Lung function in the general population : the complex interplay of variants in "Serpina1" and other genes with the environment

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.