This study, which analyses the possible relationship between AATD and risk of lung cancer in never-smokers, is based on one of the largest sample sizes reported to date, in that it included 457 cases and 631 controls. No higher risk of lung cancer was found among individuals who were homozygous or heterozygous carriers of the most frequent AAT deficiency alleles (PI*S, PI*Z) as compared to carriers of the normal genotype (PI*MM). Similarly, no effect was observed for subjects by sex or age group.
These results are in contrast with those obtained in a previous study published in 2015 by Torres-Durán et al. , using a similar population, albeit with a smaller sample size, in which an increased risk of LC was found in homozygous S allele carriers (PI*SS) (OR: 4.64 95% CI = 1.08–19.92). This risk was higher in women (OR: 7.58: 95% CI 1.40–40.87) and subjects with exposure to ETS (OR: 12.10; 95% CI 1.18–123.77).
In the last 30 years, different studies have been conducted with the principal aim of analysing the possible increase in risk of LC associated with AATD. They have fundamentally been undertaken in the USA and Europe, and among these mention should be made of the results of Yang et al. , who conducted a case–control study in the USA, which observed a 70% increase in risk of LC associated with AAT deficiency genotypes, with predominance of adenocarcinoma and squamous cell carcinoma lineages. In a case–control study conducted on the Serbian population, Topic et al.  observed that being a carrier of an AAT deficiency genotype increased the risk of squamous cell carcinoma (OR: 4.51 IC95% = 1.66–12.29); however, this association was not found in adenocarcinoma and large cell carcinoma histology.. Recently, a systematic review was published , which included 6 studies with more than 4,000 patients and whose results suggest the existence of a relationship between AATD and risk of LC. This risk could be higher in individuals exposed to tobacco smoke and in those with diagnosis of COPD. This might be linked to the effects of AATD at a pulmonary level and their close relationship with tobacco use, which is the principal factor implicated in early development of emphysema in patients with severe AATD. Indeed, some studies have highlighted the association between pulmonary emphysema and risk of lung cancer .
Different mechanisms have been proposed which could be implicated in this association . Among these, one of the most important relates to pulmonary damage caused by the decrease in plasma AAT concentrations, which gives rise to a protease-antiprotease imbalance and, in turn, favours the development of an inflammatory state that promotes carcinogenesis and tumour progression . Another of the mechanisms proposed would be air trapping associated with pulmonary emphysema, since this could increase the time of contact with agents inhaled through the airway, thus increasing exposure to environmental carcinogens  and, by extension, to all those contained in tobacco smoke.
Analysing the possible causes that would account for the fact that the current study does not show an association between risk of LC and being a carrier of AAT deficiency alleles, when compared to the results of the previous study , various factors could be considered: firstly, the current study found a smaller percentage of S allele carriers than did the previous study (21.9% currently vs. 25.9%), and the same applies to Z allele carriers (3.7% currently vs. 5.2%). Likewise, the percentage of patients exposed to ETS was also smaller.
The current study also found no evidence of an increased risk of LC associated with AATD in the analysis by subgroups according to age or sex. In the previous study , this risk was higher among women (OR: 7.58 95% CI 1.40–40.87; p = 0.02), though it has to be said that the analysis was not performed in men due to the small number included (18.9%), a percentage which in the current study rose slightly, i.e., to 20.3%. To our knowledge, there is no epidemiological evidence to show that the distribution of carriers of AAT deficiency alleles in a given geographical area might be different in the two sexes. That said, however, the fact that women had a higher incidence of S allele carriers might account for these results. In contrast, the current study’s larger sample size is an indicator of greater statistical power when it comes to the validity of its results.
We analysed the characteristics of the nine cases of LC in which the PI*SS genotype was found, in view of its previously observed association with an increased risk of LC. In this sample, all but one of the cases of LC associated with a PI*SS genotype appeared in women, with 55% being adenocarcinomas and 45% being squamous cell carcinoma. Adenocarcinoma is the most frequent histological type in never-smokers, in some series attaining percentages of more than 70% . Taken overall, of the cases included in this study, 77.5% were adenocarcinomas and only 7.7% corresponded to squamous cell carcinoma. Yet these relative frequencies were different in this subgroup of patients who were carriers of the PI*SS genotype, with the high proportion of squamous cell carcinoma warranting special mention, in view of the fact that these patients were never-smokers. These data agree with the results of previous studies that have analysed the relationship between AATD and LC: Topic et al.  identified an increased risk of squamous cell carcinoma (OR = 4.51; 95% CI = 1.66–12.29) in carriers of the PI*MZ and PI*MS genotypes; Yang et al.  observed an increased risk of adenocarcinoma in carriers of AAT deficiency alleles, bronchoalveolar carcinoma (OR = 2; 95% CI = 1.1–3.8) and squamous cell carcinoma in particular (OR = 2.5; 95% CI = 1.2–5.3); and Li et al.  also detected 55.3% of adenocarcinomas. None of these 9 patients suffered from COPD, and high-resolution computed tomography showed no presence of emphysema.
The advantages of our study are, firstly, its sample size, which is one of the largest reported to date and practically doubles the number used in our previously conducted study, including a greater number of men which thus made it possible to analyse their risk, unlike the earlier study. The exclusive use of never-smokers meant that possible biases in the interpretation of results attributable to tobacco use could be ruled out. Indeed, this and the previous study are the only ones published to date to have analysed the risk of LC associated with AATD in never-smokers. A further advantage was having access to measurements of residential radon levels, which constitute the main risk factor for LC in never-smokers and thus enabled the association between AATD and LC to be established with greater certainty.
The principal limitation of our study is common to all studies of rare diseases, in this case AATD, and relates to the low overall prevalence of the disorder, which means that the number of carriers of deficiency alleles is inevitably small irrespective of the size of sample used. Furthermore, not having plasma AAT levels means that there is the possibility that some of the genotypes rated normal by PCR might correspond to rare or null deficiency alleles, though this finding would be somewhat exceptional. Lastly, respiratory function or emphysema status was not specifically analysed in this study, something that might have been of interest in order to examine its role as an intermediary agent in lung cancer among never-smokers potentially associated with AAT deficiency.