recommendations were also given to eliminate or limit the consumption of cream, butter, margarine, sweetened drinks, confectionery, industrial bakery products, chips or similar products, and precooked dishes or foods. No energy restrictions were suggested. In addition, depending on group assignment, participants were given either free virgin olive oil (1 L/wk) for cooking and dressing or free sachets of nuts (raw and unsalted) for daily consumption [walnuts (15 g/d), hazelnuts (7.5 g/d), and almonds (7.5 g/d)] for 3 mo. Participants in the CTRL group were advised by the dietitian to reduce intake of all types of fat and were given a leaflet with written recommendations following the AHA guidelines (23).

    Dietary measures. Food consumption at baseline and after the 3-mo intervention period was determined by a previously validated FFQ (24, as well as by a simplified 14-item questionnaire indicating a score of higher adherence to the traditional MD. Values of 0 or 1 were assigned to each of 14 dietary components (6).

    Biochemical analyses. Before and after 3 mo of intervention, blood and urine (first morning void) samples were obtained after an overnight fast. They were shipped to central laboratories and frozen at –80°C. Determinations at baseline and after 3 mo for an individual were conducted in the same batch and in duplicate. Serum glucose, cholesterol, triglycerides, HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) were determined as previously reported (6). Serum concentrations of high-sensitivity CRP were measured by particle enhanced immunonephelometry in a Synchron LXi 725-Synchron Access Clinical system (Beckman Coulter). The lower limit of detection for this assay was 0.1 mg/L. Inter- and intra-assay CV were 1.8 and 0.9%, respectively. We measured serum soluble ICAM-1 and VCAM-1 (R&D Systems) and IL-6 (Biosource International) using standard ELISA assays. Intra- and interassay CV for ICAM-1, VCAM-1, and IL-6 ranged between 1.8 and 5.4% and between 0.9 and 9.9%, respectively. In addition, biological assessment of the intervention compliance was performed on a subsample (n = 273) of participants selected at random from the 3 groups. Tyrosol and hydroxytyrosol, the major phenolic compounds in olive oil, were measured in urine by GC-MS on a Hewlett–Packard gas chromatograph (HP5980) coupled to a mass spectrometer detector system (HP5973) as biomarkers of compliance of the MD+VOO group (6). The plasma -linolenic, measured by GC on a Shimadzu GC-2010 gas chromatograph (Shimadzu), was used as biomarker of compliance of the MD+NUTS group (6).

    DNA extraction and genotyping. Genomic DNA was extracted from buffy-coat with the MagNaPure LC DNA Isolation kit (ROCHE Diagnostics). The COX-2 -765G>C polymorphism was determined as previously described (11). The IL-6 -174G>C was genotyped on a 7900HT Sequence Detection system (Applied Biosystems) using a fluorescent allelic discrimination TaqMan assay.

    Statistical analysis. Triglyceride, CRP, VCAM-1, ICAM-1, and IL-6 concentrations were log-transformed for the statistical analyses. Pearson ² and Fisher tests were used to test differences in percentages. T and ANOVA tests were applied to compare crude means of inflammation markers. Values in tables are means ± SD or means (95% CI). We carried out multivariate adjustments of the association by ANCOVA with post hoc comparisons (Tukey's honestly significant difference). We adjusted models for the potential confounders: age, gender, BMI, diabetes, dyslipemia, hypertension, tobacco smoking, adherence to MD score (at baseline), and medication use (antihypertensive drugs, statins, antidiabetic drugs, nonsteroidal antiinflammatory agents, and aspirin). The statistical homogeneity of the effects by gender was tested using interaction terms. We examined 3-mo changes in dietary and inflammation markers with ANCOVA for repeated measures, including control for potential confounders. We also performed ANCOVA for repeated measures to test gene x diet interactions. In these analyses, we studied the statistical effects of the genotype alone, the effect of the diet (change in the corresponding inflammation marker over the intervention period), and the effect of the interaction of both factors (genotype and diet), which is indicative of the different response to diet depending on the polymorphism analyzed. Statistical analyses were performed with the SPSS package, version 15.0. Our study, including 721 participants equally distributed into 3 intervention groups, was adequately powered to detect significant gene x diet interaction terms considering a mean dietary effect of 15%, a frequency of 35% for the carriers of the minor allele and a mean difference of 10% between genotype groups, an of 5% and a standard β of 20% in a repeated-measures model. The greater the difference between groups for a specific parameter, the higher was the corresponding statistical power in the specific analysis.

	Results

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Men and women who completed the study (Table 1) did not differ in genotype distribution for either the COX-2 -765G>C or for the IL-6 -174G>C variants. Frequencies of these polymorphisms did not differ according to the participant recruitment center (P = 0.135 for the COX-2 distribution by centers and P = 0.804 for the IL-6 polymorphism by center) and did not deviate from the Hardy-Weinberg equilibrium. Carriers of the C allele for the COX-2 -765G>C polymorphism were combined because of the low prevalence of CC participants and their similar genotypic effects. At baseline, carriers of the -765C allele did not differ in BMI or serum glucose or lipid concentrations from GG homozygotes (Table 2). However, the COX-2 -765G>C polymorphism was associated with lower IL-6 (P = 0.002) and ICAM-1 (P = 0.018) concentrations. After adjustment for confounders, these associations remained significant (Table 2). Serum VCAM-1 and CRP were not associated with these polymorphisms. Moreover, we found a consistent homogeneity by gender. In both men and women, the COX-2 -765G>C polymorphism was associated with lower ICAM-1 and IL-6 concentrations (P for COX-2 x gender: 0.900; P = 0.021 for mean differences in men and P = 0.037 for mean differences in women). Neither was any heterogeneity by gender for this polymorphism observed in the other variables analyzed (P for heterogeneity > 0.4).

View larger version (14K): [in this window] [in a new window]   FIGURE 1  Serum IL-6 concentrations in men and women by the IL-6 -174G>C polymorphism at baseline. Values are means ± SE, n = 314 men and n = 407 women and were adjusted for age, BMI, diabetes, hypertension, hyperlipidemia, tobacco smoking, MD score, and medication use (antihypertensive drugs, statins, antidiabetic drugs, nonsteroidal antiinflammatory agents, and aspirin). The P-value for the interaction term was obtained in the multivariate-interaction model. Within a gender, means without a common letter differ, P < 0.05 (Tukey test).

    Dietary intervention and gene x diet interaction. At baseline, demographic, clinical, genetic, and dietary variables did not differ among the 3 groups. After the 3-mo dietary intervention with MD+VOO or MD+NUTS, the MD diet score increased in these groups (Table 4). More details about other dietary changes have been reported in our previous work (6). According to the questionnaire responses, all participants, both those who received the VOO supplement as well as all those who received nuts, stated that they had consumed them. In addition, biochemical measurements in plasma and urine from the random group of participants revealed good adherence to supplemented foods. Compared with the control (CRTL) group, the MD+VOO group had increased urinary tyrosol (12 µg/L; 95% CI: 7–16; P = 0.001) and hydroxytyrosol (0.08 µg/L; 95% CI: 0.05–0.011; P = 0.01); those allocated to the MD+NUTS had increased plasma -linolenic acid (60 µg/L; 95% CI: 45–79; P = 0.04). Intervention with MD+VOO or MD+NUTS decreased serum inflammation markers (IL-6, ICAM-1, or VCAM-1). These markers did not decrease in the CRTL group (Table 4).

View larger version (33K): [in this window] [in a new window]   FIGURE 2  Serum IL-6 (A) and serum ICAM-1 concentrations (B) classified by the diet group (MD+VOO, n = 241; MD+NUTS, n = 240; and CRTL, n = 240), at baseline and at 3 mo, and the - COX-2 765G>C polymorphism (n = 453 GG and n = 268 C allele carriers). Values are means ± SE and were adjusted for gender, age, BMI, diabetes, hypertension, hyperlipidemia, tobacco smoking, and medication use. The P-values for main effects and the interaction terms were obtained in the multivariate-interaction model for repeated measures. D, Diet; G, genotype; D x G, diet x genotype interaction. Within a diet group, means without a common letter differ, P < 0.05 (Tukey test). # Different from the CTRL after the 3-mo intervention period, P < 0.05 (Tukey test).

	Discussion

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

When we analyzed the effect of the IL-6 -174G>C polymorphism, we found less consistent associations with serum IL-6 concentrations than when examining the COX-2 polymorphism. Although dozens of studies exist, consistency of the associations found is low (18,19,31–35). Fishman et al. (31) demonstrated the in vitro functionality of the IL-6 -174G>C polymorphism, showing a lower expression of the -174C allele. However, the controversial results in epidemiological studies, as well as the identification of novel regulatory regions in the IL-6 promoter (32), suggest that regulation of IL-6 expression is more complex than previously thought. Hence, there are studies that associate the -174C allele with greater serum IL-6 concentrations (19,33) and studies in which no such association was found (21,34,35). These discrepancies are also found when that polymorphism is related to cardiovascular risk (17,33–37). This fact could be due to the existence of a relevant modulation depending on the characteristics of the population. Here, we found an interaction with gender; in women, serum IL-6 concentrations did not differ, whereas in men, IL-6 concentrations were significantly increased in -174C carriers. Although some studies have also reported increased serum CRP concentrations in -174C carriers (17,21,38), we did not find those associations in this high cardiovascular risk Mediterranean population. However, this polymorphism was associated with higher serum ICAM-1 concentrations.

We studied whether these polymorphisms act by modulating the effect of a dietary intervention with MD, administered over 3 mo, on the decrease of serum IL-6, CRP, ICAM-1, and VCAM-1 concentrations, because we found in a previous work a beneficial effect of the MD on those markers (6) and others have reported similar decreases (4,7). We did not find significant gene x diet interactions for either of the inflammation markers analyzed. In the case of the COX-2 polymorphism, although at baseline, the IL-6 concentrations were higher in the -765GG homozygotes, the intervention with MD diet, either supplemented with VOO or nuts, reduced serum IL-6 concentrations in both groups. The same situation of no statistical gene x diet interaction was found for the reduction of serum ICAM-1. This fact, in which a dietary intervention reduces high concentrations of a risk marker in individuals with high baseline concentrations related to their genotype, has been called a "biological" gene x diet interaction (39). The term biological interaction is commonly applied in monogenic diseases and is currently used in some dietary interventions in clinical practice to prevent the disease. A statistical interaction exists if the degree or direction of the effect of 1 factor (e.g. a polymorphism) differs according to values of a 2nd factor (e.g. a dietary intervention). Accordingly, the vast majority of reports examining gene x diet interactions focused on statistically significant interactions (39). However, biological interaction needs to be considered when designing preventive and therapeutic dietary interventions to modify specific phenotypes in genetically susceptible individuals.

One of the potential limitations of our study is that an important part of the differences observed in inflammation markers might be attributed to supplementary foods, because adherence to them was higher than to the general dietary patterns.

In conclusion, the COX-2 -765C > G polymorphism is a relevant genetic marker in determining serum IL-6 and ICAM-1 concentrations in a high cardiovascular risk Mediterranean population. We did not find statistical gene x diet interactions, so intervention with MD+VOO or MD+NUTS reduced serum concentrations of inflammation markers regardless of the studied genotypes. Hence, this intervention, besides being beneficial for the general population, would especially benefit those participants whose genotype in the COX-2 or in the IL-6 genes provides them with higher concentrations of inflammation markers. This observation is considered a biological gene x diet interaction.

	FOOTNOTES

 
¹ Supported by grants PI052368, PI051458, PI042234, PI051839, PI052584, PI040233, PI070240, PI070954, G03/140, RD06/0045/0000, RD06/0045/0001, CNIC06, and CB06/03 from the Instituto de Salud Carlos III, Madrid, Spain; by grants GRUPOS2004-43 and ACOMP06109 from the Generalitat Valenciana, Spain; and by grant PI41/2005 from the Navarra Government, Spain. The Fundación Patrimonio Comunal Olivarero and Hojiblanca SA (Málaga, Spain), California Walnut Commission (Sacramento, CA), Borges SA (Reus, Spain), and Morella Nuts SA (Reus, Spain) donated the virgin olive oil, walnuts, almonds, and hazelnuts, respectively, used in the study.

² Author disclosures: D. Corella, J. I. González, M. Bulló, P. Carrasco, O. Portolés, J. Díez-Espino, M. I. Covas, V. Ruíz-Gutierrez, E. Gómez-Gracia, F. Arós, M. Fiol, M. C. Herrera, J. M. Santos, G. Sáez, R. Lamuela, C. Lahoz, E. Vinyoles, Emilio Ros, and R. Estruch, no conflicts of interest.

³ Documents describing the dietary interventions in English and Spanish are available with the online posting of this paper at jn.nutrition.org.

²¹ Abbreviations used: COX-2, cyclooxygenase-2; CRP, C-reactive protein; CTRL, control diet (no intervention with Mediterranean diet); HDL-C, HDL cholesterol; ICAM-1, intercellular adhesion molecule 1; IL-6, interleukin-6; LDL-C, LDL cholesterol; MD, Mediterranean diet; MD+VOO, Mediterranean diet supplemented with virgin olive oil; MD+NUTS, Mediterranean diet supplemented with nuts; VCAM-1, vascular cell adhesion molecule 1.

Manuscript received 21 May 2008. Initial review completed 20 June 2008. Revision accepted 21 October 2008.

	LITERATURE CITED

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 

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