Host, Gender, and Early-Life Factors as Risks for Chronic Obstructive Pulmonary Disease

Although smoking results in lung pathology in many, still not all smokers develop chronic obstructive pulmonary disease (COPD). Roughly a quarter of patients with COPD have never smoked. An understanding of both host and environmental factors beyond smoking that contribute to disease development remain critical to understanding disease prevention and ultimately effectively intervene. In this article, we summarize host factors, including genetics and gender, as well as early-life events that contribute to the development of COPD.

Key points

  • Genetic susceptibility may account for as much as 30% of variation in risk for developing chronic obstructive pulmonary disease (COPD), although the attributable risk contribution from most individual genes to the development of COPD is likely small.

  • Female gender may be associated with increased disease susceptibility, both from tobacco smoke but also non–tobacco-related COPD. It is important to remember that environmental and social factors all have the potential to impact disease presentation and progression.

  • It has been estimated that exposures to vapors, gas, dust, or fumes contribute to the population burden of COPD by approximately 15%. Recent evidence also suggests outdoor air pollution may also contribute to COPD development.

  • As many as half of individuals with COPD do not experience accelerated lung decline in adulthood, but rather have low attained peak lung function in early adulthood and normal age-related lung function decline through adulthood. This is likely related to early-life factors including preterm birth, maternal smoking, and respiratory infections in childhood.


Although smoking results in lung pathology in many, still not all smokers develop COPD. Further, roughly a quarter of patients with chronic obstructive pulmonary disease (COPD) have never smoked. Hence, an understanding of both host and environmental factors beyond smoking that contribute to disease development remain critical to disease prevention and ultimately cure. In this article, we summarize host factors, including genetics and gender, as well as early-life events that contribute to the development of COPD.

Host factors


Supporting a role for genetics in COPD susceptibility, family studies, as well as analyses of unrelated individuals suggests a heritable component to the disease, accounting for perhaps 30% of variation in risk. Alpha-1 antitrypsin deficiency is the most well-described genetic association with COPD, caused by a single mutation in the alpha-1-antitrypsin gene (SERPINA1). It has been estimated that A1AT disease accounts for roughly 1% of COPD. Several different gene mutations in this gene have been described, resulting in impaired production of the protein alpha-1 antitrypsin, which inactivates neutrophil elastase, which if left unchecked results in emphysematous destruction of the lung. Even individuals with MZ likely have lower lung function.

Outside of A1AT deficiency, 2 well-described genes associated with lung function and COPD susceptibility include Hedgehog-Interacting Protein (HHIP) and Family with frequency similarity 13 member A (FAM13 A). The CHRNA3/CHRNA5/IREB2 region on chromosome 15q25 has also been associated with COPD susceptibility, although some evidence supports the existence of 2 COPD genome-wide association study (GWAS) loci in that region, one related to nicotine addiction (the nicotinic acetylcholine receptor genes, such as CHRNA3 and CHRNA5) and one unrelated to nicotine addiction (related to IREB2). Several GWAS loci have also been associated with emphysema on computed tomography (CT) imaging. These include the aforementioned CHRNA3 in addition to MMP12 and the AGER region that encodes the sRAGE protein biomarker that has also been strongly associated with emphysema.

As the attributable risk contribution from individual genes to COPD development is relatively small, attempts have been made to combine data from multiple genes to create genetic risk scores. A recent analysis used data from the MESA Lung and SPIROMICS cohorts used 83 single nucleotide polymorphisms (SNPs) to create a genetic risk score that was associated with lower lung function and increased COPD risk, as well as lower lung density, smaller airway lumens, and fewer small airways without effect modification by smoking. The COPD gene study has convincingly associated 20 genetic loci with COPD affection status; additional loci demonstrating associations with various COPD-related phenotypes. Using data from 8 cohorts, a meta-analysis found 2 SNPs (rs112458284 and rs6860095) not previously described in genome-wide studies that were associated with Global Initiative for Chronic Obstructive Lung Disease spirometric stage III–IV COPD at genome-wide significance levels. One was believed to be related to SERPINA1 Z allele. Data from the UK Biobank was used to create a genetic risk score for COPD susceptibility with an odds ratio of 1.24 per 1 SD of the risk score (∼6 alleles). This analysis identified enrichment for genes involved in development, elastic fibers, and epigenetic regulation pathways. A recent investigative group completed a GWAS of 35,735 cases and 222,076 controls from the UK Biobank and studies from the International COPD Genetics Consortium; 82 loci associated with COPD or lung function measures. Forty-seven were previously known, whereas 13 of 35 new loci related principally to lung function. COPD genetic risk loci were associated with quantitative imaging measures and comorbidities supporting COPD genetic susceptibility and heterogeneity. Furthermore, gene-enrichment analysis confirmed the importance of developmental pathways suggesting that a substantial portion of COPD risk may relate to early life. Interestingly, a combinatorial approach has suggested that incorporating a number of COPD risk alleles may improve the ability to define risk of lung function abnormality. Integrated genomics has also been suggested to define potential biologically relevant biomarkers. These approaches may yield insights to potentially druggable targets. At this point, however, genetic testing beyond A1AT remains primarily suited for research as opposed to clinical purposes.


Female gender also appears to modify risk for disease. When examining gender, however, we must think beyond simply the X chromosome and must also consider environmental or social factors that are unique to female gender. Smoking is arguably the biggest risk factor for the development of COPD. Although historically tobacco use was more common among men, women have been rapidly catching up. In the United States, smoking among men peaked in the 1970s followed by women in the 1980s. Global trends are similar. Currently the prevalence of smoking among women varies dramatically by country, ethnicity, and socioeconomic status. However, the absolute number of women who smoke is greater in developing countries, whereas the percentage of smokers who are women is higher in developed countries. Moving forward, unfortunately global estimates suggest the proportion of female smokers will rise from approximately 12% in the first decade of this century to 20% by 2025. Again this increase will be seen more predominantly in developing countries. However, because of lag time between exposure and disease development, the historic trends toward increasing tobacco smoking by women are likely to be reflected in a high COPD burden among women for some time to come.

Smoking habits themselves, the reasons why individuals choose to begin smoking and continue to smoke, differ between genders. The perception of tobacco representing female empowerment (widely promoted via advertising from tobacco companies) and body weight control are 2 reasons for smoking that may influence women more than men. , , Further, some evidence suggests that it is more difficult for women to stop smoking ; and in fact, the US Surgeon General concluded that across all treatments for smoking cessation, women have more difficulty giving up smoking than men, both at short-term and long-term follow-up.

Although not fully understood, several studies also suggest that women may be more susceptible to developing COPD or experience more rapid lung function decline than men with similar tobacco exposures. A meta-analysis examining longitudinal loss of lung function concluded that female current smokers had significantly faster annual decline in forced expiratory volume in 1 second (FEV 1 )% predicted than their male counterparts. One of the largest single studies to examine this question comes from an analysis of nearly 250,000 individuals from the UK Biobank. In this study, the association between airflow obstruction and smoking status was stronger in women (odds ratio [OR] for ex-smokers 1.44; OR current smokers 3.45) than men (OR ex-smokers 1.25; OR current smokers 3.06), P <.001 for the interaction ( Fig. 1 ). Interestingly, the increase in risk at lower doses was also steeper among women. These data suggest it is even more important that women who do smoke quit, which is underscored by data from the Lung Health Study showing that pulmonary function improved more with smoking cessation in women than in men (ΔFEV 1 , 3.7% vs 1.6%; P <.001).

Fig. 1

Spirometry and smoking history of participants in the UK Biobank have similarly shown that women have higher risk of airflow obstruction when compared with men with comparable smoke exposure. Association of airflow obstruction and pack-years among women ( left ) and men ( right ) ex-smokers. Shaded area represents 95% confidence interval. Bars show the distribution of smoking characteristic (pack-years) among ex-smokers.

( Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. All rights reserved. From Amaral AFS, Strachan DP, Burney PGJ, Jarvis DL. Female Smokers Are at Greater Risk of Airflow Obstruction Than Male Smokers. UK Biobank. Am J Respir Crit Care Med. 2017;195(9):1226-1235. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.)

If women are more susceptible, the reason is not fully understood. A study of early-onset COPD families found a very high prevalence (71.4%) of affected women in particular. In this study, female first-degree relatives of probands who were also current or ex-smokers showed significantly greater bronchodilator responsiveness and reduced FEV 1 than their male first-degree relatives. As these differences were seen only among current and ex-smokers, the data suggest a genetic predisposition for smoking-related lung damage that is gender specific. Some have speculated that women may underreport tobacco consumption. However, a meta-analysis of 26 studies found that self-reported smoking data are generally accurate. Another possible explanation for gender differences in tobacco susceptibility is that it is a dose-dependent effect with the lungs of women being smaller; hence, each cigarette represents a proportionately greater exposure for women than men. Social factors including secondhand smoke exposure and differences in cigarette brand preferences have also been hypothesized to play a role. Some have suggested that cigarette metabolites in the lungs of women, sex-related differences in cigarette smoke metabolism, and differences in smoking pattern, with women preferentially engaging the ribcage whereas men engage the abdominal compartment.

Although tobacco smoke exposure remains an important risk factor for developing COPD in both genders, worldwide smoke generated from biomass fuel remains a major risk factor for the development of COPD in women in particular because of greater exposure due to cooking and domestic responsibilities. , Globally, roughly 50% of total households and 90% of rural households rely on biomass fuels as their primary source of domestic energy. As an example of the potential damage, fewer than 1% of women in India smoke, yet the prevalence of COPD in women is estimated between 1.2% and 19% in women. Yet in certain parts of India, nonsmoker women with COPD constituted 65% of all female patients who meet spirometric criteria for COPD. Women exposed to biomass fuel during the age period 5 to 9 years old have higher odds of developing COPD than those exposed at 20 years (OR 2.9 vs 1.3). The problem, however, is not isolated to developing countries. In the CanCOLD (Canadian Cohort Obstructive Lund Disease) study, a population-based study performed in Canada, exposure to passive smoke and biomass fuel for heating were independent risk factors for COPD in women. Although we may not think that air pollution is a significant risk factor for lung impairment among developed countries, more than 11 million US homes are heated with a wood stove. The World Health Organization (WHO) estimates that in North America, exposure to outdoor PM2.5 pollution from residential heating with solid fuels resulted in 9200 deaths in 2010, an increase from 7500 in 1990. Interestingly, women exposed to biomass fuel smoke may have an airway-predominant as opposed to emphysema-predominant phenotype. A recent cohort study in rural India noted that nonsmoking-related COPD (NS-COPD) was seen in younger subjects with equal male-female predominance; NS-COPD was defined by a predominantly small-airway disease phenotype and slower rate of decline in lung function.

Environmental and occupational exposures

The role of environmental exposure in COPD causation is often underrecognised, with the evidence of mechanistic causation poorly understood. It has been estimated that exposures to vapors, gas, dust, or fumes contribute to the population burden of COPD by approximately 15%, whereas the attributable fraction of COPD due to cigarette smoking has been estimated to be between 80% and 90%. Using survey data regarding exposures to vapors, gas, dust, or fumes, one study reported the risk for COPD development among exposed individuals was 2.5 (95% confidence interval [CI], 1.9–3.4). Although certain occupations, such as coal mining, have been well studied, other cottage industries, such as brick making, fish smoking, tobacco curing, and leather working also pose potential respiratory health threats. Of particular concern are the significant number of women worldwide who are employed by or run cottage industries.

Although the relationship between outdoor air pollution and exacerbations of respiratory disease has been reported, evidence now suggests outdoor air pollution may also contribute to COPD development. A UK study of postmen documented the prevalence of COPD to be higher among those working in more polluted areas, independent of personal smoking history. Data from other population studies of individuals living near roads with heavy motor vehicle traffic support these findings, in particular a large Danish study demonstrating a small but positive association between long-term exposure to traffic-related air pollution and incident COPD. Similarly, a recent population-based study in Pisa, Italy, suggested a strong association of COPD incidence with PM10 exposure (OR 2.96; 95% CI 1.50–7.15). Importantly, SPIROMICS investigator recently demonstrated that long-term historical ozone exposure was associated with reduced lung function, greater CT-defined emphysema, worse respiratory symptoms and quality of life, and higher odds of any and severe exacerbations.

Early-life factors

Recent data suggest that although accelerated lung function decline in adulthood is part of the COPD picture, in roughly one-half of individuals, low attained peak lung function in early adulthood contributes to the development of COPD despite normal age-related lung function decline in adulthood ( Fig. 2 ). Hence, early-life risk factors, such as maternal smoking, maternal exposure to air pollution, preterm birth, low birth weight, and childhood respiratory infections, which have all been reported to impair respiratory health later in life, have the potential to increase risk for COPD. In fact, a recent cohort study suggests that as much as 75% of adult COPD burden was associated with modifiable early-life exposures.

Aug 16, 2020 | Posted by in GENERAL | Comments Off on Host, Gender, and Early-Life Factors as Risks for Chronic Obstructive Pulmonary Disease

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