Severe, early-onset COPD is rare and only a small percentage of subjects with COPD from the COPDGene Study met our criteria for severe, early-onset COPD at presentation for study enrollment. Nonetheless, early-onset COPD has the potential to provide important insight into COPD risk factors. Our findings from the first 2,500 subjects enrolled in the COPDGene Study are consistent with and support the hypothesis that female sex is important in the development of severe, early-onset COPD as female sex predominated with our case definition, the case definition used by Silverman and colleagues, and others (5
). In comparison with older subjects with COPD, subjects with early-onset COPD had significantly less tobacco exposure in terms of pack-years of smoking. This implies that the magnitude of tobacco exposure is not the primary factor in the development of early-onset COPD, suggesting that additional factors, such as genetic determinants, maternal factors, and their interactions, may be more important. Although we strongly believe that further elucidation of these additional factors is of paramount importance, an alternative explanation for the reduced risk for pack-years of smoking in the early-onset COPDGene subjects [OR, 0.98; 95% CI, 0.96–1.0; P
= 0.03] is that subjects with early-onset COPD are significantly younger than the older subjects with severe COPD and have had less time to accumulate additional pack-years of smoking. The presence of maternal respiratory disease may be among these additional factors that promote acceleration of lung function loss due to smoking in these susceptible individuals. These findings support the importance of investigating specific contributions from mitochondrial and X chromosome genes as well as gene-by-sex interactions.
In the initial, family-based report of early-onset COPD by Silverman and colleagues (5
), first-degree relatives who actively smoked had significantly lower lung function compared with currently smoking or ex-smoking control subjects, suggesting that susceptibility to lung impairment was not explained solely by tobacco smoking. Relatives of probands were 58% more likely to report parental COPD (OR, 4.4; 95% CI, 1.5–12.4) and chronic bronchitis. A subsequent report from this cohort has determined that current or formerly smoking first-degree relatives have more bronchodilator responsiveness (23
). Further data suggesting a genetic predisposition to early-onset COPD have been supported by the finding of familial aggregation in nonsmokers for a spirometric phenotype, FEF25–75
(forced expiratory flow, midexpiratory phase) (24
). This cohort was also the subject of the first and subsequent linkage analyses for COPD-related phenotypes (25
). These findings and our data suggest the excellent potential for investigating early-onset COPD to provide clues to COPD pathogenesis.
Lung growth and development differ by sex. Airway and parenchymal growth are proportional in females in contrast to the dysynapsis that occurs in males, where parenchymal growth exceeds that of the airways. Female lung function growth peaks before that of males. Studies have demonstrated that growth in FEV1
peaks at age 13 in girls (300 ml/yr) and plateaus at age 16, whereas growth in FEV1
peaks at age 14 in boys (400 ml/yr) and plateaus after age 18 (29
). Other factors that affect maximal lung function include height and thoracic width, which are smaller in females. Current or former smoking female first-degree relatives of subjects in the original Boston Early-onset COPD Study were demonstrated to have significantly more bronchodilator responsiveness compared with current or formerly smoking control subjects, defined as the percentage increase from baseline FEV1
(5.8 ± 8.1 vs. 2.9 ± 5.1%, P
< 0.01) (10
). In addition, women with mild COPD in the Lung Health Study were demonstrated to have significantly more bronchial hyperreactivity in response to methacholine challenge (30
), a factor that predicted greater loss in lung function over time (31
). It has been articulated that COPD should be considered a pediatric disease as prenatal and early life exposures in concert with maternal smoking, maternal atopy, and maternal genotype result in alterations in childhood lung health leading to susceptibility to develop COPD in adulthood (32
). Our results are similar to those of Svanes and colleagues, where maternal asthma and maternal smoking were associated with reduced lung function in a population-based study of young adults (33
). Exposure to maternal smoking in utero
has also been demonstrated to affect maximally attainable lung function and airway development (29
), with greatest effect among children with asthma (38
). Although we did not fully evaluate the impact of maternal smoking during pregnancy in our cohort, the problem is not trivial. It has been reported that 10% of pregnant African American women and 16% of pregnant white women report smoking during pregnancy (39
). Early life exposure to tobacco smoke has also been postulated to affect alterations in immune function with increased susceptibility to respiratory disease (40
). Therefore, severe, early-onset COPD may potentially develop in susceptible females because of the intricate interaction of early or decreased attainment of maximal lung function or reduction in lung growth potentiated by maternal behaviors and maternal respiratory history, tobacco smoking, asthma, genetic factors, or hormonal influences.
Our data are unique in the inclusion and evaluation of African American subjects with COPD for the clinical characteristics associated with severe, early-onset COPD. The reason why COPD develops in African Americans at younger ages and with less intense smoking, in comparison with white subjects with COPD, is unknown. There may be multiple potential mechanisms influencing this varied susceptibility to the adverse consequences of cigarette smoking. There are known differences in the pharmacokinetics of nicotine; African Americans have higher serum cotinine levels per cigarette smoked, lower renal clearance of cotinine, higher intake of nicotine per cigarette smoked (41
), and more loss of lung function per cigarette smoked (7
). There is a high prevalence of asthma in African Americans and differences in airway reactivity that when compounded by tobacco smoking could result in disproportionately increased risk for airflow obstruction (42
). Significant differences in occupational and environmental exposures may also potentially exist. The explanation for the early development of COPD in African Americans is likely complex and multifactorial with interactions between social, environmental, and genetic risk factors. The airway wall findings and the lesser degree of CT emphysema in our subjects with severe, early-onset COPD are suggestive that early-onset COPD may be an airway wall–predominant disorder.
Limitations to our study include that the COPDGene Study is not population based and differences in recruitment could have contributed to our findings. Our cross-sectional study design and study questionnaires do not allow us to exclude the possibility that a proportion of the older subjects in the cohort may have initially had early-onset COPD. In fact, 38 (12%) of the older COPD group self-reported a diagnosis of COPD at an age less than 55 years. Seventeen were male (6%) and 21 were female (7%). As a result, our effect estimates are likely underestimations. Thus, the definition of severe early-onset COPD in subjects less than 55 years of age can be definitively applied only to the younger portion of our cohort. Although our sample size of subjects with severe, early-onset COPD is small, we nonetheless found differences by race and sex. Our finding that African American race may also be associated with the development of severe, early-onset COPD is plausible as it has been reported that this group may develop COPD at earlier ages and with shorter durations of smoking (6
). In contrast to the report by Chatila and colleagues (8
), where 42 (3.4%) African American subjects out of the 1,218 total subjects enrolled in the NETT Study were analyzed, our study enrolled 640 (26%) African Americans. We do recognize that overrepresentation of younger African Americans could also impact our findings; however, the prevalence of COPD in African Americans may be influenced by early mortality from other smoking-related disorders (44
). We acknowledge that recall bias for maternal factors such as smoking and lung disease might differ in early-onset compared with later-onset COPD. Importantly, maternal COPD history was associated across all age strata, suggesting maternal history may be a susceptibility marker for severe COPD. In addition, our study does not thoroughly address the role of socioeconomic factors in explaining the occurrence of severe early-onset COPD in African American or white subjects. Last, although known α1
-antitrypsin (AAT)–deficient subjects were not eligible for COPDGene, it is possible that some undiagnosed subjects with AAT deficiency have been included.
Changes in the epidemiology of COPD have shifted the focus from a male-predominant disease to one in which the prevalence and adverse consequences are increasingly affecting females. Our findings in the COPDGene Study support the recommendation that future genetic and molecular studies of COPD should include particular attention to the contribution of maternally inherited factors such as mitochondrial and X chromosome genes, as well as gene-by-sex interactions and gene-by-race interactions.