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American Journal of Clinical Nutrition, Vol. 85, No. 6, 1606-1614, June 2007
© 2007 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Whole-grain consumption is associated with a reduced risk of noncardiovascular, noncancer death attributed to inflammatory diseases in the Iowa Women's Health Study 1,2,3,4

David R Jacobs, Jr, Lene Frost Andersen and Rune Blomhoff

1 From the Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (DRJ, LFA, and RB); the Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN (DRJ)

2 The contents of this manuscript are solely the responsibilities of the authors and do not necessarily represent the official view of the funding bodies.

3 RB was supported by grants from the Norwegian Research Council, The Johan Throne Holst Nutrition Research Foundation, and The Norwegian Cancer Society. DRJ was supported by the Norwegian Research Council and by a grant (RO1 CA39742) from the National Cancer Institute.

4 Address reprint requests to DR Jacobs Jr, Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454-1015. E-mail: jacobs{at}epi.umn.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: It has recently been shown that oxidative stress, infection, and inflammation are predominant pathophysiologic factors for several major diseases.

Objective: We investigated the association of whole-grain intake with death attributed to noncardiovascular, noncancer inflammatory diseases.

Design: Postmenopausal women (n = 41 836) aged 55–69 y at baseline in 1986 were followed for 17 y. After exclusions for cardiovascular disease, cancer, diabetes, colitis, and liver cirrhosis at baseline, 27 312 participants remained, of whom 5552 died during the 17 y. A proportional hazards regression model was adjusted for age, smoking, adiposity, education, physical activity, and other dietary factors.

Results: Inflammation-related death was inversely associated with whole-grain intake. Compared with the hazard ratios in women who rarely or never ate whole-grain foods, the hazard ratio was 0.69 (95% CI: 0.57, 0.83) for those who consumed 4–7 servings/wk, 0.79 (0.66, 0.95) for 7.5–10.5 servings/wk, 0.64 (0.53, 0.79) for 11–18.5 servings/wk, and 0.66 (0.54, 0.81) for ≥19 servings/wk (P for trend = 0.01). Previously reported inverse associations of whole-grain intake with total and coronary heart disease mortality persisted after 17 y of follow-up.

Conclusions: The reduction in inflammatory mortality associated with habitual whole-grain intake was larger than that previously reported for coronary heart disease and diabetes. Because a variety of phytochemicals are found in whole grains that may directly or indirectly inhibit oxidative stress, and because oxidative stress is an inevitable consequence of inflammation, we suggest that oxidative stress reduction by constituents of whole grain is a likely mechanism for the protective effect.

Key Words: Whole-grain foods • carbohydrate • fiber • inflammation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Habitual whole-grain food consumption has consistently been associated with a reduced risk of both coronary heart disease (CHD) and type 2 diabetes (1), and several studies also suggest that whole-grain intake reduces the risk of other diseases (2, 3). Refined grains, in contrast, do not appear to offer protection and may instead increase the risk of chronic diseases (4). The Dietary Guidelines for Americans therefore recommends an intake of 3 servings of whole-grain products/d (5). In the United States, the mean intake of whole grains is <1 serving/d, and that of refined grains is 5 servings/d (6).

It was previously reported that whole-grain intake in postmenopausal women in Iowa is associated with a reduction in total mortality of {approx}15%, with reductions clearest in mortality attributed to cardiovascular diseases and suggestive in noncardiovascular, noncancer mortality, including that due to nonmalignant respiratory diseases (7) and diabetes (8). There has been little investigation of what other diseases contribute to the reduction in mortality reduction associated with whole-grain consumption.

Likely candidates for such other diseases are inflammatory diseases. Although inflammation of short duration may help restore disrupted tissue structure and function, prolonged inflammation can contribute to pathogenesis. Inflammation has recently been suggested to be a common underlying mechanism of a variety of different diseases, including diseases of infectious origin, diabetes, and rheumatoid arthritis (9, 10). Numerous examples support this suggestion. Other pathologic mechanisms are clearly active in these diseases, but inflammation seems to contribute significantly to the severity of these diseases. Furthermore, inflammation promotes the production of reactive oxygen (ROS) and reactive nitrogen species (RNS) to ward off foreign invaders, which ultimately leads to oxidative stress (11, 12). Thus, chronic or prolonged inflammatory reactions inevitably lead to oxidative stress, and antioxidant therapy (ROS or RNS decomposition catalysts or selective antioxidant enzyme mimics) has been shown to prevent in vivo tissue injury during inflammation (13-15). Several epidemiologic studies have identified whole grains as part of a food pattern that is inversely related to inflammatory markers, whereas refined grains are positively associated with these markers (16-19). One short-term clinical study of whole-grain intake showed reductions in oxidative stress and related inflammatory factors (20).

Thus, it is reasonable to hypothesize that intake of whole grains may not only reduce the risk of cardiovascular disease and cancer, which clearly are related to inflammation (9, 21, 22), but may also reduce the risk of other diseases for which inflammation or oxidative stress is a predominant pathophysiologic factor. We have studied this hypothesis in postmenopausal women in Iowa aged 55–69 y after they were recruited in 1986. For this purpose, we formed a composite of causes of death selected a priori for which inflammation has been documented as a significant pathologic factor. Because whole-grain intake may reduce plasma biomarkers of inflammation, we investigated whether intake of whole or refined grains was associated with death attributed to this novel categorization of inflammatory diseases.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The Iowa Women's Health Study (IWHS) cohort comprises 41 836 women aged 55–69 y recruited via a baseline questionnaire mailed in 1986 and followed through 31 December 2001. A previous report explained how self-reported baseline risk factors were assessed and defined (23). Baseline histories of physician-diagnosed cancer (other than skin cancer), heart disease, or angina were obtained. In the present study we excluded women who were not postmenopausal (n = 569) and those with self-reported baseline heart disease (n = 3459), nonskin cancer (n = 3497), diabetes (n = 2386), chronic colitis (n = 2357), or liver cirrhosis (n = 313) and those who reported <600 or >5000 kcal/d or left >30 items on the diet questionnaire blank (n = 3096). Data were missing for waist-hip ratio for 134 women, estrogen use for 147 women, physical activity status for 579 women, and smoking status for 510 women. Some exclusions overlapped; the models used included 27 312 women. The study was approved by the Institutional Review Board of the University of Minnesota.

Dietary intake at baseline was assessed by using a 127-item food-frequency questionnaire (24). As previously described (25), servings per week of several whole-grain foods were computed. Whole-grain foods included the following verbatim items: dark bread, cold breakfast cereal, brown rice, popcorn, wheat germ, bran, cooked oatmeal, and other grains (eg, bulgar, kasha, and couscous). The participants were asked to name the single breakfast cereal usually eaten, which was then evaluated for whole-grain and bran contents. Breakfast cereals were considered to be whole grain if the product contained ≥25% whole grain or bran by weight. Bran cereals were included in the whole-grain category because findings were similar for bran cereals and nonbran, whole-grain cereals. The reliability and validity of the questionnaire were evaluated in 2 studies (26, 27). Correlations with 28 d of food records were 0.75 for cold breakfast cereals and 0.66 for dark bread (28).

Deaths were identified by annual linkage of cohort identifiers to Iowa state-wide death records through 31 December 2003. Deaths for subjects who had emigrated from Iowa were identified through the National Death Index. Cause of death was that assigned as the single underlying cause by State Health Department. We considered noncardiovascular, noncancer inflammatory diseases to be those that had an inflammatory, oxidative stress, or infectious component as the predominant pathophysiology. However, there is no simple rule for categorizing thousands of International Classification of Disease (ICD) codes. Therefore, we examined each ICD code that occurred in our sample, and those that we classified as having a predominantly inflammatory cause are listed below according to the major ICD grouping (ICD9 codes begin with a number; ICD10 codes begin with a letter):

  1. ) infectious diseases: 11.6, 28.9, 31.0, 38.0, 38.1, 38.4, 38.9, 42.9, 46.1, 54.3, 54.7, 70.3, 70.5, 75.0, 78.5, 117.5, 117.9, 135.0, 136.3, 137.0, A04.4, A04.7, A08.4, A31.9, A40.3, A41.2, A41.4, A41.9, A49.0, A81.0, A92.3, B16.9, B18.2, B37.8, B44.1, B49, B94.2, B94.8, and B99 (n = 59);
  2. ) endocrine, nutritional, and metabolic diseases: 250.0, 250.1, 250.3, 250.6, 277.3, 279.3, E10.2, E10.5, E10.7, E10.9, E11.2, E11.5, E11.9, E14.1, E14.2, E14.4, E14.5, E14.6, E14.7, E14.9, E85.3, E85.4, and E85.9 (n = 60);
  3. ) nervous system disorders: 322.9, 323.9, 331.0, 332.0, 335.2, 340.0, 341.9, 348.3, 355.9, 357.0, G03.9, G04.9, G12.2, G20, G30.1, G30.9, G31.9, and G35 (n = 241);
  4. ) respiratory system diseases: 466.0, 473.9, 480.9, 481.0, 482.0, 482.1, 482.3, 482.4, 482.8, 485.0, 486.0, 487.1, 491.2, 491.8, 491.9, 492.0, 493.1, 493.9, 494.0, 496.0, 507.0, 515.0, J11.0, J11.1, J12.9, J15.1, J15.2, J15.4, J15.9, J18.0, J18.1, J18.9, J20.9, J22, J40, J42, J43.9, J44.0, J44.1, J44.8, J44.9, J45.9, J46, J47, J69.0, J80, J84.1, and J98.4 (n = 569; 151 pneumonia and 418 respiratory diseases that were not infections);
  5. ) digestive system diseases: 303.0, 530.1, 531.4, 531.5, 531.9, 540.0, 541.0, 555.9, 556.0, 558.0, 562.1, 566.0, 567.2, 571.1, 571.2, 571.3, 571.4, 571.5, 571.6, 573.3, 574.1, K25.4, K25.5, K25.9, K50.9, K52.9, K65.9, K73.2, K74.6, K75.0, K81.0, K81.9, and K85 (n = 60);
  6. ) skin diseases: 682.6, 707.0, L02.9, L08.9, and L40.5 (n = 4);
  7. ) musculoskeletal and connective tissue disorders: 710.0, 710.1, 710.4, 714.0, 715.3, 725.0, 729.4, M00.9, M05.1, M06.9, M19.9, M30.0, M30.1, M31.3, M34.1, M34.8, M34.9, M46.2, M47.8, and M86.9 (n = 42); and
  8. ) genitourinary diseases: 580.8, 583.8, 585.0, 586.0, 614.4, N11.9, N12, N180, N189, N19, N258, N321, and N390 (n = 37).
The boldface ICD codes are separately classified as infectious diseases, regardless of ICD major grouping (n = 233); the nonboldface codes are the remaining noncardiovascular, noncancer inflammatory diseases (n = 839). Note that we previously defined this mortality variable on the basis of 15 y of follow-up (28); after 2 y of additional follow-up in the present study, we identified several more ICD codes that belong to the inflammatory category. Noncancer, noncardiovascular causes of death that were not included in the inflammatory category included injury, acute organ failure, psychoses, substance abuse, and some metabolic disorders.

Statistical analyses were performed with SAS software (version 8.2; SAS Institute, Inc, Cary, NC). Whole-grain consumption was categorized in approximate quintiles. Cox proportional hazards regression analysis was used to assess the association between whole-grain food consumption and death, presented as estimates of hazard ratios and their 95% CIs. In the models below, the interaction of whole-grain food intake (continuous variable) with time in study was nonsignificant; therefore, the proportionality assumption was deemed acceptable. The minimally adjusted model included only age (y) and energy intake (continuous; kcal) as covariates. The multivariable-adjusted model also included smoking (5 categories: never; current smokers, <15 cigarettes/wk; current smokers, ≥15 cigarettes/wk; past smokers, <15 cigarettes/wk; past smokers, ≥15 cigarettes/wk), intake of alcohol (continuous, as a quadratic function; g/d), body mass index (BMI), waist-hip ratio, education (less than high school, high school, more than high school), physical activity (low, moderate, high), use of estrogen (never used, current use, past use), use of multivitamin supplements (yes, no or don't know), and intakes of coffee (continuous; servings/d), refined grain (continuous; servings/d), red meat (continuous; servings/d), fish and seafood (continuous; servings/d), and total fruit and vegetables (continuous; servings/d). We performed a test for trend by treating whole-grain food intake as a continuous variable. The a priori focus of this work was the composite variable noncardiovascular, noncancer inflammatory disease mortality. The primary contrast being the remaining noncardiovascular, noncancer deaths. In response to the blind reviewers, we explored the association of whole-grain intake with the subcategories of diseases provided above, with 2 separate subgroupings: major ICD categories and infectious versus noninfectious inflammatory conditions.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The mean (±SD) consumption of whole- and refined-grain foods in the IWHS was 11.3 ± 8.9 and 14.5 ± 11.2 servings/d, respectively. As previously described, whole-grain intake (25) was generally associated with a healthier lifestyle, including increased physical activity, reduced smoking, and a choice of other foods generally thought to be healthy (Table 1Go). Women who habitually consumed whole-grain food were generally somewhat thinner than those who rarely consumed whole-grain food. Only a general question was asked about arthritis, an important noncardiovascular, noncancer inflammatory condition. Almost 50% of the women responded affirmatively to this question at baseline, with no gradient across whole-grain intake category. Of the 27 312 participants, 5552 had died after 17 y of follow-up; the death of 1071 of these participants was attributed to inflammatory causes.


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  		TABLE 1. Subject characteristics according to quintile (Q) of whole grain food intake in 27 312 women free of cancer (other than skin), heart disease, diabetes, colitis, and liver cirrhosis at baseline in the Iowa Women's Health Study, 1986

 
Noncardiovascular, noncancer inflammatory death showed an inverse association with total whole-grain intake (Table 2Go). Compared with the women who rarely or never ate whole-grain foods, the hazard ratio was 0.69 for those who consumed 4–7 servings of whole grain/wk, 0.79 for 7.5–10.5 servings/wk, 0.64 for 11–18.5 servings/wk, and 0.66 for ≥19 servings/wk. These mortality rates followed corresponding patterns for dark bread, whole-grain breakfast cereal, and other whole-grain foods; the pattern was weakest for whole-grain breakfast cereals (Table 3Go, Table 4Go, and Table 5Go). As previously reported (7) after a shorter follow-up duration, inverse associations were observed for total and CHD mortality. Exclusion of the first 5 y of death did not substantially alter any of the findings.


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  		TABLE 2. Hazard ratios (and 95% CIs) for total and cause-specific mortality according to quintile (Q) of total intake of whole-grain food in 27 312 women in the Iowa Women's Health Study, 1986–2003

 

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  		TABLE 3. Hazard ratios (and 95% CIs) for death attributed to noncardiovascular, noncancer, inflammatory diseases according to total intake of dark bread in 27 312 women in the Iowa Women's Health Study, 1986–2003

 

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  		TABLE 4. Hazard ratios (and 95% CIs) for death attributed to noncardiovascular, noncancer, inflammatory diseases according to total intake of whole-grain breakfast cereals in 27 312 women in the Iowa Women's Health Study, 1986–2003

 

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  		TABLE 5. Hazard ratios (and 95% CIs) for death attributed to noncardiovascular, noncancer, inflammatory diseases according to total intake of other whole-grain foods in 27 312 women in the Iowa Women's Health Study, 1986–2003

 
The relation of whole-grain intake to subsets of the noncardiovascular, noncancer inflammatory death variable is reported in Table 6Go. Most associations were inverse, although digestive, endocrine, nutritional, and metabolic (including primarily diabetes), musculoskeletal, and genitorenal disorders were each based on small numbers of cases. The strongest and statistically most robust associations were for respiratory system disorders, especially noninfectious ones. Mortality attributed to nervous system disorders showed little relation to whole-grain intake.


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  		TABLE 6. Hazard ratios for subsets of noncardiovascular, noncancer, inflammatory disease mortality according to quintile (Q) of total intake of whole-grain food in 27 312 women in the Iowa Women's Health Study, 1986–20031

 
The association of whole-grain food intake with noncardiovascular, noncancer inflammatory death did not vary by obesity status (normal weight, overweight, obese; P interaction = 0.76).

We conducted the same type of analysis for refined-grain intake. Of the several causes of death, noncardiovascular, noncancer inflammatory death was related, but only suggestively after multivariate adjustment, to refined-grain intake (Table 7Go). Compared with the women with intakes in the lowest quintile, the hazard ratios in the adjusted model were 0.98, 0.95, 1.12, and 1.21 (P for trend = 0.04) for women with intakes in quintiles 2, 3, 4, and 5, respectively.


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  		TABLE 7. Hazard ratios (and 95% CIs) for total and cause-specific mortality according to quintile (Q) of total intake of refined-grain foods in 27 312 women in the Iowa Women's Health Study 1986–20031

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We prospectively studied the relation of whole-grain food intake with death attributed to oxidative stress, inflammatory, and infectious processes as a predominant pathophysiologic cause. Inflammatory disease as an underlying cause includes most infectious and various chronic degenerative diseases, such as rheumatoid arthritis, gout, chronic obstructive pulmonary disease, emphysema, asthma, ischemia-reperfusion, ulcerative colitis, Crohn disease, type 1 and 2 diabetes, and several types of neurodegenerative diseases. A common feature in all of these infections and chronic degenerative diseases is that tissue degradation and repair, and hence inflammation, are causally linked to the progression of the diseases. In the present study, we excluded cardiovascular diseases and cancer from the inflammation categorization because other mechanisms (eg, deposition of atherosclerotic plaque, DNA changes) are likely to be at least as important causes of mortality in several of these diseases.

We found a reduction in risk of death attributed to inflammatory disease of >35% for those who reported the highest intake of whole grain. This risk reduction was numerically somewhat larger than the 28% reduction in risk for CHD death. It was also a greater reduction than the 20% risk reduction found for risk of incident diabetes in this study (8). Therefore, it may be that there is a specific effect of whole-grain intake on the reduction of chronic inflammatory processes that is also involved in the reduction in risk of CHD death and incident diabetes. In contrast, there was little relation between refined-grain intake and any cause of death, and its relation with inflammatory death was positive, but barely statistically significant. These modest associations are consistent with the findings for refined grain reported after 9 y of follow-up in the IWHS (7).

The results of one short-term study in which whole grain was provided as a supplement support this idea (20). A powder consisting of whole grains (mostly brown rice and barley) and legumes was provided in a drink for 16 wk to male patients (n = 76) with coronary artery disease. The control group maintained their usual diet. Fasting serum glucose concentrations, 2 measures of lipid peroxidation (serum malondialdehyde and urinary 8-epiprostaglandin F2), and homocysteine concentrations decreased significantly and serum retinol, {alpha}-carotene, and {alpha}-tocopherol significantly increased after 16 wk in the whole-grain and legume-drink group compared with the control group. Epidemiologic studies also identify whole-grain foods as inversely related to inflammatory markers (16-19).

Whole-grain foods contain fiber, vitamins, minerals, phenolic compounds, phytoestrogens, and other phytochemicals that are removed during the refining process (29-33). Interestingly, many of these compounds can support the antioxidant defense and thereby reduce the damaging effects of chronic inflammation via several mechanisms, including cell cycle control, protein chaperoning and repair, DNA and chromatin stabilization and repair, removal of reactive molecular species, and induction of antioxidant defense and detoxification mechanisms (33, 34). Many of these compounds are redox-active secondary plant metabolites (ie, redox-active antioxidants or reductants) (32, 33, 35, 36) that are produced by plants in response to oxidative and other types of stress and activate defense-related genes in plant cells. It has been suggested that these molecules also can mount an antioxidant defense in animal cells (after intake by the animal) by inducing gene expression of similar genes for antioxidant and detoxification enzymes (33, 37, 38). Therefore, we think it is plausible that whole-grain intake may reduce the risk of inflammatory conditions, possibly through support of antioxidant defense mechanisms.

We previously analyzed the total content of redox active molecules (ie, antioxidant capacity) in several thousand foods (32, 33, 35, 36) and were surprised to learn, after analyzing 1113 food samples obtained from the US Department of Agriculture National Food and Nutrient Analysis Program, that coffee and several whole-grain products were at the top of the ranked list. Furthermore, we recently studied the association between coffee consumption, the main antioxidant contributor in the diet, and risk of death attributed to inflammatory diseases in the IWHS using the same type of inflammatory categorization that we used in the present study (28). In the fully adjusted model, the hazard ratio of death attributed to inflammatory diseases was 0.72 for consumption of 1–3 cups (237–711 mL)/d, 0.67 for 4–5 cups (948–1185 mL)/d, and 0.68 for ≥6 cups (1422 mL)/d. We suggest that whole grains and coffee, both of which are rich in phytochemicals and other molecules that support the antioxidant defense, reduce the risk of cardiovascular disease and other inflammatory diseases in postmenopausal women via similar mechanisms. For example, dietary intake of both whole grains and coffee are positively associated with plasma enterolactone concentrations (39-41). Enterolactone, which is produced by the intestinal microflora from lignan precursors found in foods such as whole grains and coffee, is a phytoestrogen with antioxidant properties that has been linked to a reduced risk of inflammation-related diseases (42-44).

Caution is in order when interpreting our present findings. Although the formation of the inflammatory death endpoint is novel, most existing prospective studies assemble little information about the set of diseases that we included here. Use of the underlying cause of death as the indicator or inflammatory processes is likely to underestimate the number of women who suffer from the diseases; violent death, cancer, and cardiovascular diseases are preferentially coded as underlying cause if they coexist with one of the less common diseases studied here. It has long been thought that fiber is related to inflammatory diseases (45), and recent observations tend to support this view (46, 47). However, these studies have not focused specifically on whole grains or even cereal fiber. Residual confounding is a possibility, particularly because the correlates of the inflammatory death endpoint are not well known; however, we identified several other powerful predictors of this endpoint and adjusted for those variables. Reverse causality remains a possibility because there are inflammatory conditions that we did not ask about at baseline; however, we did exclude those with many of the most prevalent historical inflammatory conditions.

In conclusion, our results are consistent with a protective effect of whole-grain food intake on death attributed to pathology of inflammatory, oxidative stress, and infectious origin. These findings may lead to additional areas of research that will help to elucidate the reduced chronic disease risk associated with whole-grain food intake.


   ACKNOWLEDGMENTS
 
The authors' responsibilities were as follows—DRJ and RB: had original idea and obtained funding; LFA and DRJ: had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis; all authors: contributed to the analysis and interpretation of data and critically revised and approved the manuscript for important intellectual content. None of the authors had a conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication October 25, 2006. Accepted for publication January 12, 2007.




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