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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Men have higher prevalence rates of chronic obstructive pulmonary disease (COPD) than women, which has been attributed to the historically higher rates of cigarette smoking in males. However, the increased rates of cigarette smoking in females within the last several decades have been associated with steadily increasing rates of COPD in women. As part of a study of the genetics of severe, early-onset COPD, we assembled a group of 84 probands with severe, early-onset COPD (without severe alpha1-antitrypsin deficiency) and 348 of their first-degree relatives. We found a markedly elevated prevalence (71.4%) of females among the early-onset COPD probands. Among the entire group of first-degree relatives of early-onset COPD probands, univariate analysis demonstrated similar spirometric values and bronchodilator responsiveness in males and females; however, among current or ex-smokers, female first-degree relatives had significantly lower FEV1/ FVC (81.4 ± 17.2% in females versus 87.0 ± 12.9% in males, p = 0.009) and significantly greater bronchodilator responsiveness (expressed as percentage of baseline FEV1) (7.7 ± 9.4% pred in females versus 4.1 ± 6.4% pred in males, p = 0.002). Female smoking first-degree relatives were significantly more likely to demonstrate profound reductions in FEV1 (< 40% pred) than male smoking first-degree relatives (p = 0.03). Multivariate analysis, performed with generalized estimating equations, demonstrated that current or ex-smoking female first-degree relatives had significantly greater risk of FEV1 < 80% pred (OR 1.91, 95% CI 1.03- 3.54), FEV1 < 40% pred (OR 3.56, 95% CI 1.08-11.71), and bronchodilator response greater than 10% of baseline FEV1 (OR 4.74, 95% CI 1.91-11.75). These results suggest that women may be more susceptible to the development of severe COPD.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema, is a major cause of
morbidity and mortality in the United States (1, 2). Men have
higher prevalence rates of COPD than women, which has
been attributed to the historically higher rates of cigarette
smoking in males
the major known environmental risk factor for the development of COPD (3). However, the increased
rates of cigarette smoking in females within the last several decades have been associated with steadily increasing rates of
COPD in females (4). Several studies have suggested greater
susceptibility among women to develop COPD by demonstrating larger reductions in FEV1, after adjustment for smoking intensity, among female smokers compared with male smokers (5).
We have studied families of probands with severe, early-onset COPD who do not have severe alpha1-antitrypsin deficiency as part of an ongoing research effort to identify novel genetic risk factors for the development of COPD. In our initial group of 44 severe, early-onset COPD families, we demonstrated increased risk for reduced FEV1, chronic bronchitis, and increased bronchodilator responsiveness among current or ex-smoking first-degree relatives of early-onset COPD probands compared with current or ex-smoking control subjects (8, 9). In these first 44 families with severe, early-onset COPD, recruited primarily from lung transplant and lung volume reduction surgery programs, we noted a surprisingly high proportion of females (79.6%) among the early-onset COPD probands (8). In the present report, we have expanded our study population to include 40 additional early-onset COPD families, and we have assessed the gender-related (also known as sex-related) differences among the 84 early-onset COPD probands and their first-degree relatives for reduced spirometric values, chronic bronchitis, and bronchodilator responsiveness.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Participants
Enrollment of probands with severe early-onset COPD was performed in two phases. In Phase 1 (from September 1994 to October 1996), 44 probands were enrolled; these data have been reported previously (8). In Phase 2 (from January 1998 to June 1999), 40 additional probands were enrolled. In both phases, probands with severe, early-onset COPD were identified primarily from lung transplant programs and lung volume reduction surgery programs at Brigham and Women's Hospital and Massachusetts General Hospital. Pulmonary clinics at these hospitals, pulmonary clinics at the Brockton/West Roxbury VA Hospital, and referrals from outside physicians served as additional sources of early-onset COPD probands. Enrollment criteria for both sets of probands with severe early-onset COPD included FEV1 less than 40% of the predicted value (40% pred), age less than 53 yr, and absence of severe alpha1-antitrypsin deficiency (e.g., PI Z, PI null-null). The arbitrary age threshold of 53 yr was chosen to balance our goal of identifying very young probands with our need to identify an adequate number of probands. In Phase 1 of the study, subjects were eligible only if they had not yet undergone lung volume reduction surgery (LVRS); in Phase 2 of the study, subjects who were post-LVRS were included if preoperative pulmonary function tests were available. For the five post-LVRS probands, only preoperative spirometry results were used in the analysis. Subjects who had undergone lung transplantation were not eligible to participate in either Phase 1 or Phase 2. All available first-degree relatives of the enrolled COPD probands were invited to participate.
Participants gave written informed consent and completed a protocol that included a questionnaire, spirometry (before and after bronchodilator), and a blood sample. The protocol was completed at the subjects' homes (> 90% of cases) or at the Outpatient General Clinical Research Center at Brigham and Women's Hospital. The protocol was approved by the Human Research Committees of Partners Health Care (Brigham and Women's Hospital and Massachusetts General Hospital) and the Brockton/West Roxbury VA Hospital.
Questionnaire
Each participant completed a modified version of the 1978 ATS-DLD
Epidemiology Questionnaire (10), which has been expanded to include questions about passive tobacco smoke exposure and diet (8).
The questionnaire was used in two forms, one for adults (age > 12 yr)
and one for children (age 
12 yr) (completed by their parents). Pack-years of cigarette smoking was calculated as the product of the duration of smoking (in years) and the average number of cigarettes
smoked per day, which was divided by 20 to convert to packs. Chronic
bronchitis was defined from affirmative responses to questionnaire
items for both chronic cough and chronic phlegm production for at
least 3 mo/yr for at least 2 yr. Questions regarding smoking behavior
were not included in the childrens' questionnaire; the 12 children under 12 yr of age were assumed to be lifelong nonsmokers.
Pulmonary Function Tests
Spirometry was performed with a Survey Tach Spirometer (Warren E. Collins, Braintree, MA). The maneuvers were performed in a standardized manner with the subject seated and wearing a nose clip. To obtain three acceptable measures, subjects were asked to perform up to eight attempts. Spirometry was performed in accordance with ATS specifications (11); we report the best FEV1 value, and the FEV1/FVC value from the best-test effort. Height was measured in stocking feet to the nearest 0.5 inch. Pulmonary function test results are expressed as a percentage of the predicted value, using prediction equations from Crapo and coworkers for adult white participants (12). For white participants under age 18 yr, predicted values for FEV1 were determined from Hsu and coworkers (13) and for FEV1/FVC were determined from Knudson and coworkers (14). For the 10 black participants, predicted spirometric values were determined from Hankinson and coworkers (15).
Subjects were asked to avoid bronchodilator use for at least 4 h before spirometry, unless respiratory symptoms required bronchodilator treatment. After the initial spirometry was performed, subjects were given 180 µg (2 puffs) of albuterol through a spacer device, and spirometry was repeated.
Alpha1-Antitrypsin Studies
The PI type of each early-onset COPD proband was determined by isoelectric focusing of dithioerythritol-treated serum at pH 4.2-4.9 in polyacrylamide gels (16). In addition, immunoreactive and functional alpha1-antitrypsin levels were measured for the early-onset COPD probands. Immunoreactive alpha1-antitrypsin levels were measured in serum by enzyme-linked immunosorbent assay (ELISA) with a mouse monoclonal antibody to human alpha1-antitrypsin (17). Functional alpha1-antitrypsin levels were assessed by measurements of serum elastase inhibitory capacity against active site-titrated human leukocyte elastase, essentially as previously described, using the elastase substrate methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide (18).
The PI types of all first-degree relatives of the four early-onset COPD probands who were Z allele heterozygotes (three PI MZ, one PI FZ) and the one proband who was M null were determined by isoelectric focusing as described above.
Statistical Methods
Fisher exact tests, Student t tests, and univariate odds ratios were calculated with the SAS statistical package (SAS Statistical Institute, Cary, NC) on a SUN Microsystem computer. Quantitative values are expressed as means ± standard deviation. Probabilities for sex distributions in probands were determined by using the normal approximation to the binomial distribution (21). Multivariate analysis was performed with generalized estimating equations (GEEs) in SAS (GEE version 2.03, Heidelberg Macro) using both qualitative and quantitative phenotypes to include a common familial correlation, as well as the covariates of age and pack-years of smoking (22). For the GEE analyses of sex effects, odds ratios greater than 1.0 correspond to increased risk in females. p values < 0.05 were considered significant.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Early-onset COPD Probands in Phase 1 and Phase 2: Demographics and Spirometry
Forty-four early-onset COPD probands were enrolled in Phase 1 of the study, and 40 early-onset COPD probands were enrolled in Phase 2 of the study (8). The age, smoking history, and spirometric values of the Phase 1 and Phase 2 probands were similar (Table 1), with profound airflow obstruction in both groups. The predominance of females in Phase 1 (79.6%) was markedly different from the predicted equal sex distribution (p < 0.001). An excess of females was also noted in Phase 2 (62.5%), but the Phase 2 enrollment in isolation only provided a statistical trend toward difference from an equal sex distribution (p = 0.11). Among the entire group of 84 early-onset COPD probands, a significantly greater percentage of female probands (71.4%) than male probands (28.6%) was observed (p < 0.001).
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The PI types of the first 44 probands (38 PI M, 3 PI MS, 2 PI MZ, and 1 FZ) and the next 40 probands (31 PI M, 7 PI MS, 1 PI MZ, and 1 PI S) revealed no subjects with severe alpha1-antitrypsin deficiency; functional and immunological alpha1-antitrypsin measurements revealed that one of the PI M subjects in the second phase had functional and immunological levels in the MZ range, suggesting that he was M null. No other subjects had immunoreactive or functional alpha1-antitrypsin levels that were not reflected by PI type.
Chest computed tomography (CT) scan reports were obtained for 64 of the 84 early-onset COPD probands; three reports provided limited information about lung parenchyma and were excluded. Of the remaining 61 probands with chest CT scans, most of the subjects had reported emphysema. Of the Phase 1 probands, 35 of 36 had evidence of emphysema; of Phase 2 probands, 25 of 25 had evidence of emphysema.
Of the 84 probands, 82 were white and 2 were black. Only three of the early-onset COPD probands were lifelong nonsmokers.
Sex-related Differences in COPD Probands
Demographic and spirometric data from the 84 early-onset COPD probands, from Phases 1 and 2, are stratified by sex in Table 2. The 60 female probands tended to smoke less than the 24 male probands, but this difference was not significant. The female and male probands had similar levels of severe airflow obstruction. A similar percentage of female (43.3%) and male (50.0%) probands met criteria for chronic bronchitis.
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No significant differences were noted for bronchodilator responsiveness between the female and male probands, expressed as a percentage increase in baseline FEV1 (18.1 ± 13.9% in females; 16.0 ± 17.9% in males), an absolute volume difference in FEV1 (84 ± 67 ml in females; 100 ± 107 ml in males), or as a percentage increase in predicted FEV1 (3.16 ± 2.55% in females; 2.66 ± 2.94% in males)
All First-degree Relatives of Early-onset COPD Probands: Univariate Analysis
The 192 female first-degree relatives of early-onset COPD probands were compared with 156 male first-degree relatives for age, pack-years of smoking, spirometry, and bronchodilator responsiveness (as a percentage increase in baseline FEV1) (Table 3). When all male and female first-degree relatives were compared, there were no significant differences in quantitative spirometric measurements or bronchodilator responsiveness. However, when the analysis was limited to current or ex-smokers, female first-degree relatives had significantly lower FEV1/FVC (percent predicted) (p = 0.009) and significantly greater bronchodilator responsiveness (as a percentage of baseline FEV1) (p = 0.002). A trend toward lower FEV1 values in female current or ex-smoking first-degree relatives (74.8 ± 23.6% pred) compared with male current or ex-smoking first-degree relatives (79.6 ± 19.8%) was not significant (p = 0.11).
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The analysis of FEV1 also was performed as a qualitative trait with various thresholds of reduction, including FEV1 < 80% pred, FEV1 < 60% pred, and FEV1 < 40% pred. In the entire group of first-degree relatives, there were no significant differences between males and females for these thresholds. However, with current or ex-smokers only, female first-degree relatives were significantly more likely to have FEV1 < 40% pred (p = 0.03). This tendency toward more severe airflow obstruction among current or ex-smoking female first-degree relatives is demonstrated in Figure 1, in which 14.2% of females and 5.7% of males have FEV1 values below 40% pred.
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Among all first-degree relatives, chronic bronchitis was more common in males (23.7%) than females (13.0%), with p = 0.01. However, when the analysis was limited to current or ex-smokers, the rates of chronic bronchitis in males (31.7%) and females (22.6%) were not significantly different (p = 0.16).
Asthma tended to be diagnosed more frequently in female than male first-degree relatives; however, this difference was not significant in the entire group of first-degree relatives (p = 0.07). When only smokers were considered, females were significantly more likely to be diagnosed with asthma by a physician (p = 0.0005). As might be expected, first-degree relatives who had been diagnosed with asthma by a physician had significantly greater bronchodilator responsiveness than first-degree relatives without such a diagnosis, expressed as a percentage increase in baseline FEV1 (7.87 ± 8.56% in 54 subjects with asthma, 4.33 ± 6.76% in 280 subjects without asthma; p = 0.005), an absolute volume difference in FEV1 (166 ± 154 ml in subjects with asthma, 101 ± 129 ml in subjects without asthma; p = 0.002), or as a percentage increase in predicted FEV1 (4.97 ± 4.52% in subjects with asthma, 3.06 ± 4.00% in subjects without asthma; p = 0.002).
PI types were assessed for first-degree relatives of the five early-onset COPD probands who were carriers of a Z or null allele. No individuals with severe alpha1-antitrypsin deficiency were identified.
Siblings of Early-onset COPD Probands: Univariate Analysis
When only siblings of early-onset COPD probands were considered, the entire group of male and female siblings had similar quantitative values for FEV1, FEV1/FVC, and bronchodilator responsiveness, and similar rates of chronic bronchitis (data not shown). In addition, male and female siblings had similar rates of FEV1 below defined thresholds, including FEV1 < 40% pred, FEV1 < 60% pred, and FEV1 < 80% pred.
When only current or ex-smoking siblings were considered, female siblings had lower FEV1/FVC values (80.6 ± 17.6% pred) than male siblings (86.5 ± 12.7% pred), with p = 0.04, and there was a nonsignificant trend toward lower FEV1 values in female (75.3 ± 24.5% pred) compared with male (80.5 ± 19.6% pred) smoking siblings, with p = 0.22. There was also a trend toward more female smoking siblings with FEV1 < 40% pred (p = 0.09). In addition, female smoking siblings tended to have greater bronchodilator responsiveness expressed as change from baseline FEV1 (7.4 ± 9.4%) than male smoking siblings (4.4 ± 6.6%), with p = 0.06.
First-degree Relatives of Early-onset COPD Probands: Multivariate Analysis
To account for potential familial correlations, as well as the effects of age and pack-years of smoking, generalized estimating equations (GEEs) were used to calculate odds ratios between female and male first-degree relatives for qualitative traits including various levels of reduction in FEV1, chronic bronchitis, and bronchodilator responsiveness (Table 4). When all female and male first-degree relatives were compared, reduced risk of chronic bronchitis in females (odds ratio 0.53 with 95% confidence interval [CI] 0.31 to 0.92, p = 0.03) and increased risk of bronchodilator responsiveness (defined as at least 10% increase from baseline FEV1 after bronchodilator) in females (odds ratio 2.40 with 95% CI 1.14 to 5.06, p = 0.02) were noted. Although females tended to have increased odds of FEV1 below the thresholds of 80% pred or 40% pred, these differences were not significant. However, when the analysis was limited to current or ex-smoking first-degree relatives, females had increased odds of FEV1 below 80% pred (odds ratio 1.91 with 95% CI 1.03 to 3.54, p = 0.04), FEV1 below 40% pred (odds ratio 3.56 with 95% CI 1.08 to 11.71, p = 0.04), and bronchodilator response > 10% of baseline FEV1 (odds ratio 4.74 with 95% CI 1.91 to 11.75, p = 0.001).
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When the analysis was limited to siblings, a similar pattern emerged, with higher odds of reduced FEV1 in females than males, and with larger odds ratios for greater reductions in FEV1 (Table 4). The only significant odds ratio for reduced FEV1 was found when the analysis was limited to current or ex-smoking siblings; smoking female siblings had significantly increased odds of FEV1 below 40% pred (odds ratio 9.27 with 95% CI 1.34 to 64.4, p = 0.03). Increased bronchodilator responsiveness also was more likely among current or ex-smoking female siblings (odds ratio 6.66 with 95% CI 1.98 to 22.4, p = 0.002).
GEE analysis also was performed using FEV1 (% predicted), FEV1/FVC (% predicted), and bronchodilator responsiveness (expressed as a percentage of baseline FEV1) as quantitative variables (Table 5). Among all first-degree relatives, reduced FEV1/FVC (p = 0.02) and increased bronchodilator responsiveness (p = 0.04) were significantly more likely among females; when the analysis was limited to smoking first-degree relatives, reduced FEV1/FVC (p = 0.004) and increased bronchodilator responsiveness (p = 0.0007) were even more likely among females. Among nonsmoking first-degree relatives, there was no significant effect of sex on FEV1 (% predicted) (p = 0.18), FEV1/FVC (% predicted) (p = 0.79), or bronchodilator responsiveness (p = 0.16).
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With the analysis restricted to all siblings, reduced FEV1/ FVC (p = 0.006) and increased bronchodilator responsiveness (p = 0.04) were more likely in female siblings. With smoking siblings only, FEV1 (p = 0.045), FEV1/FVC (p = 0.005), and bronchodilator responsiveness (p = 0.02) all differed by sex.
Potential Etiologies of Female Predominance: Effects of Height
To determine if geometric factors related to lung size, reflected by height, contributed to the tendency for female probands and female first-degree relatives to develop severe airflow obstruction, the heights of probands and their siblings were compared. The 60 female probands (62.8 ± 2.4 in.) were slightly but significantly shorter than the 87 female siblings (63.8 ± 2.6 in.) (p = 0.02). However, when female probands were compared with female siblings without airflow obstruction (and at least 10 pack-years of smoking) or with female siblings with moderate airflow obstruction (defined as FEV1, < 60% pred and FEV1/FVC < 90% pred), no significant differences in height were noted. No significant differences in height were noted between the 24 male probands (68.2 ± 2.8 in.) and the 70 male siblings (69.2 ± 2.5 in.) (p = 0.12); in addition, there were no significant differences in height between the 24 male probands and the 27 male siblings without airflow obstruction (and at least 10 pack-years of smoking) (p = 0.19).
Potential Etiologies of Female Predominance: Effects of Enrollment Rate and Mortality
We attempted to determine if nonparticipation, related to differential enrollment or mortality, influenced the sex-related differences observed in early-onset COPD probands and their first-degree relatives with severe airflow obstruction. To recruit early-onset COPD probands, 103 subjects who appeared to meet the enrollment criteria after physician referral and medical record review were contacted by letter; subsequently, 84 subjects with severe, early-onset COPD were enrolled. Nineteen of the contacted subjects were not enrolled: 3 subjects did not meet eligibility criteria after the visit (one was PI Z, one had interstitial lung disease rather than COPD, and one had spirometry with FEV1 > 40% pred). The other 16 subjects were not enrolled for the following reasons: death after contact (3), post-LVRS (in Phase 1, when post-LVRS patients were not eligible) or post-lung transplant (4), refusal to participate (6), and unable to schedule/contact (3). Of these 16 nonenrolled subjects, there were 12 females and 4 males. Thus, failure to enroll identified potential male probands did not cause the predominance of female probands. We do not have data regarding the sex distribution of potential probands who died before they could be referred to this study.
We collected systematic information regarding the parents of the early-onset COPD probands. One early-onset COPD proband was adopted; 51 of the 166 biological parents of the other 83 probands were enrolled. We were more likely to enroll female parents (n = 33) than male parents (n = 18), with p = 0.02. This difference reflected the higher percentage of deceased fathers (63.9%) than deceased mothers (44.6%) of early-onset COPD probands. Among the deceased parents, the proband questionnaire responses regarding parental diagnosis of COPD, defined as affirmative if the proband indicated that the parent had been diagnosed with chronic bronchitis and/or emphysema, were tabulated. There was a trend toward more COPD in deceased mothers (16 of 32; 50%) than among deceased fathers (18 of 53; 34%), with p = 0.17. Thus, we have not found compelling evidence to suggest that there were more deceased fathers than mothers with COPD within our early-onset COPD families.
We did not collect questionnaire data regarding disease status of siblings; however, during pedigree construction with the family proband, disease status of other family members was noted. Only one sibling (a male) reportedly died of COPD.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Chronic obstructive pulmonary disease has historically occurred more frequently in men, which has been attributed to sex-related differences in smoking patterns in the United States (1, 2). We have assembled a group of 84 probands with severe, early-onset COPD without severe alpha1-antitrypsin deficiency and 348 of their first-degree relatives. In our initial report on 44 early-onset COPD families, we noted a surprisingly high prevalence of females among the early-onset COPD probands (79.6%) (8). We have enrolled 40 additional early-onset COPD families, and have continued to find an elevated prevalence of females among the early-onset COPD probands, with 62.5% females in the Phase 2 group of probands. Although there was a significant predominance of females in the combined group of Phase 1 and Phase 2 probands, the excess of females was not significant in the Phase 2 group of probands. Therefore, we have not demonstrated a significant excess of female early-onset COPD probands in two separate populations, and additional replication will be required.
Possible sex-related effects on first-degree relatives of early-onset COPD probands were examined in the entire group of first-degree relatives (parents, siblings, and children) and in siblings only. For the entire group of first-degree relatives, univariate analysis demonstrated similar spirometric values and bronchodilator responsiveness in males and females; however, when the analysis was limited to current or ex-smokers, female first-degree relatives had significantly lower FEV1/ FVC and significantly greater bronchodilator responsiveness (expressed as a percentage of baseline) (Table 3). Although a trend toward lower FEV1 values was noted in smoking female compared with smoking male first-degree relatives, this difference was not significant. Differences in FEV1 were also assessed by comparing male and female first-degree relatives who met various thresholds of reduction in FEV1. Among current or ex-smokers, female first-degree relatives were significantly more likely to demonstrate profound reductions in FEV1 (below 40% pred).
Multivariate analysis was performed with generalized estimating equations to adjust for age, pack-years of smoking, and common familial correlations in our data. Using threshold values for reduction in FEV1 (% predicted) and increased bronchodilator responsiveness, smoking-related risk to females was demonstrated among first-degree relatives of early-onset COPD probands, in which female smokers had significantly greater risk of FEV1 < 80% pred, FEV1 < 40% pred, and bronchodilator response above 10% of baseline FEV1. Using quantitative phenotype values in multivariate analysis, significantly lower FEV1/FVC (% predicted) and significantly greater bronchodilator responsiveness were found among smoking female first-degree relatives. The failure to find a significant reduction in FEV1 (% predicted) as a quantitative phenotype among smoking female first-degree relatives may relate to the nonnormal and apparently bimodal distribution for FEV1 (% predicted) in this group (Figure 1). A small but substantial percentage of current or ex-smoking female first-degree relatives had FEV1 below 40% pred.
Our data set included only a modest number of first-degree relatives with FEV1 below 40% pred, and our analysis included multiple thresholds of reduction in FEV1, a form of multiple comparisons for which we did not statistically adjust. Therefore, the sex-related effects in first-degree relatives must be interpreted cautiously. However, the results observed in the first-degree relatives support the highly significant results in the probands and suggest that females who have smoked cigarettes have increased susceptibility to severe airflow obstruction. Of interest, no increased risk for chronic bronchitis was noted among females; trends toward higher risk for chronic bronchitis among males, which reached significance only in the comparison of all male and female first-degree relatives, were noted. Thus, we have found evidence of increased risk for severity of airflow obstruction, but not of chronic bronchitis, among female first-degree relatives of early-onset COPD probands.
Previous studies of severe COPD have demonstrated an excess of male subjects (25). However, our data must be interpreted in the context of the relatively recent increase in cigarette smoking among females; previous studies performed in regions where men smoke significantly more than women might not be able to demonstrate increased female susceptibility to severe, early-onset COPD-especially if severe, early- onset COPD is a rare phenomenon. Moreover, our set of probands was younger and more severely affected than previously reported populations with severe COPD (25).
Burrows and coworkers were among the first investigators to suggest increased female susceptibility to a certain form of COPD (29). From studies based on a general population sample, Burrows and colleagues suggested that there were two main types of COPD, chronic asthmatic bronchitis and emphysema (29). Chronic asthmatic bronchitis, which was associated with minimal decline in pulmonary function and low mortality in subjects with modest smoking histories, included a high percentage of females. The emphysematous type, which was associated with rapid decline in pulmonary function and high mortality in subjects with significant smoking histories, included primarily male subjects. The early onset of severely reduced pulmonary function among probands in the current study, most of whom were smokers, indicates that they have a severe clinical course more consistent with Burrow's emphysema group, despite the predominance of females.
Several lines of evidence have suggested that females may have increased susceptibility to COPD. Prescott and colleagues demonstrated that female smokers had greater reductions in FEV1 than males at comparable levels of smoking intensity; they also found increased risk for hospitalization due to COPD in female smokers, after adjusting for smoking intensity (5). In a cross-sectional study of 1,149 adults in Saskatchewan, Chen and colleagues found greater smoking-related declines in FEV1 and FEF25-75% in women than in men (6). In the Vlagtwedde-Vlaardingen Study, Xu and colleagues found significantly greater rates of FEV1 decline among female smokers than among male smokers (7).
There are several possible explanations for the high prevalence of severe COPD in both female probands and their female first-degree relatives in our study. One possibility is that the elevated prevalence of females represents a false-positive result. Although difficult to exclude absolutely, the evidence of increased female susceptibility in both probands and their first-degree relatives makes this unlikely. Differences in lung geometry between the sexes are also possible factors, because females, on average, would be expected to have smaller airways and smaller lung volumes than males (30). However, no consistent differences in height, which would be expected to be proportional to lung volume, were demonstrated between probands and their same sex siblings who did not have airflow obstruction.
Another possible contributor to the observed female predominance in airflow obstruction relates to differences in participation rates, related to sex-related differences in willingness to participate, geographic accessability, and/or mortality. Among early-onset COPD probands, subjects who were contacted about participation and appeared to meet eligibility criteria but who refused to participate were largely female (12 of 16).
We cannot exclude the possibility that potential male probands were not referred to our study because of increased mortality or other factors. In a study of 15,517 individuals who sought emergency room treatment, Sunyer and colleagues demonstrated higher rates of mortality among males who had been diagnosed with COPD (31). From reviewing survival rates in Japan among COPD patients using long-term home oxygen, Miyamoto concluded that women with severe COPD (on supplemental oxygen) survive longer than men with similar disease severity (32). Therefore, it is possible that potential male COPD probands and severely affected male relatives in our early-onset COPD families have shorter life spans and would therefore be less likely to be enrolled in our study. However, among first-degree relatives of early-onset COPD probands, differences in mortality appear to be unlikely. Although one sibling was reported to have died of COPD, we found no systematic differences among COPD rates among deceased parents; in fact, proband questionnaire data demonstrated a nonsignificant trend toward higher rates of COPD in deceased female parents compared with deceased male parents.
A variety of biological mechanisms could contribute to increased female susceptibility to severe COPD. Hormonal differences could be involved, but other sex-related differences are also possible contributors. In previous work in these early-onset COPD pedigrees, we demonstrated that female sex was associated with increased bronchodilator responsiveness in smoking first-degree relatives of COPD probands compared with smoking control subjects (9).
Other studies of airway hyperresponsiveness to methacholine and bronchodilator responsiveness to 
-adrenergic agonists have provided conflicting results regarding sex-related
differences. Females with mild COPD in the Lung Health
Study had greater airway hyperresponsiveness to methacholine than did males with mild COPD, but these differences were
not significant when adjusted for baseline lung function (33).
However, in a general population sample, Paoletti and colleagues
found increased airway hyperresponsiveness to methacholine
among females, independent of baseline lung function (34). In
the IPPB trial, Anthonisen and colleagues found greater bronchodilator responses among women with COPD (35), but in a
general population sample, Dales and coworkers noted similar bronchodilator responsiveness in males and females (36).
In the current study of severe, early-onset COPD families, we have found increased bronchodilator responsiveness, expressed as change from baseline FEV1 after inhaling 180 µg of albuterol, in smoking female first-degree relatives compared with smoking male first-degree relatives. Female first-degree relatives were more likely to be diagnosed with asthma by a physician, and subjects diagnosed with asthma had greater bronchodilator responsiveness than subjects without asthma. Thus, sex-related differences in bronchial reactivity may relate to differential susceptibility to develop severe, early-onset COPD.
One genetic mechanism that could cause an excess of females would be an X-linked dominant gene. However, five of the male probands reported that their fathers had chronic bronchitis and/or emphysema; this apparent male-to-male transmission of susceptibility would not be consistent with an X-linked dominant mechanism. Nonetheless, environmental phenocopies, incomplete penetrance, and genetic heterogeneity are likely involved in the complex condition that is labeled as COPD. Therefore, an X-linked dominant gene acting in a subset of our families cannot be excluded, but we do not have compelling evidence to suggest such a mechanism.
Previously, we demonstrated increased risk for reduced FEV1, chronic bronchitis, and increased bronchodilator responsiveness among current or ex-smoking first-degree relatives of COPD probands compared with current or ex-smoking control subjects (8). We hypothesized that genetic factors interacting with cigarette smoking contributed to the development of COPD. Further investigation will be required to determine if the development of severe COPD in female early-onset COPD probands and their female first-degree relatives represents a genotype-by-gender interaction that confers on women an increased susceptibility to develop severe COPD.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Edwin K. Silverman, M.D., Ph.D., Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115. E-mail: ed.silverman{at}channing.harvard.edu
(Received in original form March 20, 2000 and in revised form July 28, 2000).
Acknowledgments: The authors thank Dana Mandel and Krista McQueeney for assisting with data entry and Jonathan Mosley for helpful discussions. They appreciate assistance from many physicians in recruiting subjects for this study. They are especially thankful for the enthusiastic support for this study from the members of the early-onset COPD families.
Supported by NIH Grants NCRR GCRC MO1 RR02635 to the Brigham and Women's Hospital General Clinical Research Center; HL07427 (Training Grant), HL 61575 (E.K.S.), and an American Lung Association Research Grant (E.K.S.) to the Channing Laboratory, Brigham and Women's Hospital; P50 HL56383 and HL48621 (H.A.C.) to the Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital; and HL46440 (E.J.C.) to the University of Utah Health Sciences Center.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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