RESULTS

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The study sample included 7,352 NHANES III participants 45 years of age or older with adequate information on meat consumption and lung function. The mean age was 64.5 years and 48.0% were male. Those excluded because of missing measures of cured meat, fish, fruit and vegetable consumption, or lung function were older (mean age = 71.0 yr) and had a higher prevalence of physician-diagnosed emphysema or chronic bronchitis (12.8 vs. 9.54% in the study sample). The distributions of sex, race/ethnicity, and smoking status were similar between the two groups. Those missing lung function data had cured meat consumption similar to participants in the study sample.

The study sample represented 68.2 million adults aged 45 years or older in the United States. The characteristics of this population, stratified by frequency of cured meat consumption are shown in Table 1. Individuals who consumed cured meats frequently were more likely to be male, of lower socioeconomic status, and tobacco users, and were less likely to report physician-diagnosed asthma than individuals who never consumed cured meats. Those who consumed cured meats more frequently had lower intakes of vitamin C, β-carotene, fish, fruits, vegetables, and vitamin or mineral supplements; had higher intakes of vitamin E and total calories; and had lower serum levels of vitamin C and E and β-carotene. The distributions of age, body mass index, and total:high-density lipoprotein cholesterol ratio were similar across categories of cured meat consumption.

Greater frequency of cured meat consumption was associated with lower FEV₁, FVC, and FEV₁/FVC after adjustment for demographics and height (Table 2, model 1). After controlling for smoking status, pack-years, cotinine levels, and household environmental tobacco smoke (ETS) exposure, these inverse associations were attenuated, but remained statistically significant (Table 2, model 2). After simultaneous adjustment for multiple additional confounding variables, individuals who ate cured meat consumption 14 times/month or more had a significantly lower FEV₁ (−110 ml; p for trend < 0.001) and FEV₁/FVC (−2.13%; p for trend < 0.001) compared with those who never ate cured meats. FVC did not differ significantly across categories of cured meat consumption. Each time-per-month increase in cured meat consumption was associated with a 3.85 ml decrease in FEV₁ and −0.07% decrease in FEV₁/FVC.

The frequency of cured meat consumption was positively associated with odds of COPD (Table 3). The OR for COPD among individuals who consumed cured meat 14 times or more per month was 1.93 (95% confidence interval [CI], 1.41–2.64; p for trend = 0.001) compared with those who did not consume cured meats, after adjustment for age, sex, race/ethnicity, height, and smoking variables. Further adjustment for other confounding variables yielded similar results. Each time-per-month increase in cured meat consumption was associated with a 2% increased risk for COPD (multivariate OR, 1.02; 95% CI, 1.01–1.03). Figure 1 shows a monotonic increase in OR for mild, moderate, severe, and severe or very severe COPD across these categories. Severe and very severe COPD categories were combined because of the small number of participants with very severe COPD (n = 34) in this study. The separate ORs were 2.51 for severe COPD and 352 for very severe COPD; both ORs were statistically significant.

Figure 1. Odds ratios of chronic obstructive pulmonary disease (COPD) comparing individuals who consumed cured meat 14 times or more per month with those who did not consume cured meats according to COPD severity. Error bars are 95% confidence intervals for the estimated values. The results were adjusted for the following: age; sex; race/ethnicity; smoking status; pack-years of smoking; serum cotinine concentration; household environmental tobacco smoke; education; family income; body mass index; physician diagnosis of asthma; use of acetaminophen, aspirin, and ibuprofen; serum total:high-density lipoprotein cholesterol ratio; serum levels of vitamins C, D, and E, β-carotene, and selenium; dietary intake of vitamin C, vitamin E, β-carotene, fish, fruits, vegetables, and total calories; and use of vitamin or mineral supplements.

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The sensitivity analysis using the LLN definition of COPD (FEV₁/FVC < [FEV₁/FVC]_LLN and FEV₁< [FEV₁]_LLN) yielded similar results (15). The multivariate-adjusted OR for COPD in this analysis was 1.67 (95% CI, 1.04–2.69; p for trend = 0.01) comparing the highest to the lowest category of cured meat consumption after adjustment for all the potential confounding factors.

Multivariate analyses stratified by smoking status showed that the inverse associations of cured meat consumption with FEV₁ and FEV₁/FVC persisted among 2,823 never-smokers, 2,155 past smokers, and 1,929 current smokers (Table 4), although the standard threshold of statistical significance was not met for current smokers. There was no apparent modification of the relations between cured meat consumption and lung function by smoking status (p for interaction was 0.64 for FEV₁, 0.94 for FVC, and 0.66 for FEV₁/FVC).

Consumption of ham and pork (e.g., cured and noncured meats, respectively) was inversely associated with lung function but these associations did not attain statistical significance. The multivariate differences between individuals consuming ham and pork five times or more per month (the highest two categories were combined because of less consumption of ham and pork) and those who never ate cured meats were −40.1 ml (p = 0.12) for FEV₁, −49.7 ml (p = 0.09) for FVC, and −0.11% (p = 0.82) for FEV₁/FVC. The multivariate OR for COPD comparing the two extreme categories (highest vs. lowest) of ham and pork consumption was 1.18 (95% CI, 0.80–1.73).

According to the ATS standard, we did not exclude participants with a nonreproducible test from the study. Sensitivity analyses for cured meats excluding 104 individuals with only one acceptable curve (n = 7,248) showed similar differences in lung function and in risk of COPD in the main analyses. Compared with those who did not consume cured meats, individuals who consumed cured meats 14 times or more per month had a significantly lower FEV₁ (−107 ml; p for trend < 0.001) and FEV₁/FVC (−2.08%; p for trend < 0.001) after adjustment for all the potential confounders. The multivariate OR for COPD comparing the highest to the lowest category of cured meat consumption was 1.78 (95% CI, 1.28–2.46) in this sensitivity analysis.

DISCUSSION

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This study of a representative sample of U.S. population aged 45 years or older showed that frequent consumption of cured meats was associated with lower FEV₁ and FEV₁/FVC and an increased odds of COPD after adjustment for multiple known risk factors. The magnitude of the risk of COPD increased with severity of COPD.

Cured meats may contribute to the development of COPD because of their high content of nitrites (9, 19). Nitrites are prooxidants and are involved in the formation of reactive nitrogen species that include both nitrating (i.e., NO₂) as well as nitrosating (i.e., nitrosonium + NO or dinitrogen trioxide [N₂O₃]) agents (20, 21). Reactions of nitrite with H₂O₂/myeloperoxidase (22), H₂O₂/Fe²⁺ (23), and H₂O₂/hypochlorous acid (24) all result in protein tyrosine nitration. 3-Nitro-tyrosine, which has been used as a biomarker for studying disease states associated with nitrative/nitrosative stress, is elevated in the inflammatory cells (25) and bronchial submucosa (26) of patients with COPD, suggesting that nitrating and nitrosating reactions may be increased in COPD.

Paik and colleagues showed that nitrating and nitrosating reactions induce extracellular matrix protein changes that include covalent nonenzymatic collagen cross-linking (27, 28) and elastin fragmentation in model system experiments paralleling the aging/diabetes model system of nonenzymatic glycation (29). Such in vitro findings are pertinent to COPD because both biochemical and histopathologic studies indicate that collagen and elastin damage occurs during the development of human pulmonary emphysema (30–32). These findings are also consistent with animal studies that demonstrated that rats fed long term with dietary nitrite developed dilated coronary arteries and pulmonary emphysema (8). Elastin and collagen integrity are principally responsible for the maintenance of both long-term coronary vessel diameter and alveolar airspace size, suggesting that supraphysiologic nitrite supplementation damages the connective tissue matrix. Although these experimental and animal studies suggest that nitrite exposure may cause lung damage through its effects on connective tissues in the lung, this is the only article of which we are aware that has examined the association between a principal source of dietary nitrite, cured meat intake, with lung function or COPD in humans.

Tobacco smoke is another major source of nitrite in the body. Of the approximately 4,000 different compounds in tobacco smoke, several compounds are present in relatively high amounts and include carbon monoxide, nicotine, and nitrogen oxides (NOx) (33). NOx comprise mainly nitric oxide (NO) and NO₂, and almost all of the NOx inhaled in cigarette smoke are retained in the body (34). NOx gas is converted exclusively to nitrite as it enters the pulmonary circulation (35), and inhaled NO results in marked increases in serum nitrite and nitrate (36, 37). Although the precise mechanisms underlying the tissue damage by cigarette smoking are poorly understood, nitrite precursors in cigarette smoke may contribute mechanistically to lower lung function through these mechanisms.

Prior epidemiologic studies have reported an inverse association between intake of fish, fruits, vegetables, and antioxidant vitamins (e.g., vitamins C and E, β-carotene) and FEV₁ or COPD (38). According to our data, those who consumed cured meats more frequently had lower intakes of fish, fruits, vegetables, vitamin C, β-carotene, and vitamin or mineral supplements, but had higher intake of vitamin E. Adjustment for these dietary factors in our analyses did not appreciably change the findings, suggesting the observed association between cured meats and lung function was unlikely to be explained by these potential dietary confounding factors reported in previous studies.

The major strength of this study was its large representative sample and multiple measures of smoking, including serum cotinine levels and ETS exposure. A limitation of the study was its cross-sectional design, which may introduce reverse causation and selection bias. Reverse causation was unlikely in that COPD probably did not cause participants to increase their cured meat consumption. Selection bias was minimized by the population-based, representative sampling of NHANES III participants. Cross-sectional studies of lung function can also yield different results from longitudinal studies of lung function for other reasons, including effect size, which was modest in this study. Smoking is the primary cause of COPD, so residual confounding by smoking was a potential concern. We adjusted, however, not only for self-report of smoking status, pack-years, and household ETS but also for serum cotinine levels as a biomarker of current smoking dose and current ETS exposure. In addition, we used cotinine levels to correct self-reported smoking status. Finally, the lack of effect modification by smoking status of the association of cured meats with lung function and the statistically significant inverse associations among never-smokers suggested true independent associations. We cannot rule out the possibility that unmeasured aspects of an unhealthy lifestyle may have caused the lower lung function and increased risk of COPD in those who ate cured meats frequently, although we adjusted for multiple dietary variables considered to be correlated with cured meat consumption in our multivariate analyses. We also lacked robust measures of dietary nitrite intake, post-bronchodilator lung function, and occupational exposures. Because food intake was self-reported and cured meats with varying nitrite content were grouped together in NHANES III, misclassification of nitrite consumption was inevitable and could bias the observed associations. Lack of post-bronchodilator measures can inflate prevalence estimates of COPD (39), but was unlikely to affect our results unless bronchodilator responsiveness was appreciably greater in those with high cured meat consumption. However, self-reported asthma was less frequent in those with high cured meat consumption, and we used relatively conservative definitions of COPD in the main and sensitivity analysis.

In conclusion, frequent cured meat consumption was associated with an obstructive pattern of lung function and increased odds of COPD independent of other major risk factors. High dietary nitrite intake warrants further evaluation in prospective, longitudinal studies as a novel risk factor for COPD.