The development of COPD in the setting of severe AAT deficiency is highly variable. Host factors such as modifier genes probably interact with environmental factors to contribute to an individual's manifestations of lung disease. Many people are tested for AAT deficiency due to existing lung disease, and this ascertainment scheme biases observations of the natural history of lung function. Previous studies have raised concerns about the influence of ascertainment bias in studies designed to investigate determinants of lung disease in PI ZZ subjects. One important and unique feature of our cohort is that it represents the first large collection of sibling pairs and family members systematically enrolled on the basis of homozygosity for the Z mutation of the SERPINA1 gene, irrespective of the presence of lung or liver disease. Evaluating the predictors of airflow obstruction in the non‐index individuals in such families may provide insight into predictors of variable severity of COPD in AAT deficient individuals.
Our study suggests that asthma, pneumonia, chronic bronchitis and sex have the largest impact on non‐index subjects with AAT deficiency, many of whom still have lung function in the normal range; asthma and chronic bronchitis are not significant predictors in index individuals. When we focused on identifying risk factors for severe COPD, sex, smoking, pneumonia and chronic bronchitis all had odds ratios >2, and these predictors could identify important pathways for genetic modifiers of COPD in AAT deficiency. A childhood history of asthma, although present in a small number of individuals in our study, was associated with the most severe COPD. Although the individual predictors that we investigated have been suggested as predictors of lung function in some previous studies of AAT deficient individuals, this observed difference in families for predictors of lung function between index and non‐index individuals, as well as men and women, provides insight into the variable susceptibility to COPD in AAT deficiency as well as familial discordance for COPD, despite similar smoking histories.
Cigarette smoking is the most important risk factor for the development of emphysema in AAT deficient individuals, but the variability and dose‐response to this exposure suggest the importance of genetic and other environmental factors. Similar to other investigators,13,14,15,16,17,18
we have observed that smoking was often but not always associated with lower FEV1
. Individuals with AAT deficiency who smoke often develop obstructive lung disease at an early age,13,14,16
but we have corroborated that some current and former smokers have preserved lung function.4
We also observed that sex, smoking and a history of pneumonia were important predictors of lung function in index and non‐index individuals. Chronic bronchitis and a physician diagnosis of asthma contributed to the severity of COPD in non‐index individuals. This observation in non‐index individuals, who tend to have higher FEV1
, provides an insight into the types of symptoms (cough, sputum and wheeze) that may portend susceptibility to lung function decline and COPD among ZZ individuals. Further research will be required to determine whether the increased risk of airflow obstruction in individuals with symptoms of chronic cough and phlegm and episodes of pneumonia could relate to bronchiectasis, which is also associated with AAT deficiency.19
Airway hyperresponsiveness and wheezing may be susceptibility phenotypes for worse lung outcomes, especially in the setting of cigarette smoking. In this cohort, 25% had at least a 10% increase in FEV1
and this reversibility was associated with lower lung function. Although emphysema/COPD may be misdiagnosed as asthma in adults with AAT deficiency,20
a diagnosis of asthma in childhood is unlikely to be due to emphysema/COPD. In individuals in Sweden identified with AAT deficiency as part of neonatal screening, 15% were given a diagnosis of asthma by age 22 and 29% self‐reported recurrent wheezing episodes.21
We observed that a physician diagnosis of asthma before age 16 was strongly associated with reduced FEV1
and severe COPD in adulthood, suggesting asthma (or the presence of asthma‐like symptoms) may define a particularly susceptible subset of PI ZZ individuals. In our study the most profound reduction in lung function was among men with a history of asthma before age 16, and a physician diagnosis of asthma remained an important predictor of airflow obstruction in non‐index men (but not women), which suggests that one potential difference between men and women with COPD may be related to lung inflammation. Inflammation associated with asthma may portend the development of airflow obstruction in later life through limiting the level of maximally achieved lung function or through accelerating lung function decline. Previous studies have shown an association between asthmatic features and COPD in adults with AAT deficiency,5,6,22
and asthmatic symptoms in adults have previously been suggested as a risk factor for lower FEV1
Pneumonia was associated with lower FEV1
and severe airflow obstruction in individuals with AAT deficiency in our study cohort, although it is unclear if pneumonia precedes or follows COPD. Although pneumonia has been suggested as a risk factor for COPD in the past,4
this has not been a consistent observation.3,15
Interestingly, we observed that, although a physician diagnosis of pneumonia was associated with lower lung function in both men and women, a report of pneumonia before age 16 was not, suggesting that pneumonia may be a consequence rather than a cause of COPD.
Sex has been reported as a risk factor for lower FEV1
in some but not all previous studies of AAT deficient individuals. An increased risk for lung disease in men has been noted by various investigators.3,13,14
No significant effect was observed by Silverman and colleagues,4
but the small sample size in that study may have limited the ability to detect a gender effect. The higher number of men among identified PI Z individuals has been attributed to higher rates of smoking among men,18,23
but our current data and previous data in non‐smokers3
suggest that there are sex‐based differences for susceptibility to lung disease in AAT deficiency in addition to cigarette smoking. Men had lower spirometric measurements than women in our cohort, regardless of index case or smoking status, age and/or a history of pneumonia, chronic bronchitis or asthma. Larsson and colleagues14
noted a low prevalence of COPD in non‐smoking women in their cohort. Tobin and colleagues13
observed wide variability in lung function among PI Z non‐smokers but also noted that older female non‐smokers had less limitation of lung function than older males. They also noted that FEV1
percentage predicted was lower in men than women and that the effects of sex and smoking on multiple regression analysis were significant, although there was no significance of a sex‐by‐smoking interaction term.13
Although we, like Tobin and colleagues, did not observe a significant interaction term for smoking and sex (results not shown), it may be more likely that the significant interaction will be modifier gene‐by‐sex factors. Other environmental exposures, such as occupational dust exposures, are also important to consider as potential modifiers of the risk for COPD in AAT deficiency. Piitulainen and colleagues3
observed that male non‐smokers were at increased risk for low lung function compared with female non‐smokers. In a sex‐stratified analysis they observed that age was an independent predictor of FEV1
in both men and women but “wheeziness” was a predictor only in men. In our study, men had lower spirometric measures than women and, among the non‐index cases, symptoms of chronic bronchitis and a physician diagnosis of asthma were significant predictors of severe airflow obstruction only for men. Although this may be because of the lower number of non‐index women with airflow obstruction, as noted above, men with AAT deficiency may have increased inflammation associated with asthma and chronic bronchitis symptoms.
There have been many previous studies of risk factors for reduced lung function in PI ZZ individuals, but our study has several unique features. First, only subjects with a confirmed PI ZZ genotype were considered; second, we used standardised spirometry with the same spirometry system across centres to minimise technical variability from the spirometric measures; third, we collected a large number of non‐index cases and adjusted for potential familial correlations within the multivariate models. Limitations include a potential effect of recall bias for childhood asthma as well as physician's diagnosis of pneumonia and asthma. There is also the potential for misclassification bias associated with COPD diagnosed as asthma. We do not have corroborating data such as chest radiological studies, sputum assessments for pneumonia or methacholine testing for asthma. Ascertainment bias is also important to consider as a limitation, although focusing on the observations in the non‐index subjects partially broaches this bias. Although a complete understanding of the natural history of lung disease in PI ZZ individuals will require enrolling subjects without ascertainment bias from a large general population sample, our current study confirms that (in addition to cigarette smoking) sex, asthma, chronic bronchitis and possibly pneumonia are risk factors for reduced FEV1 and severe airflow obstruction in PI ZZ individuals. These results suggest that, among those with severe AAT deficiency, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.
Genetic modifiers are likely to be important in the variable development of COPD in individuals with severe AAT deficiency. We have identified several determinants of COPD in a large collection of siblings homozygous at the PI ZZ risk locus. Using family‐based genetic methods, these epidemiological factors may identify important genetic modifiers (such as asthma genetic modifiers of COPD in PI ZZ individuals) and key interactions (such as gene‐by‐sex) that will provide new insights into the pathophysiology and natural history of lung disease in PI ZZ individuals with AAT deficiency.