Copyright © 1977 by The Johns Hopkins University School of Hygiene and Public Health

Vol. 105, No. 3 Printed in U.S A.

RISK FACTORS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) BERNICE H. COHEN, WILMOT C. BALL, JR., SHIRLEY BRASHEARS, EARL L. DIAMOND, PAUL KREISS, DAVID A. LEVY, HAROLD A. MENKES, SOLBERT PERMUTT AND MELVYN S. TOCKMAN Cohen, B. H. (Johns Hopkins U. School of Hygiene and Public Health, Baltimore, MD 21205), W. C. Ball, Jr., S. Brashears, E. L. Diamond, P. Kreiss, D. A. Levy, H. A. Menkes, S. Permutt and M. S. Tockman. Risk factors in chronic obstructive pulmonary disease. Am J Epidemiol 105:223-232,1977. In a genetic-epidemiologic study of chronic obstructive pulmonary disease (COPD), observations adjusted for age, sex, race, and smoking indicate certain factors to be associated with increased pulmonary function aberrancy, and suggest that they are risk factors for COPD. These presumptive "risk factors" include not only cigarette smoking, but also alpha.-antitrypsin (Pi system) variation, one or more other familial components, low socioeconomic status (SES), and, in whites, ABO blood tyoe (either absence of "B" or presence of "A"). alpha,-antitrypsin; blood groups; bronchitis; emphysema; genetics, human; pulmonary emphysema; smoking; socioeconomic factors

chronic bronchitis) as a clinical and public health problem and the need for a better insight into its etiology, pathogenesis and Received for publication Augus£ 13, 1976, and in natural history are well recognized (1). In a genetic-epidemiologic study of chronic final form October 20, 1976. Abbreviations: 1° relatives, first degree relatives; obstructive pulmonary disease (COPD), ASRS, age, sex, race, and smoking; a,-at, alpha,antitrypsin; CC, closing capacity, (i.e., CC as "meas- an attempt has been made to determine urement" = RV + CV; CC as "test" used = CC/ risk factors for COPD, using pulmonary TLC%); COPD, chronic obstructive pulmonary dis- function aberrancy as an indicator of inease; CV, closing volume; D S B, single breath diffusing capacity; DSs, steady state diffusing capacity; cipient or potential clinical manifestation FEV, forced expiratory volume; FEV,, forced expi- of COPD. An earlier publication (2) deratory volume in one second; FEV,%, (FEV./FVO x scribed the study design of this ongoing 100; FVC, forced vital capacity; P.F., pulmonary function; Pi, protease inhibitor; RV, residual vol- multidisciplinary investigation to examume; SES, socioeconomic status; TLC, total lung ine the role of various genetic and envicapacity: V, volume; V, flow. ronmental factors singly and in combinaFrom the Departments of Epidemiology and Bio- tion and gave some of the study's prelimichemical and Biophysical Sciences, The Johns Hopkins University School of Hygiene and Public nary observations. The purpose of this reHealth, and the Department of Medicine, The Johns port is to confirm the preliminary findings Hopkins University School of Medicine, Baltimore, utilizing rates adjusted for age, sex, race MD 21205. Reprint requests to: Dr. Bernice H. Cohen, Johns and smoking (ASRS) and the larger body Hopkins University School of Hygiene, Department of data now available, and to delineate a of Epidemiology, 615 North Wolfe St., Baltimore, series of presumed risk factors for COPD The significance of chronic obstructive pulmonary disease (emphysema and

MD 21205. The authors express their appreciation to Dr. A. M. Lilienfeld, Dr. L. Gordis, and Dr. L. Naggan for their helpful suggestions, and to the research staff for their invaluable assistance in this project and in preparation of the manuscript. This study was supported in part by the following HEW grants and contracts: NIH-NHLI #HL14135

and N01-HR-12216 from the National Heart and Lung Institute. Dr. B. H. Cohen was also supported in part by Grants No. 5 P01 CA 11489 from the National Cancer Institute and 5 T01 HL05297 from the National Heart and Lung Institute. 223



suggested by these observations. Many of these factors have been implicated individually but have not previously been examined in combination in a single study. Ample evidence exists to indicate the relationship of cigarette smoking to COPD (3, 4). However, since not all cigarette smokers develop COPD and some individuals who have never smoked do, smoking cannot fully explain the causation of this disease. Familial aggregation of emphysema has long been indicated (514), and this was supported by the preliminary findings of this study (2). Moreover, since the early 1960's, the association of alpha,-antitrypsin (a,-at) deficiency with emphysema has become well established (15-27). The identification of the genetically-determined, electrophoretically distinguishable qualitative variants of a,-at has emphasized the need to examine the relationship of those phenotypes and COPD, rather than decreased levels of serum a,-at alone (16, 19-27). The term protease inhibitor, or Pi, has been used for the phenotypes because a r a t inhibits numerous proteases, not just trypsin. Pi M, the most frequent type found in all populations screened, 90 per cent in most Caucasian groups and higher in Africans and Orientals, is considered the "normal" or usual type, whereas "Z" is the well-recognized «i-at deficiency-related gene. (For simplicity, any Pi type other than Pi M is referred to as a "variant" type or "Pi variant".) A few other of the more than 25 identified variant "alleles" also are associated with decreased levels of a,-at (e.g., S, P), while the very rare, presumed silent gene, "null" (Pi"), is postulated to result in complete absence of a,-at. Although Pi Z individuals (homozygous PizPi* or Pi*Pi~) with extremely low trypsin inhibitory capacity (under 40 mg/ml) clearly have an increased risk of developing COPD, even more intriguing is the less well-established and controversial role of heterozygosity for Z and other variants in homozygous and/or heterozygous form (SS, SZ,

MS and FM, etc.) (15-28). Also implicated in COPD have been socioeconomic status (SES), the biologic component of which is unknown, and more specific environmental agents and occupational exposures, which have been amply reviewed by numerous investigators (1, 29). MATERIAL AND METHODS

In the Johns Hopkins investigation, a multifaceted approach was undertaken which combined laboratory and field survey procedures, incorporating epidemiologic, genetic, and clinical techniques, as described in a previous report (2). Briefly, the investigation consists of two projects: a modified case-control and familial aggregation study with both hospital- and community-derived comparison series and an ancillary study involving more intensive kindred analysis (2). All study subjects were brought into the Johns Hopkins Medical Institutions where they were interviewed regarding demographic, medical, family history, and other epidemiologic data, had blood samples drawn, saliva specimens collected and received pulmonary function and other tests. Socioeconomic status (SES) was classified on the basis of place of residence using 1970 census tract data. Since pulmonary function tests may be used to identify and categorize COPD, they are therefore utilized in this study as indicators of incipient or potential clinical manifestation of COPD. Accordingly, subjects were evaluated with tests of forced expiration, single breath nitrogen, and diffusing capacity. The following measurements were made: forced expiratory volume in one second as a percentage of forced vital capacity (FEV,%), FEV,% minus predicted (FEV,% - P), maximum flow (VMAX), maximum flow at 50 per cent vital capacity (V50), maximum flow at 25 per cent vital capacity (V25), closing volume (CV), residual volume (RV), closing capacity (CC = RV + CV), steady state


diffusing capacity (Dss), and single breath diffusing capacity (DSB). Aberrancy of pulmonary function (P.F.) was defined as follows. Based on pooled data on more than 1200 study subjects, excluding patients, results from the tests were divided into five categories, 1 through 5, for each test, with "1" specifying the best performance and "5" the worst; categories "1" through "3" were classified as being likely within the range of normal variation; and "4" and "5" were considered to be aberrant or "abnormal." Only subjects from two community dwelling series and relatives of patients (see below) were used for establishing the categories: 1232 individuals for FEV% - P, 1217 for flow volumes, 1020 for CV, 1196 for D ss , 1199 for RV/TLC and 1048 for DSB. The number of subjects indicated for various tests differs because satisfactory tests are not obtained on every subject nor are all tests satisfactory on any given subject. Unlike other studies in which different sample populations were used to classify individuals for different tests, in this study the same sample of nonpatient subjects was used for developing the classification for all tests. This was done prior to making comparisons with regard to risk factors. The definitions and abbreviations for the various tests and the boundaries for aberrancy are presented in the Appendix. The proportions of individuals with aberrant pulmonary function were compared for subjects with and without the putative factor under examination (e.g., current smokers versus never smokers, Pi M subjects versus Pi variant subjects, etc.). Pulmonary function aberrancy is tabulated for all study subjects except the two groups of index subjects ascertained on the basis of pulmonary disease (COPD cases and lung cancer patients). Age, sex, race, and cigarette smoking were taken into account by a direct method of statistical adjustment (30) except when one of these was the variable of interest in the


comparison. In that case, it was omitted from the adjustment. The study subjects comprise the following:, a) relatives of hospital patients, b) two community dwelling series and c) pooled subjects from various comparison series. The relatives included family members of three groups of hospital patient index subjects (COPD, lung cancer, and nonpulmonary disease patients, respectively) as well as relatives from other comparison series, considered pooled (e.g., figures 1 and 2) or by group (e.g., figure 3). The community dwelling series not selected either because of their biologic relationship to hospital patients or their own health status, but rather as comparison series for COPD patients and their relatives included 1) a group of neighborhood controls matched by age, sex, race and census tract to COPD cases, and 2) a group of employees of the Baltimore Department of Education, predominantly teachers. The pooled comparison subjects included not only subjects from a) and b) above but also the nonpulmonary disease patients, subjects in supplementary comparison series, and the a r a t families. RESULTS AND DISCUSSION

The results summarized below extend the previously reported observations not only in terms of the increased number of subjects and the inclusion of additional factors such as socioeconomic status, etc., but also in the simultaneous consideration of age, sex, race and smoking in all the comparisons. The number of subjects involved in each specific tabulation, category, and/or test is indicated in each figure. In addition to the restrictions imposed by subclassification, groupings, etc., the number of individuals for different tests varies because not all tests are satisfactory for every individual, as has been noted. Figure 1 presents the age-, sex-, and race-adjusted percentages of current smokers and never smokers with pulmo-



,.M ,_OT ,,„ „ , « l l l si,., ,,„. N*

" 1 318 FEV^-P

270 336 VmA%

271 336 V

271 336 *2

244 309 CV


253 319 Oss


2S5 312 RV/TLC

211 264 D

40 20 0

237 299 CC



6 0

% Tb« N-

« I « l « l » l » I « l iSl «fl B.l 22.4 206 357 FCV%-P I

14.8 23.6 205 354 V MIX

* * * • P

Risk factors in chronic obstructive pulmonary disease (COPD).

AMERICAN JOURNAL OF EPIDEMIOLOGY Copyright © 1977 by The Johns Hopkins University School of Hygiene and Public Health Vol. 105, No. 3 Printed in U.S...
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