Body Mass Index and Asthma in Adults in Families of Subjects with Asthma in Anqing, China JUAN C. CELEDÓN, LYLE J. PALMER, AUGUSTO A. LITONJUA, SCOTT T. WEISS, BINYAN WANG, ZHIAN FANG, and XIPING XU Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Program of Population Genetics, Harvard School of Public Health, Boston, Massachusetts; and Anhui Medical Center for Ecogenetics and Disease Control, Anqing, China

We conducted a cross-sectional study of 7,109 adults from families of subjects with asthma in the province of Anhui, China. Asthma was defined either as a combination of physician-diagnosed asthma, airway responsiveness to methacholine at  25 mg/ml and two or more respiratory symptoms or asthma attacks (“asthma”); or as a combination of airway responsiveness to methacholine at  8 mg/ml and two or more respiratory symptoms or asthma attacks (“symptomatic airway hyperresponsiveness [AHR]”). After adjusting for intensity of cigarette smoking and other variables, both extremes of the body mass index (BMI) distribution were associated with symptomatic AHR in men and women (p  0.01). In the multivariate analysis, both under- and overweight were associated with asthma in women, and underweight was associated with asthma in men. Among men, those with BMIs of 16 and 30 kg/m2 had 2.5 and 2.3 times higher odds of symptomatic AHR, respectively, than those whose BMI was 21 kg/m2 (95% CI for OR16 vs. 21 kg/m 2  1.4 to 3.8; 95% CI for OR30 vs. 21 kg/m 2  1.2 to 5.0). Among women, those with BMIs of 16 and 30 kg/m2 had 2.0 and 2.3 times higher odds of symptomatic AHR than those whose BMI was 21 kg/m2 (95% CI for OR16 vs. 21 kg/m 2  1.3 to 3.1; 95% CI30 vs. 21 kg/m 2  1.2 to 4.5). Among adults in families of subjects with asthma living in rural China, both underweight and overweight are associated with an increased risk of asthma. Keywords: asthma; body mass index; China

Asthma, a major public health problem, affects more than 17 million people in the United States (1). Although current epidemiologic data suggest that the prevalence of asthma is lower in mainland China than in industrialized countries (2–4), the absolute number of individuals with asthma is larger in China than in the United States because of the size of the Chinese population. Results of cross-sectional (5) and longitudinal (6) studies conducted in industrialized countries have shown an association between both increased body mass index (BMI) (5, 6) and weight gain (6) and self-reported asthma in adult women. Little is known, however, about the relation between BMI and asthma among adults living in rural areas. Since the mean BMI of adults in rural China (7) is significantly lower than that

(Received in original form May 9, 2001; accepted in final form August 23, 2001) Supported by NIH grant AI56371 and by Millennium Research. Dr. Celedón is supported by a Charles A. King Trust Fellowship Award. Dr. Palmer is a Winston Churchill Memorial Trust Fellow and an Australian–American Educational Foundation Fulbright Fellow. Correspondence and requests for reprints should be addressed to Juan C. Celedón, M.D., Dr.P.H., Channing Laboratory, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115. E-mail: juan.celedon@channing. harvard.edu This article has an online data supplement, which is accessible from this issue’s table of contents online at www.atjournals.org Am J Respir Crit Care Med Vol 164. pp 1835–1840, 2001 DOI: 10.1164/rccm2105033 Internet address: www.atsjournals.org

of adults in industrialized countries (6, 8), likely because of differences in ethnicity, physical activity, and dietary habits (7), we were interested in examining the relation between BMI and asthma in 7,109 adults participating in a study of the genetics and epidemiology of asthma in Anqing.

METHODS This study was conducted in collaboration with Anhui Medical University (Hefei, Anhui, China) and the Anqing Health Bureau (Anqing, Anhui, China). The study site has been previously described (9). Families with asthma from the eight counties of Anhui Province were enrolled in the study through a multistage process reported elsewhere (9). The following criteria were used for inclusion of asthma families in the study: (1) presence of at least two siblings,  6 yr old, with physician-diagnosed asthma; (2) availability of both parents; and (3) not more than one parent with physician-diagnosed asthma. Data were collected between July 1, 1994 and January 26, 1998. The following procedures (described in detail elsewhere) (9) were carried out: (1) completion of a modified American Thoracic Society (ATS)-Division of Lung Diseases questionnaire; (2) spirometry (10); (3) methacholine challenge testing, using the protocol of Chatham and coworkers (11), in all subjects whose FEV1 was  60% of predicted; and (4) skin testing of reactivity to 10 allergens along with a positive and a negative control (12). Height and weight were measured after subjects had removed their shoes and outerwear. Height was measured to the nearest 0.1 cm on a portable stadiometer. Weight was measured to the nearest 0.1 kg with the subject standing motionless on the scale. The study was approved by the Institutional Review Boards of the Brigham and Women’s Hospital (Boston, MA), the Anhui Medical Center for Ecogenetics and Disease Control (Anqing, Anhui, China), and the Harvard School of Public Health (Boston, MA). Our primary definition of asthma was based on the presence of all of the following: affirmative answers to the questions “Do you have asthma?” and “Has your asthma been confirmed by a doctor?”; at least two respiratory symptoms (cough, wheezing, dyspnea, or nocturnal cough/wheezing/dyspnea) or a history of recurrent asthma attacks; and airway hyperresponsiveness to methacholine, defined as a  20% fall in FEV1 from baseline after administration of  25 mg of methacholine per ml. Our secondary definition of asthma (henceforth referred to as “symptomatic airway hyperresponsiveness”) was based on the presence of at least two respiratory symptoms or history of asthma attacks, as well as a  20% fall in FEV1 from baseline after administration of  8 mg of methacholine per ml. BMI was calculated for each subject as weight in kilograms divided by the squared height in meters. The intensity of cigarette smoking in pack-years was calculated as the product of the period of tobacco use (in years) and the average number of cigarettes smoked per day, which was divided by 20 to convert to packs. A skin test to an allergen was considered positive if the diameter of the wheal was  3 mm after subtraction of the negative control. Bivariate relations between predictor and outcome variables were analyzed by 2 tests in the case of pairs of categorical variables or twotailed t tests in the case of a categorical and a continuous variable. To account for correlations between individuals from the same household, methods developed by Zeger and Liang (13), with generalized estimating equations for the logistic case, were used to evaluate the relation between BMI and the outcomes of interest while controlling for potential confounders and examining interactions.

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RESULTS The study originally included 9,314 adults ( 18 yr) in 2,756 families with asthma in Anqing. The current analysis was limited to the 7,109 adults in 2,544 families for whom there was complete information on BMI, airway responsiveness to methacholine, and skin test reactivity to allergens. The mean BMI ( SD) of subjects included in the current analysis was slightly greater than that of those excluded (21.3  2.3 versus 20.6  2.6, p  0.01). As previously shown (9), subjects with missing information were more likely to be older and to have more severe airflow obstruction than those with complete information. Table 1 shows the characteristics of 3,386 men and 3,723 women included in the current study. Of the 3,386 men participating in the study, 2,566 (75.8%) were younger than 45 yr. Of the 3,723 women participating in the study, 2,809 (75.4%) were younger than 45 yr. Generalized estimating equations were used to study the association between BMI and asthma in study participants while adjusting for familial correlations and potential confounders. Table 2 shows the relation between quintiles of BMI and the prevalence of either asthma or symptomatic airway hyperresponsiveness (AHR) in adults of both sexes. Because the prevalence of symptomatic AHR in both men and women was higher at the extremes of the BMI distribution and the prevalence of asthma was higher in under- and overweight women and underweight men, we tested for a log-quadratic relationship between BMI and either asthma or symptomatic AHR by determining the difference in goodness of fit between the log-quadratic model and log-linear or qualitative models (e.g., dividing BMI into quintiles). After adjustment for familial correlations, age, skin test reactivity to at least one aeroallergen, and intensity of cigarette smoking, there was a

TABLE 1. CHARACTERISTICS OF 7,109 STUDY PARTICIPANTS IN ANQING, CHINA Variable Age, yr (mean  SD) Body mass index, kg/m2 (mean  SD) Percentiles of body mass index, kg/m2  5th 5th–14th 15th–85th 86th–95th  95th Cigarette smoking, n (%) Never Former Current  5 pack-years of cigarette smoking, n (%) Number of positive skin tests to allergens, n (%) 0 1 2 3 4 5 6 Physician-diagnosed asthma, n (%) Airway responsiveness to methacholine, n (%) PD20  25 mg/ml PD20  8 mg/ml

Men (n  3,386)

Women (n  3,723)

37.7  11.9 21.1  2.2*

37.5  12.0 21.5  2.5

15.0–18.0 18.1–19.1 19.2–23.1 23.2–25.1 25.2–33.3

14.8–17.8 17.9–19.0 19.1–23.9 24.0–25.8 25.9–35.5

795 (23.5)* 260 (7.7) 2,331 (68.8)

3,571 (95.9) 17 (0.5) 135 (3.6)

1,966 (58.1)*

75 (2.0)

1,617 (47.8)* 538 (15.9) 407 (12.0) 337 (9.9) 169 (5.0) 130 (3.8) 188 (5.6) 532 (15.7)

2,119 (56.9) 539 (14.5) 392 (10.5) 289 (7.8) 163 (4.4) 95 (2.5) 126 (3.4) 591 (14.1)

1,010 (29.8)* 590 (17.4)†

984 (26.4) 584 (15.7)

* p  0.01 when compared with female subjects. † p  0.05 when compared with female subjects.

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significant quadratic relationship between BMI and the estimated log odds of either asthma or symptomatic AHR in men and women (Table 3). Figures 1 and 2 show the U-shaped relation between BMI and the probability of either asthma or symptomatic AHR in both men and women participating in our study. The first and fourth columns of Table 4 show the adjusted odds of having either asthma or symptomatic AHR for men and women in the lower (16 kg/m2) and upper (30 kg/m2) quintiles compared with adults with an average BMI ( 21 kg/m2). There was no significant modification of the effect of BMI on either asthma or symptomatic AHR in men and women by any of the variables included in the models. In addition, there was no appreciable change in the relation between BMI and either asthma or symptomatic AHR if alternative definitions of skin test reactivity to allergens (e.g., as three categories or as a continuous variable) were used. To avoid potential residual confounding by cigarette smoking, we repeated the multivariate analyses after stratifying by history of cigarette smoking (Table 4). In the 3,386 men, there was a significant association between underweight and either asthma or symptomatic AHR in both former/current smokers (n  2,591) and individuals who never smoked (n  795). Among men who never smoked, there was a nonstatistically significant trend for an association between overweight and either asthma or symptomatic AHR. Among men who were former or current smokers, overweight was significantly associated with symptomatic AHR but not with asthma. Because there was a small number of women who were former and current smokers (n  152), we were able to perform a multivariate analysis only on women who never smoked (n  3,571). Among women who never smoked, both under- and overweight were significantly associated with either asthma or symptomatic AHR. To avoid potential residual confounding by illnesses related to advanced age (e.g., congestive heart failure), we repeated the multivariate analysis in both men and women after excluding subjects  45 yr of age; the results of this restricted analysis in adults of both sexes were not appreciably different.

DISCUSSION In a study of adults in families of subjects with asthma in rural China, we found for both men and women a U-shaped relationship between BMI and a definition of asthma independent TABLE 2. RELATION BETWEEN QUINTILES OF BODY MASS INDEX AND ASTHMA AND SYMPTOMATIC AIRWAY HYPERRESPONSIVENESS IN ADULT MEMBERS OF FAMILIES OF SUBJECTS WITH ASTHMA IN ANQING, CHINA Asthma* [n (%)]

Symptomatic AHR† [n (%)]

Men (n  3,386) Quintile of BMI, kg/m2 Q1 (15.0 to 19.4) Q2 (19.4 to 20.4) Q3 (20.4 to 21.3) Q4 (21.3 to 22.6) Q5 (22.6 to 33.3)

65 (9.9) 40 (6.0) 54 (8.1) 33 (5.0) 37 (5.6)

83 (12.3) 63 (9.3) 64 (9.4) 45 (6.4) 70 (10.4)

Women (n  3,723) Quintile of BMI, kg/m2 Q1 (14.8 to 19.4) Q2 (19.4 to 20.6) Q3 (20.7 to 21.8) Q4 (21.8 to 23.4) Q5 (23.4 to 35.5)

50 (6.8) 55 (7.5) 43 (5.9) 39 (5.3) 48 (6.6)

69 (9.3) 56 (7.5) 57 (7.6) 46 (6.2) 61 (8.2)

* Eighty-one men and 73 women did not have information on physician-diagnosed asthma. † At least two respiratory symptoms or a history of asthma attacks and PD 20 with methacholine  8 mg/ml.

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Celedón, Palmer, Litonjua, et al.: Body Mass Index and Asthma in China TABLE 3. MULTIVARIATE ANALYSIS OF THE RELATION BETWEEN BODY MASS INDEX AND ASTHMA AMONG ADULT MALE AND FEMALE STUDY SUBJECTS IN ANQING, CHINA Male Subjects (95% CI)

Female Subjects p Value

(95% CI)

p Value

Asthma Age, yr Age2 BMI, kg/m2 BMI2 Smoking, pack-years Atopy*

0.156 (0.08, 0.23)

0.0016 ( 0.002, 0.001)

0.982 ( 1.58, 0.38) 0.020 (0.006, 0.033)

0.001 ( 0.01, 0.01) 0.147 ( 0.14, 0.43)

 0.001  0.001 0.001 0.003 NS NS

0.007 ( 0.001, 0.004) —

0.623 ( 1.07, 0.17) 0.014 (0.004, 0.02) 0.015 (0.002, 0.03) 0.64 (0.37, 0.91)

NS — 0.007 0.006 0.02  0.001

Symptomatic AHR† Age, yr Age2 BMI BMI2 Smoking, pack-years Atopy*

0.107 (0.04, 0.17)

0.0009 ( 0.002, 0.0002)

0.873 ( 1.39, 0.36) 0.019 (0.01, 0.03) 0.011 (0.004, 0.017) 0.27 (0.04, 0.51)

0.001 0.01  0.001 0.001 0.002 0.02

0.003 ( 0.01, 0.01) —

NS —  0.001  0.001 0.003 0.003

0.743 ( 1.20, 0.31) 0.016 (0.01, 0.03) 0.019 (0.01, 0.03) 0.367 (0.12, 0.61)

* Skin test reactivity to one or more allergens. † Airway hyperresponsiveness to methacholine (PD 20  8 mg/ml).

of a physician’s diagnosis (“symptomatic AHR”). Using a definition of asthma that incorporated a physician’s diagnosis (“asthma”), there was a U-shaped relationship between BMI and asthma in women and an association between underweight and asthma in men. Our study is unique in that we employed two definitions of asthma that included an objective assessment of airway responsiveness. Misclassification of subjects with other cardiorespiratory diseases (e.g., chronic obstructive pulmonary disease, congestive heart failure) as asthmatic or residual confounding by cigarette smoking is an unlikely explanation for our finding of an association between underweight and either asthma or symptomatic AHR in adults of both sexes, because our results were not appreciably changed after exclusion of former and current smokers from the analysis. Furthermore, the observed association between underweight and either asthma or symptomatic AHR was essentially unchanged after the analysis was restricted to subjects younger than 45 yr of age. In a study of 2,254 adults in the United States, subjects weighing  20% less than their expected weight had reduced lung function (14). A cross-sectional study of Taiwanese adolescents (15), on the other hand, found an association between low BMI and reduced risk of increased airway responsiveness

in girls but not in boys. An association between underweight and either “bronchial and lung conditions” (16) or asthma (17) was found in large cross-sectional studies of Israeli male adolescents (16) and Italian individuals 15 yr or older (17). In the Italian study (17), the age-adjusted prevalence of selfreported asthma was significantly higher in underweight men than in men of normal weight (odds ratio [OR] for men with BMI  20 kg/m2  1.4, 95% confidence interval [CI]  1.2– 1.8). Although several studies in industrialized countries did not find an association between low BMI and asthma in adult men (5, 18) or women (5, 6, 18), they were limited by both lack of an assessment of airway responsiveness and inadequate information about subjects with a BMI  19 kg/m2 (the current lower limit of U.S. weight guidelines for healthy adults) (19). The cross-sectional nature of our data does not allow us to determine whether weight loss preceded the development of asthma or whether asthma led to failure to thrive and malnutrition during childhood that persisted into adult life. In animal models, protein and calorie restriction during the prenatal and early postnatal periods can result in permanent abnormalities in lung structure and function (20, 21). It has been speculated that, in humans, factors that reduce weight gain in utero may constrain fetal lung growth (22). In examining this hy-

Figure 1. Relation between body mass index (kg/m2) and risk of asthma and symptomatic airway hyperresponsiveness in 3,386 men in Anqing, adjusting for age, intensity of cigarette smoking, skin test reactivity to one or more allergens, and familial correlations.

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Figure 2. Relation between body mass index (kg/m2) and risk of asthma and symptomatic airway hyperresponsiveness in 3,723 women in Anqing, adjusting for age, intensity of cigarette smoking, skin test reactivity to one or more allergens, and familial correlations.

pothesis, some studies have found an association between impaired fetal growth and asthma in children (23–26), adolescents (27), and young adults (5), whereas others have not (28– 30). In older children, malnutrition is associated with significant reductions in lung function, even in the absence of known respiratory illnesses (31). It is thus plausible that, in some of our study subjects, malnutrition during the pre- and postnatal periods led to abnormal lung growth, reduced airway caliber, increased susceptibility to environmental insults (e.g., viral respiratory infections), and asthma. Because boys have smaller airways for lung size than girls (32, 33), this may make them particularly susceptible to the effects of malnutrition, possibly explaining the sex differences in the strength of the association between low BMI and asthma in our study. Increased weight has been associated with reduced lung function in adult men and women (14, 34). Both being overweight at baseline and gaining weight during a 6-yr period were associated with a decline in lung function among Canadian men (35). Conversely, profound weight loss has led to improvement in pulmonary function in some morbidly obese individuals (36). In cross-sectional studies, asthma has been associated with overweight or obesity in children of both sexes

(37, 38), adult men (17), and adult women (5, 8, 17, 18). An increased BMI at baseline and weight gain during a 4-yr period were associated with asthma among women participating in the Nurses’ Health Study II (6). After adjustment for potential confounders (including physical activity and energy intake), women whose BMI was  30 kg/m2 had 2.7 times the risk of developing asthma than women whose BMI was between 20 and 22.4 kg/m2 (95% CI for relative risk [RR]  2.3–3.1) (6). A longitudinal study showed that girls who become overweight or obese between 6 and 11 yr of age have an increased risk of developing new asthma symptoms and increased bronchodilator responsiveness during the early adolescent years (39). Although there was a trend for an association between increased BMI at age 11 or 13 yr and wheezing among boys, it was not significant. We found a significant association between overweight and either asthma or symptomatic AHR in women. Among men, the association between overweight and asthma was significant only when asthma was defined independently of a physician’s diagnosis (symptomatic AHR). There was, however, a nonstatistically significant trend for an association between overweight and a definition of asthma requiring a physician’s

TABLE 4. MULTIVARIATE ANALYSIS OF THE RELATION BETWEEN BODY MASS INDEX AND ASTHMA AMONG ADULT MALE AND FEMALE STUDY SUBJECTS IN ANQING, STRATIFIED BY CIGARETTE SMOKING OR (95% CI) Men

Women*

All Subjects (n  3,386) Former/Current Smokers (n  2,591) Never Smokers (n  795) All Subjects (n  3,723) Never Smokers (n  3,571) Asthma BMI, kg/m2† 16 21 30

3.4 (1.9 to 6.1) 1.0 1.3 (0.5 to 3.6)

2.5 (1.2 to 5.0) 1.0 0.9 (0.2 to 3.2)

7.5 (2.5 to 22.6) 1.0 3.8 (0.8 to 19.0)

1.8 (1.1 to 2.9) 1.0 2.1 (1.0 to 4.3)

2.0 (1.2 to 3.4) 1.0 2.7 (1.2 to 6.0)

Symptomatic AHR‡ BMI, kg/m2† 16 21 30

2.3 (1.4 to 3.8) 1.0 2.5 (1.2 to 5.0)

2.0 (1.1 to 3.5) 1.0 2.3 (1.0 to 5.1)§

3.5 (1.3 to 9.8) 1.0 3.7 (0.9 to 15.9)

2.0 (1.3 to 3.1) 1.0 2.3 (1.2 to 4.5)

2.3 (1.4 to 3.7) 1.0 3.3 (1.6 to 6.7)

* Multivariate analysis not performed because of the small number of female former/current smokers (n  152). † Adjusting for age, atopic status, and (for “all subjects” only) intensity of cigarette smoking. ‡ Airway hyperresponsiveness to methacholine (PD 20  8 mg/ml). § p  0.05.

Celedón, Palmer, Litonjua, et al.: Body Mass Index and Asthma in China

diagnosis (“asthma”) in men who never smoked. Thus, the most likely explanation for the observed sex differences in the relation between an increased BMI and our primary definition of asthma (“asthma”) is that overweight men who had respiratory symptoms and a history of former or current cigarette smoking were less likely to be diagnosed with asthma by a physician than overweight women who had respiratory symptoms and never smoked. Although we cannot exclude the possibility that the association between overweight and asthma in our study participants may be related to reduced physical activity due to asthma, current evidence suggests that weight gain precedes the development of asthma in children and adults (6, 39). Cross-sectional studies of nonasthmatic children (40) and adult smokers with mild chronic obstructive pulmonary disease (COPD) (41) have found an association between obesity and increased airway responsiveness, which may be related to reduced airway caliber (34) and/or to airway inflammation (42). There has been increased recognition that obesity is a proinflammatory state in humans (43). Although a study of adolescents (15) showed an association between increased BMI and atopy in girls, our findings were independent of the atopic status of the subjects. An increased BMI may also be associated with a sedentary lifestyle leading to increased exposure to indoor aeroallergens (44) and/or with conditions that could worsen preexisting asthma, such as gastroesophageal reflux disease (45). We recognize several limitations to our study. First, our findings may not be applicable to the general population of Anqing. Our results, however, are relevant to a group at high risk for developing asthma (relatives of asthmatic subjects). Given the low prevalence of asthma in rural China (2–4) and the fact that most adults in Anqing are thinner than their western counterparts, a prohibitively large sample size may be needed to study the relation between the spectrum of BMI and asthma in a random sample of this population. Second, our study included only a small proportion of markedly obese subjects (BMI  35 kg/m2) and our results therefore should not be extrapolated to morbidly obese individuals. Third, subjects excluded from the analysis had both a slightly higher BMI and more severe airflow obstruction than those included, likely reducing our statistical power to find an association between overweight and asthma, particularly among men who never smoked. Fourth, although the correlation between BMI and fat mass is  0.9 among young and middle-aged adults (46), BMI may be less valid as an index of adiposity among the elderly (47). Our findings, however, were essentially unchanged after subjects  45 yr were excluded from the analysis. Fifth, we did not control for confounding by dietary habits and physical activity, both of which may influence the relation between BMI and asthma. In summary, both underweight and overweight were associated with asthma among adults in families with asthma living in a predominantly rural province of China. Confirming these associations in longitudinal studies could further our understanding of the pathogenesis, prevention, and management of asthma in both rural and industrialized societies. Acknowledgment : The authors thank the study participants, the staffs of Anhui Medical University and the Anqing Health Bureau, Dr. Bernard Rosner for statistical advice, and Ms. Nancy Voynow for editorial assistance.

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