Background. One of the globally most frequent health problems are obstructive lung
diseases such as asthma and chronic obstructive pulmonary disease. Both of them
show heterogeneous phenotypes and are most commonly diagnosed by lung function
measurements. Apart from several well-established environmental risk factors,
there are also genetic factors which play an important role in determining lung
function. Notably, SERPINA1 gene variants which severely reduce the
alpha1-antitrypsin (AAT) concentration in the blood and consequently lead to a
protease-antiprotease disequilibrium in the lung have been known as risk factors
for several years. Intermediate deficiency of AAT serum level is however assumed
to be a risk factor in only part of the population, but neither is it entirely
clear how to define this range of protein concentration for the general population,
nor do we know which co-factors are health-relevant in intermediately deficient individuals.
Methods. In this work, SAPALDIA, the Swiss cohort study on air pollution and lung disease
in adults, was used to find the essential genetic polymorphisms which determine AAT serum
level. Deficiency ranges for AAT were defined in the general population, and the association
between SERPINA1 deficiency genotypes and age-related lung function decline was investigated
in a comprehensive way. The assessment of gene-environment interactions in terms of pulmonary
health was a central part of this work and embraced also genes beyond SERPINA1. The
environment-related focus was set on factors associated with inflammatory stress, namely smoking,
air pollution, high occupational exposure to vapours, gas, dusts and fumes as well as obesity.
The availability of serum inflammatory markers including AAT, genome-wide data including
additional genotype and sequence information of the SERPINA1 gene as well as very comprehensive
and detailed environmental and respiratory health data made SAPALDIA, unlike any other study,
ideally suited to investigate the aforementioned associations and interactions.
Results. This work found a smaller range of AAT serum level in subjects with intermediate AAT
deficiency than reported in the literature and clarified the role of elevated inflammatory
conditions on AAT serum level. It confirmed uncommon variants in the SERPINA1 locus as the
major genetic determinants of AAT blood level and pointed to some of the inherent weaknesses
of genome-wide association studies. A high burden of inflammatory stress was suggested to
modify the association between intermediate AAT deficiency and lung function decline. Further
genetic interaction with obesity in terms of asthma and with air pollution in terms of lung
function decline was suggested, pointing on the one hand to a still proliferative research
area of gene-environment interactions which has not yet been systematically assessed, but
revealing on the other hand the complexity of drawing firm conclusions from such analyses.
Discussion and Conclusion. In summary, this work may potentially facilitate the diagnostic
procedure for subjects with an assumed AAT deficiency. Although generally not regarded
as a risk group for adverse pulmonary health, individuals with an intermediate AAT
deficiency seem more susceptible to elevated inflammatory conditions compared to the
general population. They would potentially more strongly benefit from measures like
counselling against the uptake of smoking, for healthy diet programmes or improvements
of occupational safety
