SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort.
BACKGROUND
Severe alpha1-antitrypsin (AAT) deficiency is a strong risk factor for COPD. But the impact of gene variants resulting in mild or intermediate AAT deficiency on the longitudinal course of respiratory health remains controversial. There is indication from experimental studies that pro-inflammatory agents like cigarette smoke can interact with these variants and thus increase the risk of adverse respiratory health effects. Therefore, we tested the effect of the presence of a protease inhibitor (Pi) S or Z allele (PiMS and PiMZ) on the change in lung function in different inflammation-exposed subgroups of a large, population-based cohort study.


RESULTS
The SAPALDIA population includes over 4600 subjects from whom SERPINA1 genotypes for S and Z alleles, spirometry and respiratory symptoms at baseline and after 11 years follow-up, as well as proxies for inflammatory conditions, such as detailed smoking history, obesity and high sensitivity C-reactive protein (hs-CRP), were available. All analyses were performed by applying multivariate regression models. There was no overall unfavourable effect of PiMS or PiMZ genotype on lung function change. We found indication that PiZ heterozygosity interacted with inflammatory stimuli leading to an accelerated decline in measures in use as indices for assessing mild airway obstruction. Obese individuals with genotype PiMM had an average annual decline in the forced mid expiratory flow (ΔFEF25-75%) of 58.4 ml whereas in obese individuals with PiMZ it amounted to 92.2 ml (p = 0.03). Corresponding numbers for persistent smokers differed even more strongly (66.8 ml (PiMM) vs. 108.2 ml (PiMZ), p = 0.005). Equivalent, but less strong associations were observed for the change in the FEV1/FVC ratio.


CONCLUSIONS
We suggest that, in addition to the well established impact of the rare PiZZ genotype, one Z allele may be sufficient to accelerate lung function decline in population subgroups characterized by elevated levels of low grade inflammation.
Swiss Tropical and Public Health Institute, Basel, Switzerland.
Gian-Andri
GA
Thun
Ilaria
I
Ferrarotti
Medea
M
Imboden
Thierry
T
Rochat
Margaret
M
Gerbase
Florian
F
Kronenberg
Pierre-Olivier
PO
Bridevaux
Elisabeth
E
Zemp
Michele
M
Zorzetto
Stefania
S
Ottaviani
Erich W
EW
Russi
Maurizio
M
Luisetti
Nicole M
NM
Probst-Hensch
D000293:Adolescent; D000328:Adult; D000397:Air Pollution / Q000009:adverse effects*; D000402:Airway Obstruction / Q000453:epidemiology / Q000209:etiology; D000483:Alleles; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006331:Heart Diseases / Q000453:epidemiology* / Q000209:etiology; D006579:Heterozygote; D006801:Humans; D008137:Longitudinal Studies; D008168:Lung / Q000201:enzymology / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000378:metabolism; D059748:Proteolysis; D015203:Reproducibility of Results; D013147:Spirometry; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics
D011480:Protease Inhibitors; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin