- Email: [email protected]
Inherited Risk Factors for Chronic Lung Disease
.36 .32
• emphysema a Intermediate a 1AT deficiency
•
• •
.28
•
•24
K
.20
o-1
•
D
.16
D
a
.12
D D
.01
•
D
•
D
cmH 2
•
•
•
D
D
D
Fromm 3. Values of K of the expiratory pressure-volume curve for 12 PiMZ men ( 0 ) compared with values in 12 subjects with clinical and functional evidence of widespread 70 emphysema ( •). The parallel lines indicate the 95 percent confidence limits for values in normal subjects.
.04
0
•
20
30
so
40
et son retentissement en pathologie pulmonaire. Bull Europ Physiopath Resp 14:91-124, 1978
1 Camara M, Martin )P: Le deficit en
alph~-antitrypsine
2 Tattersall SF, Petrik Pereira R, Hunter D, et al: Lung distensibility and airway function in intermediate alpha1 antitrypsin deficiency (PiMZ). Thorax 34:637-646, 1979 3 Eriksson S, Moestrup T, Hiigerstrand 1: Liver, lung and malignant disease in heterozygous (Pi MZ)
111
-antitrypsin
deficiency. Acta Med Scand 198:243-247, 1975 4 Larsson C, Eriksson S, Dirksen H: Smoking and intermediate alpba- 1 antitrypsin deficiency and lung function in middle-aged men. Br Med J 2:922-925, 1977 5 McDonagh DJ, Nathan SP, Knudson RJ, et al: Assessment of alpha- 1 -antitrypsin deficiency heterozygosity as a risk factor in the etiology of emphysema. J Clin Invest 63:299309,1979 6 Glaister DH, Schroter RC, Sudlow MF, et al: Bulk elastic properties of excised lungs and the effect of a transpulmonary pressure gradient. Resp Physiology 17:347-364, 1973 Q. (Souhrada): How many of your patients had asthmaP A. (Pride): There is no reason to think any were asth-
matic; Q. (Woolcock): Did you measure transfer factorP A. (Pride): Yes. No change in transfer factor was found in
those with abnormal curves.
CHEST, 77: 2, FEBRUARY, 1980 SUPPLEMENT
60
)Urs
AGE
Inherited Risk Factors for Chronic Lung Disease* R. Madison, Dr. P.H.; R. Zelmon, M.S.; and Charles Mittman, M.D., F.C.C.P.
L
aurel and Ericksson's1 serendipitous discovery that severe antitrypsin deficiency is a risk factor for chronic obstructive pulmonary disease ( COPD) has been well validated. Approximately ten years ago, Lieberman, 2 Lieberman and Mittman, 8 Kueppers4 and others suggested that intermediate antitrypsin deficiency (PiMZ) might also be a significant risk factor for developing COPD. This factor is of great potential significance since it is found in approximately 3 percent of some populations. It is now well established that the PiMZ type occurs more often than expected in groups of patients with obstructive lung disease. a However, the question remains controversial since some investigators, such as Lebowitz and associates, 8 Webb and associates' and others have reported that lung function tests in community populations show no differences between subjects with the PiM (normals) and variant phenotypes. Others, such as Klayton et al, 8 Cox and associates, 9 and Cooper and colleagues,10 who performed studies in selected and healthy volunt«;ers. have supported our earlier hypothesis. In a recent editorial,a we pointed out some of the complexities involved in studying intermediate antitrypsin deficiency and suggested why properly designed longitudinal studies might be needed to resolve this
•From the City of Hope Medical Center, California State University. Northridge, and University of California, Los Angeles. Dr. Mittmon, 1500 East Duarte RoGtl, Reprint ~~: D1111rte, CallfomltJ 91010
CHRONIC OBSTRUCTIVE LUNG DISEASE 255
Table 1--l.o,..fludinal StudT: Claarta:teriada (IIIean ± SE)
Characteristice Number Age
Years of Observation Paek Years
MZ
M
Phenotype Smoking Category Famlly History
+
Yes
+
No
+
Yes
+ 58 49.44± 6.22
49.42± 3.59 NS
6.16± 0.77
5.03± 1.10
6.65± 0.75 NS
6.04± 0.53
6.27± 0.62
5.04± 0.43
5.93± 0.45
4.86± 0.45
49.30± 8.88 34.62± 11.57
39.18± 11.81 49.38± 10.45
NS
type influenced the rate of change of each lung function test (P < 0.05); the effect of family history was of questionable statistical signfficance (P < 0.10). Interactive effects between family history and phenotype and between smoking and family history inHuenced the change in residual volume (P < 0.05). In all cases where there was a pOsitive family history of lung disease, there has been a more rapid deterioration in function than in those subjects with a negative family history. In those with the MZ phenotype, deterioration was more rapid than in those with the M phenotype. For residual volume, MZ non-smokers with a positive family history had the greatest increase, albeit the numbers in the group are small. Our data suggest the presence of multiple risk factors for chronic obstructive lung disease, speciBcally sex, MZ phenotype and, independently, family history of lung disease. Similar to the study at Johns Hopkins11 and in contrast to the observations in women, changes in lung function in men were more clearly related to variables such as age, smoking and to the other risk factors of interest. Another study12 of risk factors suggests that first degree relatives of patients with known lung disease suffer an excess risk for COPD; our data substantiate this. Unlike those two studies, in our community volunteers we assessed the inHuence of a subject's report of a family history of lung disease in first through third degree relatives. In these subjects, deterioration in lung function seems to occur as rapidly as in first degree relatives of our patients. The study by Cohen et al12 initially suggested that the PiMZ phenotype added to
Table 2--l.onp,..dinal S,_tiT: .4nnual C,._.,. in l.unc Funedon 6,- P'lumDtype, S~ FamiiT HUiory- (IIIean ± SE): Illala
FEVt (ml/yr)
10
+
11
17
Ca~q_,.
and
MZ
M
Yes
+
No 15
17
+
Yes 10
5
+
No
Statistical Significance
8
-42.00±14.61 -9.74±13.57 -20.35±31.82 8.61±21.96 -69.44±28.37 -44.22±24.00 -72.00±28.94 -28.16±21.20+,••
FEFu.7a (L/min/yr) - 6.57± 3.78
RV (ml/yr)
Statistieal
Significance
17 10 17 15 11 10 43.52± 2.69 47.74± 3.15 46.94± 4.31 48.00± 3.43 40.74± 3.42 54.46± 3.97
issue. To this end, a number of years ago, we undertook a longitudinal survey to investigate the inHuence on the development of COPD exerted by antitrypsin phenotype, smoking history, family history of COPD andrelatedness to patients with COPD. The study population was drawn from two sources: relatives of patients referred to the City of Hope with respiratory disease and in tandem, volunteers from nearby churches, colleges, and industry. At the time of entry into the study, none of the subjects was under treatment for lung disease. The study groups included approximately 300 men and women about equally distributed between those with the PiM and PiMZ type. There was less than a 5 percent loss to follow-up each year. At the present time, there are 93 men and 81 women remaining. This paper only reports the data on men, since the factors of particular interest show no effect in the women. Demographic data for 53 M and 40 MZ subjects are shown in Table 1. The subjects have been divided into eight groups based on their phenotype, smoking history and whether or not they reported that an adult relative (first to third degree) bad asthma, bronchitis or emphysema. Neither age, years of observation nor smoking histories differed between the groups. The mean duration of observation was six years. Only eleven of the MZ and six of the M subjects are relatives of patients. Mean annual changes in lung function are presented in Table 2. The inHuence of various factors was assessed by analysis of covariance; shown here are group mean values adjusted for any difference in age and height. Pheno-
Phenotype Smoking Category FamllyHistory N
No
5.57± 5.50
3.82± 2.40 0.01± 3.66 -10.87± 2.40 - 4.112± 2.17 - 7.64± 7.63
- 7.00± 16.5!1 28.29±26.87 - 2.96±25.90 5.20±20.16
Statistieal Significance: Phenotype Family History Famlly History and Phenotype Smoking and Famlly History
P;:5;0.10 P;:5;0.05
258 22nd ASPEN LUNG CONFERENCE
•
+
••
++
57.95±24.63
0.21± 2.90+,••
43.36± 14.17 125.15±42.41 -45.04±30.04+,**,ooo,H
P;:5;0.01
•••
+++
0
00
000
#
H
HI
CHEST, 77: 2, FEBRUARY, 1980 SUPPLEMENT
the effect of relatedness to a patient; their more recent follow-up raises question about this influence.18 Our data show the effect of both factors. It seems clear that in addition to phenotype, other genetically determined biochemical factors will be discovered in the future to explain this added familial relationship.
fu:FERENCES 1 Laurel CB, Eriksson S: The electrophoretic A1 -globu1in pattern of serum in A1 -antitrypsin deficiency. Scand I Clin Lab Invest 15:132-140, 1963 2 Lieberman J: Frequency of heterozygous and homozygous alpha1 -antitrypsin deficiencies in patients with pulmonary emphysema. Clin Res 17:165,1969 3 Lieberman J, Mittman C, Schneider AS: Screening for homozygous and heterozygous alpha1-antitrypsin deficiency. JAMA 210:2055, 1969 4 Kueppers F, Fallat R, Larson RIC: Obstructive hmg disease and alpha, -antitrypsin deficiency gene heterozygosity. Science 165-899, 1969 5 Mittman C: The PiMZ phenotype: Is it a significant rislc factor for the development of chronic obstructive lung disease? Am Rev Respir Dis 118:649-652, 1978 6 Lebowitz MD, Knudsen RJ, Morae JO, et al: Closing volume and flow abnormalities in alpha 1-antitrypsin phenotype groups in a community population. Am Rev Respir Dis 117:179,1978 7 Webb DR, Hyde RW, Schwartz RH, et al: Serum alpha1antitrypsin variants: Prevalence and clinical spirometry. Am Rev Respir Dis 108:918, 1973 8 Klayton R, Fallat R, Cokes AB: Determinants of chronic obstructive pulmonary disease in patients with intermediate levels of alpha1 -antitrypsin. Am Rev Respir Dis 112:71, 1975 9 Cox OW, Hoeppner VH, Levison H: Protease inhibitors in patients with chronic obstructive pulmonary disease: The alpha1 -antitrypsin heterozygote controversy. Am Rev Respir Dis 113:601, 1976 10 Cooper OM, Hoeppner V, Cox D, et al: Lung function in alpha,-antitrypsin heterozygotes (Pi type MZ). Am Rev Respir Dis 110:708, 1974 11 Enjeti S, Hazelwood B, Permutt S, et al: Pulmonary function in young smokers male-female differences. Am Rev Respir Dis 118:667, 1978 12 Cohen BH, Ball WC Jr, Brashears S, et al: Risk factors in chronic obstructive pulmonary disease ( COPD). Am J Epidemiol105:223-231, 1977 13 Cohen BH, Menkes H, Beas W, et al: Multiple factors in airway obstruction. Chest 77:257, 1980
Q. (Zwalich): Because the study population was obtained by their familial relationship to patients with lung disease, will this affect the ability to generalize your conclusions to the total population? A. (Madison): Only a small number of the study population were drawn by their familial relationship to a known patient. Upon analyzing the data, the effect of this potential bias was small. Q. (Burrows): Why were no initial abnormalities in hmg function present in those who deteriorated at a fast rate? A. (Madison): We don't know.
CHEST, 77: 2, FEBRUARY, 1980 SUPPLEMENT
Multiple Factors in Airways Obstruction* Bernice H. Cohen, Ph.D.; Harold A. Menke~, M.D.; Wilma B. Bios, Ph.D.; Gary A. Chose, Ph.D.; Earl L. Diamond, Ph.D.; Carol G. Grave•, Ph.D.; Dtwid A Levy, M.D.; Mary B. Meyer, Sc.M.; Solbert Permutt, M.D.; and Melv!lfl S. Tockmtm, M.D.
A
number of risk factors have been described that influence the development of COPD. It is important not only to identify them, but to assess their relative importance in airflow limitation. The purpose of this report is to present observations on the relationship of various factors in subjects who participated in a genetic epidemiologic study of COPD and to suggest a ranking of their contribution in the development of airflow limitation. STUDY PoPULATION
The Hopkins study population comprises several groups of patients along with their relatives, neighborhood controls, teachers, and other groups. 1 • 2 For the examination of potential rislc factors, all patients were excluded. Thus, for this analysis, only those subjects over 20 years of age and not ascertained on the basis of their own health status were considered: 2,539 subjects as shown in Figure 1. In an interview, questions regarding smoking habits, family history, socioeconomic status, and other factors of epidemiologic interest were included. Tests of pulmonary function included spirometry for assessment of airways obstruction. From blood samples, determinations of ABO blood types and protease inhibitor types were made. The ability to secrete watersoluble ABH antigens into body fluids was determined from saliva samples. A binary vari!lble multiple regression procedures was carried out to adjust for 12 factors: familial component, age, sex, race, smoking history, socioeconomic status, alcohol intake as weD as genetic markers: Pi type ABO blood type, Rh blood type, ABH secretor status, and PTC taste ability. Thus, the mean FEV1S or percentage of persons with aberrant FEV 11 indicated for each factor has been adjusted for the 11 other factors in the matrix. The forced expiratory volume in one second as a percentage of forced vital capacity ( FEV1S) was used as the index of obstruction. An FEV1S of <68 was defined as "aberrant." REsuLTS AND DISCUSSION
Comparisons of Mean Adjusted FEV1S Figure 2 contains the mean adjusted FEV 11 for groups with and without the various risk factors. The greatest difference of means ( 6.6) was found when comparisons of subjects more than 45 years old were made with subjects 20-44 years old. Smokers of one or more packages of cigarettes daily had a mean FEV 11 4.6 •From The Johns Hopkins Univ~ty School of. Medicine and School of Hygiene and Public Health, Baltimore. Supported in part by NIH-NHL Grant HL14153. Contract NOI-HR-12216, National, Heart, Lung, and Blood Insti-
~~
requests: Dr. Cohen, School of Hygiene and Public HBalth, The ]ohm Hopkiru Unioemty, Btiltimore 21205
CHRONIC OBSTRUCTIVE LUNG DISEASE 257
• emphysema a Intermediate a 1AT deficiency
•
• •
.28
•
•24
K
.20
o-1
•
D
.16
D
a
.12
D D
.01
•
D
•
D
cmH 2
•
•
•
D
D
D
Fromm 3. Values of K of the expiratory pressure-volume curve for 12 PiMZ men ( 0 ) compared with values in 12 subjects with clinical and functional evidence of widespread 70 emphysema ( •). The parallel lines indicate the 95 percent confidence limits for values in normal subjects.
.04
0
•
20
30
so
40
et son retentissement en pathologie pulmonaire. Bull Europ Physiopath Resp 14:91-124, 1978
1 Camara M, Martin )P: Le deficit en
alph~-antitrypsine
2 Tattersall SF, Petrik Pereira R, Hunter D, et al: Lung distensibility and airway function in intermediate alpha1 antitrypsin deficiency (PiMZ). Thorax 34:637-646, 1979 3 Eriksson S, Moestrup T, Hiigerstrand 1: Liver, lung and malignant disease in heterozygous (Pi MZ)
111
-antitrypsin
deficiency. Acta Med Scand 198:243-247, 1975 4 Larsson C, Eriksson S, Dirksen H: Smoking and intermediate alpba- 1 antitrypsin deficiency and lung function in middle-aged men. Br Med J 2:922-925, 1977 5 McDonagh DJ, Nathan SP, Knudson RJ, et al: Assessment of alpha- 1 -antitrypsin deficiency heterozygosity as a risk factor in the etiology of emphysema. J Clin Invest 63:299309,1979 6 Glaister DH, Schroter RC, Sudlow MF, et al: Bulk elastic properties of excised lungs and the effect of a transpulmonary pressure gradient. Resp Physiology 17:347-364, 1973 Q. (Souhrada): How many of your patients had asthmaP A. (Pride): There is no reason to think any were asth-
matic; Q. (Woolcock): Did you measure transfer factorP A. (Pride): Yes. No change in transfer factor was found in
those with abnormal curves.
CHEST, 77: 2, FEBRUARY, 1980 SUPPLEMENT
60
)Urs
AGE
Inherited Risk Factors for Chronic Lung Disease* R. Madison, Dr. P.H.; R. Zelmon, M.S.; and Charles Mittman, M.D., F.C.C.P.
L
aurel and Ericksson's1 serendipitous discovery that severe antitrypsin deficiency is a risk factor for chronic obstructive pulmonary disease ( COPD) has been well validated. Approximately ten years ago, Lieberman, 2 Lieberman and Mittman, 8 Kueppers4 and others suggested that intermediate antitrypsin deficiency (PiMZ) might also be a significant risk factor for developing COPD. This factor is of great potential significance since it is found in approximately 3 percent of some populations. It is now well established that the PiMZ type occurs more often than expected in groups of patients with obstructive lung disease. a However, the question remains controversial since some investigators, such as Lebowitz and associates, 8 Webb and associates' and others have reported that lung function tests in community populations show no differences between subjects with the PiM (normals) and variant phenotypes. Others, such as Klayton et al, 8 Cox and associates, 9 and Cooper and colleagues,10 who performed studies in selected and healthy volunt«;ers. have supported our earlier hypothesis. In a recent editorial,a we pointed out some of the complexities involved in studying intermediate antitrypsin deficiency and suggested why properly designed longitudinal studies might be needed to resolve this
•From the City of Hope Medical Center, California State University. Northridge, and University of California, Los Angeles. Dr. Mittmon, 1500 East Duarte RoGtl, Reprint ~~: D1111rte, CallfomltJ 91010
CHRONIC OBSTRUCTIVE LUNG DISEASE 255
Table 1--l.o,..fludinal StudT: Claarta:teriada (IIIean ± SE)
Characteristice Number Age
Years of Observation Paek Years
MZ
M
Phenotype Smoking Category Famlly History
+
Yes
+
No
+
Yes
+ 58 49.44± 6.22
49.42± 3.59 NS
6.16± 0.77
5.03± 1.10
6.65± 0.75 NS
6.04± 0.53
6.27± 0.62
5.04± 0.43
5.93± 0.45
4.86± 0.45
49.30± 8.88 34.62± 11.57
39.18± 11.81 49.38± 10.45
NS
type influenced the rate of change of each lung function test (P < 0.05); the effect of family history was of questionable statistical signfficance (P < 0.10). Interactive effects between family history and phenotype and between smoking and family history inHuenced the change in residual volume (P < 0.05). In all cases where there was a pOsitive family history of lung disease, there has been a more rapid deterioration in function than in those subjects with a negative family history. In those with the MZ phenotype, deterioration was more rapid than in those with the M phenotype. For residual volume, MZ non-smokers with a positive family history had the greatest increase, albeit the numbers in the group are small. Our data suggest the presence of multiple risk factors for chronic obstructive lung disease, speciBcally sex, MZ phenotype and, independently, family history of lung disease. Similar to the study at Johns Hopkins11 and in contrast to the observations in women, changes in lung function in men were more clearly related to variables such as age, smoking and to the other risk factors of interest. Another study12 of risk factors suggests that first degree relatives of patients with known lung disease suffer an excess risk for COPD; our data substantiate this. Unlike those two studies, in our community volunteers we assessed the inHuence of a subject's report of a family history of lung disease in first through third degree relatives. In these subjects, deterioration in lung function seems to occur as rapidly as in first degree relatives of our patients. The study by Cohen et al12 initially suggested that the PiMZ phenotype added to
Table 2--l.onp,..dinal S,_tiT: .4nnual C,._.,. in l.unc Funedon 6,- P'lumDtype, S~ FamiiT HUiory- (IIIean ± SE): Illala
FEVt (ml/yr)
10
+
11
17
Ca~q_,.
and
MZ
M
Yes
+
No 15
17
+
Yes 10
5
+
No
Statistical Significance
8
-42.00±14.61 -9.74±13.57 -20.35±31.82 8.61±21.96 -69.44±28.37 -44.22±24.00 -72.00±28.94 -28.16±21.20+,••
FEFu.7a (L/min/yr) - 6.57± 3.78
RV (ml/yr)
Statistieal
Significance
17 10 17 15 11 10 43.52± 2.69 47.74± 3.15 46.94± 4.31 48.00± 3.43 40.74± 3.42 54.46± 3.97
issue. To this end, a number of years ago, we undertook a longitudinal survey to investigate the inHuence on the development of COPD exerted by antitrypsin phenotype, smoking history, family history of COPD andrelatedness to patients with COPD. The study population was drawn from two sources: relatives of patients referred to the City of Hope with respiratory disease and in tandem, volunteers from nearby churches, colleges, and industry. At the time of entry into the study, none of the subjects was under treatment for lung disease. The study groups included approximately 300 men and women about equally distributed between those with the PiM and PiMZ type. There was less than a 5 percent loss to follow-up each year. At the present time, there are 93 men and 81 women remaining. This paper only reports the data on men, since the factors of particular interest show no effect in the women. Demographic data for 53 M and 40 MZ subjects are shown in Table 1. The subjects have been divided into eight groups based on their phenotype, smoking history and whether or not they reported that an adult relative (first to third degree) bad asthma, bronchitis or emphysema. Neither age, years of observation nor smoking histories differed between the groups. The mean duration of observation was six years. Only eleven of the MZ and six of the M subjects are relatives of patients. Mean annual changes in lung function are presented in Table 2. The inHuence of various factors was assessed by analysis of covariance; shown here are group mean values adjusted for any difference in age and height. Pheno-
Phenotype Smoking Category FamllyHistory N
No
5.57± 5.50
3.82± 2.40 0.01± 3.66 -10.87± 2.40 - 4.112± 2.17 - 7.64± 7.63
- 7.00± 16.5!1 28.29±26.87 - 2.96±25.90 5.20±20.16
Statistieal Significance: Phenotype Family History Famlly History and Phenotype Smoking and Famlly History
P;:5;0.10 P;:5;0.05
258 22nd ASPEN LUNG CONFERENCE
•
+
••
++
57.95±24.63
0.21± 2.90+,••
43.36± 14.17 125.15±42.41 -45.04±30.04+,**,ooo,H
P;:5;0.01
•••
+++
0
00
000
#
H
HI
CHEST, 77: 2, FEBRUARY, 1980 SUPPLEMENT
the effect of relatedness to a patient; their more recent follow-up raises question about this influence.18 Our data show the effect of both factors. It seems clear that in addition to phenotype, other genetically determined biochemical factors will be discovered in the future to explain this added familial relationship.
fu:FERENCES 1 Laurel CB, Eriksson S: The electrophoretic A1 -globu1in pattern of serum in A1 -antitrypsin deficiency. Scand I Clin Lab Invest 15:132-140, 1963 2 Lieberman J: Frequency of heterozygous and homozygous alpha1 -antitrypsin deficiencies in patients with pulmonary emphysema. Clin Res 17:165,1969 3 Lieberman J, Mittman C, Schneider AS: Screening for homozygous and heterozygous alpha1-antitrypsin deficiency. JAMA 210:2055, 1969 4 Kueppers F, Fallat R, Larson RIC: Obstructive hmg disease and alpha, -antitrypsin deficiency gene heterozygosity. Science 165-899, 1969 5 Mittman C: The PiMZ phenotype: Is it a significant rislc factor for the development of chronic obstructive lung disease? Am Rev Respir Dis 118:649-652, 1978 6 Lebowitz MD, Knudsen RJ, Morae JO, et al: Closing volume and flow abnormalities in alpha 1-antitrypsin phenotype groups in a community population. Am Rev Respir Dis 117:179,1978 7 Webb DR, Hyde RW, Schwartz RH, et al: Serum alpha1antitrypsin variants: Prevalence and clinical spirometry. Am Rev Respir Dis 108:918, 1973 8 Klayton R, Fallat R, Cokes AB: Determinants of chronic obstructive pulmonary disease in patients with intermediate levels of alpha1 -antitrypsin. Am Rev Respir Dis 112:71, 1975 9 Cox OW, Hoeppner VH, Levison H: Protease inhibitors in patients with chronic obstructive pulmonary disease: The alpha1 -antitrypsin heterozygote controversy. Am Rev Respir Dis 113:601, 1976 10 Cooper OM, Hoeppner V, Cox D, et al: Lung function in alpha,-antitrypsin heterozygotes (Pi type MZ). Am Rev Respir Dis 110:708, 1974 11 Enjeti S, Hazelwood B, Permutt S, et al: Pulmonary function in young smokers male-female differences. Am Rev Respir Dis 118:667, 1978 12 Cohen BH, Ball WC Jr, Brashears S, et al: Risk factors in chronic obstructive pulmonary disease ( COPD). Am J Epidemiol105:223-231, 1977 13 Cohen BH, Menkes H, Beas W, et al: Multiple factors in airway obstruction. Chest 77:257, 1980
Q. (Zwalich): Because the study population was obtained by their familial relationship to patients with lung disease, will this affect the ability to generalize your conclusions to the total population? A. (Madison): Only a small number of the study population were drawn by their familial relationship to a known patient. Upon analyzing the data, the effect of this potential bias was small. Q. (Burrows): Why were no initial abnormalities in hmg function present in those who deteriorated at a fast rate? A. (Madison): We don't know.
CHEST, 77: 2, FEBRUARY, 1980 SUPPLEMENT
Multiple Factors in Airways Obstruction* Bernice H. Cohen, Ph.D.; Harold A. Menke~, M.D.; Wilma B. Bios, Ph.D.; Gary A. Chose, Ph.D.; Earl L. Diamond, Ph.D.; Carol G. Grave•, Ph.D.; Dtwid A Levy, M.D.; Mary B. Meyer, Sc.M.; Solbert Permutt, M.D.; and Melv!lfl S. Tockmtm, M.D.
A
number of risk factors have been described that influence the development of COPD. It is important not only to identify them, but to assess their relative importance in airflow limitation. The purpose of this report is to present observations on the relationship of various factors in subjects who participated in a genetic epidemiologic study of COPD and to suggest a ranking of their contribution in the development of airflow limitation. STUDY PoPULATION
The Hopkins study population comprises several groups of patients along with their relatives, neighborhood controls, teachers, and other groups. 1 • 2 For the examination of potential rislc factors, all patients were excluded. Thus, for this analysis, only those subjects over 20 years of age and not ascertained on the basis of their own health status were considered: 2,539 subjects as shown in Figure 1. In an interview, questions regarding smoking habits, family history, socioeconomic status, and other factors of epidemiologic interest were included. Tests of pulmonary function included spirometry for assessment of airways obstruction. From blood samples, determinations of ABO blood types and protease inhibitor types were made. The ability to secrete watersoluble ABH antigens into body fluids was determined from saliva samples. A binary vari!lble multiple regression procedures was carried out to adjust for 12 factors: familial component, age, sex, race, smoking history, socioeconomic status, alcohol intake as weD as genetic markers: Pi type ABO blood type, Rh blood type, ABH secretor status, and PTC taste ability. Thus, the mean FEV1S or percentage of persons with aberrant FEV 11 indicated for each factor has been adjusted for the 11 other factors in the matrix. The forced expiratory volume in one second as a percentage of forced vital capacity ( FEV1S) was used as the index of obstruction. An FEV1S of <68 was defined as "aberrant." REsuLTS AND DISCUSSION
Comparisons of Mean Adjusted FEV1S Figure 2 contains the mean adjusted FEV 11 for groups with and without the various risk factors. The greatest difference of means ( 6.6) was found when comparisons of subjects more than 45 years old were made with subjects 20-44 years old. Smokers of one or more packages of cigarettes daily had a mean FEV 11 4.6 •From The Johns Hopkins Univ~ty School of. Medicine and School of Hygiene and Public Health, Baltimore. Supported in part by NIH-NHL Grant HL14153. Contract NOI-HR-12216, National, Heart, Lung, and Blood Insti-
~~
requests: Dr. Cohen, School of Hygiene and Public HBalth, The ]ohm Hopkiru Unioemty, Btiltimore 21205
CHRONIC OBSTRUCTIVE LUNG DISEASE 257