1 Department of Medicine, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY.
2 Department of Social and Preventive Medicine, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY.
3 Section of Pulmonary, Critical Care, and Sleep Medicine, Veterans Administration Medical Center, Buffalo, NY.
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ABSTRACT |
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airway obstruction; antioxidants; carotenoids; lung diseases, obstructive; oxidants; oxidative stress; respiratory function tests; vitamins
Abbreviations: FEV1, forced expiratory volume in 1 second; FEV1%, forced expiratory volume in 1 second as the percentage of the predicted value; FVC, forced vital capacity; FVC%, forced vital capacity as the percentage of the predicted value; NHANES III, Third National Health and Nutrition Examination Survey
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INTRODUCTION |
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Accumulating evidence suggests that dietary antioxidant vitamins, such as vitamin C, vitamin E, and ß-carotene, are positively associated with lung function. Although vitamins C and E have been studied in some detail, the evidence is still inconsistent (7). Dietary intake of ß-carotene was positively associated with pulmonary function in several cross-sectional studies (8
10
), but the information on other carotenoids is limited. This lack of information is surprising, because many of the more than 600 carotenoids are found in the diet and have strong antioxidant activity (11
, 12
).
Recently, Grievink et al. (13) have reported that serum levels of the carotenoids lycopene,
-carotene, and ß-carotene were positively associated with lung function in an elderly sample of the Dutch population. We also observed that serum levels of carotenoids were positively associated with forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) as indicators of lung function in a general population sample (14
). However, we found the strongest association for the serum carotenoids ß-cryptoxanthin and lutein/zeaxanthin (14
). There is no "gold standard" for assessing antioxidant status, and dietary data could provide additional useful information. Until now, no epidemiologic study has investigated the association of lung function with these carotenoids in the diet.
Therefore, the goal of this study was to describe the relation of dietary antioxidant carotenoids (-carotene, ß-cryptoxanthin, lutein/zeaxanthin, ß-carotene, and lycopene) and other dietary antioxidant vitamins with pulmonary function (FEV1 and FVC) in the general population.
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MATERIALS AND METHODS |
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Study population
In brief, New York State Department of Motor Vehicles and Health Care Finance Association lists were utilized to randomly select participants aged 3579 years. Of the 4,946 eligible subjects we initially contacted, 2,537 (1,322 female and 1,215 male) agreed to participate (51.3 percent). Exclusion criteria for this analysis were race other than Caucasian or African American (n = 33); missing information on diet (n = 111); missing information on height, weight, smoking status, or education (n = 170); missing pulmonary function tests (n = 250); unacceptable or not reproducible pulmonary function tests (n = 108); or a history of chronic obstructive pulmonary disease, asthma, or pulmonary fibrosis (n = 249). The remaining 1,616 participants are included in this report. Excluded participants for whom information was available were comparable with included participants in the distribution of gender and race and were similar in their mean age, height, weight, dietary antioxidant intake, and total energy intake (p > 0.05). However, excluded subjects had lower levels of pulmonary function and education and were more likely to be smokers (p < 0.05).
Examination
The examination included an in-person interview about lifestyle habits, a self-administered questionnaire, anthropometric measurements, and spirometry. Spirometry was performed between 6:30 and 9:30 a.m. according to 1994 American Thoracic Society guidelines (14, 15
). We then used multiple linear regression to derive FEV1 and FVC prediction equations for men and women.
Nutrient intake
We assessed usual diet over the 12-month period starting 24 months before the interview and ending 12 months prior to the interview for each participant using the 100-item Health Habits and History Food Frequency Questionnaire ("Block") (16). Individual mean daily nutrient intake from foods and beverages was calculated using the DietSys (version 3.7) nutrient analysis software developed specifically for that questionnaire and updated to reflect current values for individual carotenoids; lutein and zeaxanthin were analyzed as lutein/zeaxanthin (17
, 18
). Nutrient intake calculations were based on food composition data available from the US Department of Agriculture using the following formula (16
): portion size (g) x nutrient content (per g) x frequency.
Less than 5 percent of the participants reported intake of carotenoid supplements in the 30 days prior to the interview. Of these participants the majority reported use of ß-carotene, and only one participant used lutein supplements, three used lycopene supplements, and six used cryptoxanthin supplements. Because of the small number of carotenoid supplement users, we did not calculate carotenoid intake from supplements. For vitamins C and E, we collected information on regular supplement use with the food frequency questionnaire, and we repeated the analyses for vitamins C and E adding the intakes of these two vitamins derived from supplements. All nutrient intakes are expressed as daily consumption.
Statistical methods and analysis
Based on values obtained from lifelong nonsmokers who did not report a history of chronic lung disease for men (n = 277) and women (n = 418), we obtained the following predication equations for pulmonary function in men:
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We examined the distributions of the continuous variables to determine if they were normally distributed and calculated the mean values and standard deviation. The analyzed dependent variables showed normal distributions, and we used natural logarithmic transformation for dietary variables because they were not normally distributed. To examine the correlations among variables we calculated simple Pearson's and partial correlation coefficients (r). To analyze the shape of the relation between antioxidants and lung function, we calculated the mean FEV1% and FVC% levels by quartiles of carotenoids, retinol, and vitamins C and E. We then calculated the differences between the highest and lowest quartiles with adjustment for covariates using general linear models.
To further investigate the association between antioxidant intake and FEV1 or FVC, respectively, we used multiple linear regression analysis. The dependent variables were FEV1% and FVC%, and the independent variables were dietary vitamins C and E, retinol, -carotene, ß-carotene, lutein/zeaxanthin, lycopene, and ß-cryptoxanthin. Previously, we found that weight, eosinophil count, education, smoking status, and cumulative tobacco smoke exposure in pack-years of smoking predict FEV1% with the largest variance explained and, therefore, included these variables in the baseline model (14
). Eosinophil count is a predictor of FEV1 independent of the presence of asthma and, thus, we included it in the model after excluding persons with asthma from the analysis (19
). We used the same variables in the models predicting FVC%.
First, we investigated each of the antioxidant variables separately after inclusion of total energy intake in the regression models (after logarithmic transformation). We then included all statistically significant dietary antioxidant vitamins simultaneously as independent variables in the regression model. For comparison among the various antioxidant vitamins in the regression models, the vitamin variables were expressed as a change of 1 standard deviation in intake.
We also examined models where the actually measured FEV1 and FVC and not FEV1% and FVC% were the dependent variables. For these analyses the baseline models also included age, height, gender, and race. Furthermore, we repeated the analyses using an external prediction equation based on data from the Third National Health and Nutrition Examination Survey (NHANES III) (20). We did not observe important differences using these analytical approaches and present only the results for FEV1% and FVC% obtained with our prediction equations.
To define statistical significance we used the conventional level of p < 0.05 but determined that interaction terms would be significant if the level of significance was p < 0.1. We investigated interaction by including interaction terms of antioxidant vitamin intake, smoking status, and other covariates. For the analyses we utilized the Statistical Package for Social Sciences (21) and S-PLUS software (22
).
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RESULTS |
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Analysis of FEV1% and FVC% by quartiles of vitamin intake
Table 2 shows the mean FEV1% and FVC% by quartiles of vitamins C and E, carotenoids, and retinol after adjustment for other covariates (total pack-years of smoking, smoking status, weight, education, eosinophil count, and total daily energy intake). For each of the antioxidant vi-tamins, pulmonary function was higher in the upper quartiles compared with the lowest quartiles. We observed the greatest differences between the bottom and the top quartiles for the antioxidants vitamin C, vitamin E, and lutein/zeaxanthin.
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DISCUSSION |
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Several previous studies have shown a positive association of dietary ß-carotene with pulmonary function (810
). Until now, however, studies have focused only on dietary ß-carotene and not on other carotenoids. We have investigated carotenoids other than ß-carotene because of their strong antioxidant function and because they are highly concentrated in human plasma.
Our findings indicate that, among all considered carotenoids, dietary lutein/zeaxanthin has the strongest relation to FEV1 and FVC%. This finding is somewhat surprising because dietary lycopene and ß-carotene intakes are higher than that of lutein/zeaxanthin and because lycopene has been considered to be a more powerful antioxidant than ß-cryptoxanthin and lutein/zeaxanthin (11). It has been emphasized, however, that antioxidants' activity measured in vitro, including their relative action compared with that of other carotenoids, may not resemble their activity in complex in vivo conditions (23
). For example, in comparison with other carotenoids, a stronger protection against damage of the retina has been ascribed to lutein/zeaxanthin (24
, 25
), and a negative association with prevalence of angina pectoris and carotid atherosclerosis has been reported for serum ß-cryptoxanthin (26
). However, there are limited epidemiologic data for carotenoids other than ß-carotene and their relation to human disease.
We previously found that cryptoxanthin and lutein/zeaxanthin in serum were positively related to pulmonary function (14). We report now on the relation between dietary antioxidant vitamin intake and pulmonary function. In the current analysis we could confirm the results for lutein/zeaxanthin but not for cryptoxanthin. The lack of an association between dietary cryptoxanthin intake and pulmonary function could be the result of the difficulties associated with accurately measuring cryptoxanthin in the diet. It may be that these limitations are not present for measurement of dietary lutein/zeaxanthin intake or that lutein/zeaxanthin is a stronger antioxidant than ß-cryptoxanthin, and we found a positive association in spite of limitations in the dietary measurement of this compound.
The results of this study also confirm previous findings that dietary intake of vitamin C is associated with pulmonary function when vitamin C is considered individually as a dietary antioxidant vitamin (810
, 27
30
). Recently, we have systematically reviewed the relation between antioxidants and pulmonary function (7
) and found an approximate pooled effect of a 37-ml increase in FEV1 associated with an increased intake of 100 mg of daily vitamin C. The corresponding estimate in this study is approximately 40 ml for an increased intake of 100 mg of daily vitamin C and, thus, in agreement with the pooled estimate.
Cigarette smoke contains large concentrations of oxidants (31). As a result one might expect a stronger association of antioxidant vitamins with pulmonary function in smokers if antioxidants could prevent oxidative damage. We failed to observe a statistically significant interaction of serum antioxidants with smoking, but this negative finding should be interpreted with caution. No previous study had sufficient power to detect a statistically significant interaction of vitamin C intake with smoking, but Hu and Cassano (9
) observed a stronger correlation of vitamin C with FEV1 in current smokers in an analysis of the NHANES III data, the largest data set investigated to date. Our study was not sufficiently powered to observe effect modification by smoking, but our results lend further support to the hypothesis that the effect may be stronger in current smokers. The associations between antioxidants and lung function were weak in former smokers. This finding may be a result of a prior change to a healthier lifestyle in smokers with impaired lung function that included smoking cessation and higher intake of dietary antioxidant vitamins. It is also important to note that, similar to our study, previous studies observed an attenuation of the association between pulmonary function and vitamin C when other antioxidants had been taken into account (9
, 29
). This attenuation appears to result from the correlation of the dietary vitamins C and E intake variables due to common food sources, but there is evidence that they act, at least in part, independently in the lung (32
, 33
).
The association of vitamin E with lung function has been found with less consistency than that of vitamin C. Our study adds evidence to the epidemiologic studies that found a stronger association of FEV1 with vitamin E than with vi-tamin C (34), including NHANES III (9
). The stronger association of vitamin E with pulmonary function compared with vitamin C may be a result of random error due to sampling, because other studies did not observe a positive association with vitamin E (10
) or found that the association was weakened after taking the effects of vitamin C into account (29
). However, the attenuation of an association by another nutrient is often present in the analysis of dietary data, and it is, at least in part, related to the autocorrelation of dietary nutrients. In addition, differences in measurement error between nutrients can result in falsely stronger associations of the nutrient with lower measurement error. Since dietary vitamin E intake is more difficult to measure and is associated with a greater measurement error than vitamin C intake (35
), a stronger association with vitamin C should be observed. Further support for an association of vitamin E with pulmonary function comes from our earlier analysis and the work of others on serum vitamin E and pulmonary function (9
, 14
, 36
).
In previous studies, consideration of supplemental antioxidant intake was restricted to adjusted regression models using dichotomous dummy variables (9, 10
). These studies did not report significant changes when the analysis was adjusted for supplemental vitamin use, but they left considerable uncertainty about the effect because of the lack of quantified supplement intake. We calculated the intakes of supplemental vi-tamins C and E, because these supplements were used regularly in this population. Including information on the intakes of these supplemental vitamins did not significantly alter the results. However, when we stratified by vitamin use, the association between vitamins C and E with pulmonary function tended to be weaker in regular vitamin supplement users for both dietary and total (diet and supplement) intakes. This observation could indicate that long-term users of these antioxidants reach a possible threshold or ceiling effect. The possibility of a ceiling effect is supported by the observation that the majority of supplement users were also in the highest quartile of dietary vitamin intake.
This study has several limitations. The cross-sectional design and the subsequent uncertainty about the cause-effect relation represent a weakness of our study. Longitudinal studies should provide evidence to answer this problem. Another limitation is the limited power to perform subgroup analysis by smoking status. However, even larger studies such as the NHANES III had limited power for this analytical approach (9). Furthermore, the high rate of nonresponders and missing data leaves the possibility for selection bias. Participants excluded because of missing data did not differ from those included in dietary antioxidant or energy intakes, age, height, or weight, but excluded participants had lower lung function, education, and prevalence of never smokers. Because of the possibility for selection bias, our findings can be generalized only with caution. In addition, we cannot exclude that multiple hypothesis testing led to erroneous statistically significant findings.
The strength of this study is the measurement of several dietary carotenoids in relation to lung function, an approach that has not been chosen previously. Because information on the relation of supplemental vitamin intake and pulmonary function is limited, our study adds important information to the current body of evidence. Information about long-term use of supplemental carotenoids is not available. Since less than 5 percent of the participants in this study used supplements containing carotenoids in the month prior to the interview, it is unlikely that carotenoid supplements have been taken regularly and that considering these supplements would have significantly altered the results. Another strength is that there was no important change in the results when we used the NHANES III data as an external prediction equation for FEV1% and FVC%.
Although it is not resolved completely whether vitamins C and E play a strong role in antioxidant defense in the lung and it is not completely explained why dietary lutein/zeaxanthin shows stronger effects than the other carotenoids, the magnitude of the observed effects on pulmonary function is of clinical significance. To bring the estimates into perspective, a decrease of 1 standard deviation of dietary vitamin E (72.5 mg/day) or lutein/zeaxanthin (1.8 mg/day) is equivalent to the negative effect of approximately 12 years of aging on FEV1 and FVC, respectively.
In summary, we found a positive association of vitamin C, vitamin E, and lutein/zeaxanthin intake with pulmonary function. We identified lutein/zeaxanthin as the dietary carotenoid with the strongest association with pulmonary function. When we considered carotenoids, vitamins C and E, and retinol simultaneously, the individual effects were reduced and vitamin E was most strongly related to FEV1 and lutein/zeaxanthin with FVC. We also found further evidence that smokers may show stronger associations between dietary antioxidants and lung function. Our findings emphasize that carotenoids may play a role in respiratory health and that studies should include carotenoids other than ß-carotene. Further studies are needed to confirm these results, and longitudinal studies could help to clarify whether this association is related to lung development in childhood and adolescents or whether it is the result of an accumulation of protective effects against oxidative damage throughout life. A meta-regression analysis that pools data from all studies could help to answer the question of possible effect modification of smoking on the relation between antioxidant vitamins and lung function.
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ACKNOWLEDGMENTS |
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The authors thank the personnel at the Center for Preventive Medicine, University at Buffalo, for their contribution to the study, Dr. John M. Weiner for statistical advice, and Marsha Barber for assistance.
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NOTES |
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REFERENCES |
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