Introduction

Asthma is an inflammatory airway disease associated with increased airway responsiveness, inflammation and intermittent airway obstruction (Lemanske and Busse, 2003). It affects, with regional differences, 9.5–40.9% of the European population (ECRHS, 1996, Heinrich et al, 2002). In most developed countries, an increasing prevalence of asthma in children (von Mutius et al, 1998) and adults (ECRHS, 1996; Sunyer et al, 1999) has been reported. However, recent updates revealed no further increase of asthma prevalence in Switzerland and Italy (Verlato et al, 2003; Braun-Fahrlander et al, 2004). Genetic and environmental factors including air pollution, housing conditions and other lifestyle factors have been linked to its aetiology and triggering (Lemanske and Busse, 2003). Humbert et al (1999) found more similarities than differences between atopic and non-atopic asthma and hypothesized that immunologic factors play a significant role in both variants (Humbert et al, 1999).

Recent research focuses on crucial components of typical western lifestyle such as dietary factors, which might substantially contribute to allergic sensitization (Fogarty and Britton, 2000; Filipiak et al, 2001, Douwes and Pearce, 2002). Attention was assigned to the quantity and quality of dietary fat intake (Black and Sharpe, 1997; Kankaanpaa et al, 1999). In particular, differences in the consumption of n-3 and n-6 fatty acids have been discussed in relation to the prevalence of atopy (Hirsch and Kempe, 1999; Wakai et al, 2001). Further fatty acid-related effects may be based on the configuration of the double bounds, either cis or trans, mainly of octadecenoic acid (Connor, 2000).

Epidemiological studies on children reported an association between elevated margarine consumption and atopy risk (von Mutius et al, 1998; Bolte et al, 2001). Margarine intake contributes to the intake of linoleic acid and is also a major source of trans-fatty acids (Willet and Ascherio, 1994), especially elaidic acid (C18:1 t9). Weiland et al (1999) observed in an ecological study that the dietary intake of trans-fatty acids is positively associated with allergic diseases.

According to the results of prospective (Troisi et al, 1995) and cross-sectional (Rubin et al, 2004) studies and a recent review (Caramori and Papi, 2004), dietary antioxidants, such as vitamin E, C, and -carotene, are associated with asthma risk. Clinical studies reported that asthma patients may experience increased oxidative stress (Kelly et al, 1999) and that carotenoids, vitamin C, and E influence pulmonary function (Schunemann et al, 2002).

Therefore, the present evaluation aims to examine prospectively within the European Prospective Investigation into Cancer and nutrition (EPIC)-Heidelberg, the potential effect of dietary fatty acids and antioxidants as well as their main food sources on the risk of newly physician-diagnosed asthma cases among adults.

Material and methods

Data collection

The EPIC is a prospective multicentre study to further investigate the association between diet, lifestyle and chronic diseases with emphasis on cancer (Riboli and Kaaks, 1997). The EPIC cohort in Heidelberg comprises of about 25 500 subjects aged 35–65 y in women and 40–65 y in men, recruited from June 1994 until October 1998 (Boeing et al, 1999a, 1999b). The baseline assessment of the cohort included a self-administered food frequency questionnaire (FFQ) (Boeing et al, 1997; Bohlscheid-Thomas et al, 1997) as a dietary assessment tool, a computerized lifestyle interview and standardized anthropometric measurements (Klipstein-Grobusch et al, 1997). The response rate of the first follow-up, which took place between 1998 and 2000, was 93.5%.

Outcome

During the median follow-up time of 2.1 y, 211 participants with new onset asthma were identified by comparison of self-reported baseline and follow-up data. In order to ask specifically for a diagnosis confirmed by a physician, the self-reported cases were contacted again by mail (Grassi et al, 2001). The participants identified by follow-up were asked to complete an additional questionnaire on the onset of asthma, diagnostic tests, symptoms and medication use.

Thus, 105 cases of newly physician diagnosed asthma cases were verified and characterized. The diagnosis is based on clinical examination (n=86, 81.9%), skin prick tests (n=45, 42.9%), lung function tests (n=79, 75.2%) and other tests (n=5, 4.8%). During the last 12 months, 73 (69.5%) participants experienced symptoms and 76 (72.4%) used asthma medication. The control group comprised of 420 randomly selected cohort members without self-reported prevalent asthma or other atopic diseases, matched (4:1) to the cases by sex and age group (5 y).

Variable definition

Dietary intake estimates for food groups, fatty acids and antioxidants were based on the results of the self-administered, semiquantitative food frequency questionnaire. Nutrient intake data were calculated from the food intake data by means of the German Food Composition Tables BLS, Version II.3 (Bundeslebensmittelschlüssel, Bg VV, Berlin, Germany, 1989).

The level of education was categorized as low (not more then 9 y of schooling without a specific vocational training), middle (high school degree (10 y) and/or vocational or technical training) and high (13 y of high school and/or a university degree). Participants were recategorized as nonsmokers when less than 3 months of regular smoking was reported, as ex-smokers when smoking was stopped for at least 1 y before the baseline interview and as smokers when present smoking was reported or when smoking was quitted less than 1 year before the baseline interview. Body mass index (BMI) was calculated as weight in kg/height in m². Sports activity was classified as 'yes' when any sports activity was mentioned.

Statistical methods

A case–control evaluation, with frequency matching for sex and age, was conducted. The medians and tertiles were calculated using the SAS procedure UNIVARIATE. Associations between asthma and intake of dietary fatty acids, antioxidants and food groups were evaluated by the Wilcoxon test (SAS procedure NPAR1WAY).

The tertile cut points were based on consumption levels among controls corresponding to the values of the 33- and 66 percentiles. The associations between dietary intake and the risk of asthma were assessed fitting unconditional logistic regression models. Adjusted estimates of the models are presented. The total energy intake was subdivided into energy derived from fat intake and nonfat intake. Regression models with different energy adjustment (eg as total energy intake, energy divided into intake related to fatty acid families and nonfat energy) were calculated, across which the effect estimates appeared stable (Willet, 1998). The adjustment for sports did not influence the effect estimates and was therefore not included in the models. In the final model age, fat energy intake, nonfat energy intake, BMI, smoking status, gender and educational level remained as adjustment variables in the model.

As effect estimates, the odds ratios (OR) and corresponding 95% CI (95% CI) were calculated using the PROC LOGISTIC procedure of the statistical software package SAS release 8.2 (SAS Institute, Cary, NC, USA). Tests for linear trend with two-sided P-values were calculated by using the median values of each category as continuous exposure score.

Results

Table 1 shows the basic characteristics of cases and controls. Except for the educational level, no differences between groups existed regarding BMI, smoking habits or the median follow-up time.

Table 1 - Sample characteristics of incident self-reported and verified asthma cases (n=105) and matched controls (n=420).

Full table

The median intake and the tertile cutpoints of dietary fatty acids, antioxidants and food group consumption among cases and controls are given in Table 2. There were no significant differences regarding the intake of total fat, saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), n-6- and n-3-polyunsaturated fatty acids (PUFA) between cases and controls. Moreover, cases and controls did not differ distinctly in the intake of food groups, which can be regarded as the most important food sources for fatty acids and antioxidants. However, margarine intake (P=0.029) was significantly higher in cases than in controls.

Table 2 - Dietary intake of energy, fatty acids, antioxidants and selected food groups in cases with asthma (n=105) and controls (n=420).

Full table

Table 3 shows the relationship between the intake of fatty acids and food groups and the risk of onset of clinical symptoms of asthma. An increasing intake of C18:1 (oleic acid) was positively associated with asthma with a P=0.035 for trend. The OR in the highest vs lowest intake tertile was 2.32 (95% CI=0.82–6.59). No evidence was found for the dietary intake of other fatty acids or the n6-/n3-PUFA ratio. Furthermore, the associations between the dietary intake of vitamins C, E, A and -carotene and asthma risk were analysed but none of the results were significant (data not shown).

Table 3 - Adjusted odds ratios (OR) and corresponding 95% confidence intervals (95% CI) for the association between the dietary intake of fatty acids and asthma (105 verified cases, 420 controls).

Full table

The results for the food groups, which substantially contribute to fat intake, are presented in Table 4. A high intake of margarine was associated with a significantly increased risk for the development of asthma symptoms in adults. The odds ratio in the 3rd tertile (vs 1st) was 1.73 (95% CI: 1.05–2.87) and with a borderline statistically significant trend (P=0.05). The effect of margarine intake on asthma risk was stable in different adjustment models. In grouped analysis, the effects for margarine consumption were stronger in men (2nd tertile: OR=1.66 (95% CI=0.53–5.23); 3rd tertile: OR=2.51 (95% CI=1.01–6.23); all vs 1st tertile) than in women (2nd tertile: OR=0.91 [95% CI=0.44–1.89); 3rd tertile: OR=1.47 (95% CI=0.79–2.74)). The odds ratio in the highest (vs lowest) tertile of egg intake was distinctly increased but failed to reach statistical significance. Consumption of none of the other investigated food groups revealed a significant effect on asthma risk in this study sample.

Table 4 - Adjusted odds ratios (OR) and corresponding 95% confidence intervals (95% CI) for the association between the dietary intake of selected food groups and asthma (105 verified cases, 420 controls).

Full table

Discussion

Within the frame of the EPIC-Heidelberg cohort, we investigated the relationship between dietary intake of fatty acids and antioxidants including their dietary food sources and newly diagnosed asthma at a relatively high age (>35 y). On average, the time lag between the assessment of dietary habits and the asthma diagnosis was 2.1 y. We found significant associations between the dietary intake of oleic acid (C18:1) and margarine with the risk of asthma in adulthood.

The finding of increased risk of adult onset asthma with dietary intake of the monounsaturated fatty acid oleic acid (C18:1) is consistent with the results of Heinrich et al (2001) who also reported in an ecological study that dietary intake of energy-adjusted MUFA was positively related to the prevalence of atopy. An increased risk was also observed for margarine consumption. This observation corroborates previous findings of a cross-sectional study regarding butter vs margarine consumption and the prevalence of hay fever and asthma among children (Bolte et al, 2001). In ecological studies, dietary factors, including high margarine consumption, were suggested to contribute to changes in prevalence rates of allergic disease in Eastern Germany after reunification (von Mutius et al, 1994, 1998; Hirsch and Kempe, 1999).

In the present study, individuals with asthma tended to have a lower educational level than the controls. However, the prevalence of asthma has often been linked to higher social classes, although the literature provides additional findings (Kogevinas et al, 1998; Eisner et al, 2001a). Regarding smoking status and asthma, our results are consistent with Eisner et al (2001b), who reported no association between asthma and current-smoking. In contrast to other findings, BMI was not associated with asthma (Huovinen et al, 2003; Romieu et al, 2003), which may be due to the predominant normal weight in our sample.

For the main dietary food sources of cis-C18:1 in the typical German diet, that is, meat, meat products, butter, milk, milk products and cheese, no associations with asthma were found. The intake of isoforms of trans-C18:1 is provided by ruminant fat (mainly C18:1 t11) and margarine (C18:1 t9, elaidic acid). Owing to the results found for margarine consumption, it may be speculated that a higher intake of C18:1 would accompany an increased intake of C18:1 t9. There is evidence that the configuration (cis-, trans-) of monounsaturated fatty acids affects serum and cellular fatty acid composition with possible metabolic consequences (Colandre et al, 2003; Mensink et al, 2003). Weiland et al (1999) found in an ecological study that the intake of trans-fatty acids is associated with allergic disease. It was suggested that trans-fatty acids promotes an increase in IgE production, mediated by the modulation of the desaturation and chain elongation of n-6 and n-3 fatty acids, thereby influencing the prostaglandin and leukotrienes synthesis (Precht and Molkentin, 1995).

We did not find an association between asthma and dietary intake of the n-3 PUFA, -linolenic acid (C18:3), eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6), whereas an inverse relationship between eicosapentaenoic acid (EPA, C20:5) intake and hay fever risk in adults in a recent study in the EPIC-Heidelberg cohort was observed (Nagel et al, 2003). Moreover, we found no association between n-6 PUFA intake and asthma risk. This is consistent with the prospective results of Troisi et al (1995) but in contrast to the findings of Wakai and co-workers (2001), who reported results from a cross-sectional study a positive association between allergic rhino-conjunctivitis and the intake of n-6 PUFA in adults. However, they did not observe any significant association with the intake of SFA, MUFA and n-3 PUFA.

Prostaglandin E2 (PGE2), an n-6-derived product, shifts the Th1/Th2 balance in the direction of Th2-linked diseases such as allergies (Kankaanpaa et al, 1999). Conversely, EPA (n-3 PUFA) may be negatively associated with allergic diseases (James et al, 2000). However, not only in our study but also in an evaluation dealing with hay fever risk in adults (Nagel et al, 2003) no association between increasing n-6/n-3 PUFA ratio and asthma risk was found. This is consistent with the recent results of Woods et al (2004) who found no association between the risk of asthma in young adults and any plasma fatty acid level for the n-6/n-3 ratio, respectively. Contradictory effects of single fatty acids may have annihilated the effects of the fatty acid families. Furthermore, the allergic component in the present asthma cases might have been secondary (Schafer et al, 2003).

Heinrich et al (2001) observed an inverse association between fruit intake and allergic sensitization while no association with vegetable consumption was found. Troisi et al (1995) investigated the impact of diet on adult onset of asthma and found a risk reduction with high vitamin E intake from diet (but not from supplements). Owing to the oxidative stress situation, which may occur in asthma, an effect of antioxidant intake on asthma symptoms may be hypothesized (Dworski, 2000). In our sample, however, no effects of antioxidant (vitamins C, E, A, -carotene) intake or of the consumption of antioxidant-providing food groups such as fruit (eg apples) intake, as potential dietary source of flavonoids, or meat intake, as potential source for selenium on asthma risk, were observed. This is consistent with observations of Woods et al (2003), whereas Shaheen et al (2001) observed an inverse association between apple consumption and selenium intake and asthma.

Our finding of a stronger effect of margarine consumption on asthma risk in men than in women is consistent with the results of Bolte et al (2001), who reported an association between margarine consumption and allergic sensitization in boys but not in girls. There is evidence that gender is an important factor in immunmodulation via sex hormones and glucocorticoids (Da Silva, 1999), which may lead to gender differences in immune reactions (Athreya et al, 1998; Whitacer et al, 1999).

Studies on the association between dietary factors and risk of atopic diseases must deal with two major problems: the case definition and the measurement error included in the dietary intake data. The identification of asthma 'cases' in epidemiological research is a cause of debate (Grassi et al, 2001; Peat et al, 2001). In the present evaluation, self-reported cases of asthma with first clinical onset after recruitment in the study were identified through active follow-up and verified by means of additional questioning leading to a lower number of cases and therefore statistical power of our study. Asthma cases refer to a diagnosis made by a physician. Furthermore, an investigation of self-reported prevalent hay fever of the same cohort revealed good agreement between reported hay fever and plasma IgE values (Nieters et al, 2004). In the control group it is unlikely that a misclassification other than random or nondifferential occurred, which would have biased the association towards the null. Owing to the low statistical power of the study and the large number of statistical tests, the results have to be interpreted with caution, since they may be observed by chance. Further follow-up of the cohort will contribute to clarify the present findings.

Secondly, dietary intake data may suffer from measurement error. The food frequency questionnaire used in this prospective study was validated by comparison with the results of twelve 24-h dietary recalls in the same individual. The adjusted correlation coefficients giving an indication for the goodness of fit between both instruments were in an acceptable range (Bohlscheid-Thomas et al, 1997). The same is true for food group consumption (Bohlscheid-Thomas et al, 1997). However, single fatty acids were not explored. In the 24 h data for the fatty acid intake, very good agreement with a valid biomarker, the plasma phospholipid fatty acid composition, was found (Linseisen et al, 2003).

However, the strength of the present study is the prospective and population-based study design of the EPIC-Heidelberg study with a major emphasis on diet, in which the case–control study is embedded.

In conclusion, the results of this prospective study provide evidence that dietary factors affect the risk of onset of asthma in adulthood. A high dietary intake of oleic acid (C18:1) and a high consumption level of margarine were found to increase asthma risk. The association of oleic acid intake with asthma may be explained by a concomitantly increased intake of trans-C18:1, which is relatively high in typical western diets and for one isomer, C18:1 t9 (elaidic acid), margarine is the most important dietary source. Further studies are needed to clarify these associations.

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Acknowledgements

We thank the volunteers who participated in EPIC. Furthermore, we thank first of all the EPIC team, Jutta Schmitt and Yvonne Küster, for documentation and D Zoller for the calculation of the food and nutrient data. We thank Bettina Mock for her helpful comments on earlier versions of the manuscript. EPIC is supported by the Deutsches Krebsforschungszentrum and grants from the European Community (SI2.326938) and Deutsche Krebshilfe e.V. (70-2488), J Linseisen at the TU Munich is supported by the Kurt-Eberhard-Bode-Stiftung.