SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort

Gian Andri Thun, Ilaria Ferrarotti, Medea Imboden, Thierry Rochat, Margaret Gerbase, Florian Kronenberg, Pierre Olivier Bridevaux, Elisabeth Zemp, Michele Zorzetto, Stefania Ottaviani, Erich W. Russi, Maurizio Luisetti, Nicole M. Probst-Hensch

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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. Methodology and Principal Findings: 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.

Original languageEnglish
Article numbere42728
JournalPLoS One
Volume7
Issue number8
DOIs
Publication statusPublished - Aug 13 2012

Fingerprint

lung function
Heterozygote
heterozygosity
Genotype
Lung
genotype
Alleles
alleles
Health
inflammation
Population
Inflammation
Protease Inhibitors
Smoke
Tobacco Products
C-Reactive Protein
cigarettes
Spirometry
C-reactive protein
Proxy

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Thun, G. A., Ferrarotti, I., Imboden, M., Rochat, T., Gerbase, M., Kronenberg, F., ... Probst-Hensch, N. M. (2012). SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort. PLoS One, 7(8), [e42728]. https://doi.org/10.1371/journal.pone.0042728

SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort. / Thun, Gian Andri; Ferrarotti, Ilaria; Imboden, Medea; Rochat, Thierry; Gerbase, Margaret; Kronenberg, Florian; Bridevaux, Pierre Olivier; Zemp, Elisabeth; Zorzetto, Michele; Ottaviani, Stefania; Russi, Erich W.; Luisetti, Maurizio; Probst-Hensch, Nicole M.

In: PLoS One, Vol. 7, No. 8, e42728, 13.08.2012.

Research output: Contribution to journalArticle

Thun, GA, Ferrarotti, I, Imboden, M, Rochat, T, Gerbase, M, Kronenberg, F, Bridevaux, PO, Zemp, E, Zorzetto, M, Ottaviani, S, Russi, EW, Luisetti, M & Probst-Hensch, NM 2012, 'SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort', PLoS One, vol. 7, no. 8, e42728. https://doi.org/10.1371/journal.pone.0042728
Thun, Gian Andri ; Ferrarotti, Ilaria ; Imboden, Medea ; Rochat, Thierry ; Gerbase, Margaret ; Kronenberg, Florian ; Bridevaux, Pierre Olivier ; Zemp, Elisabeth ; Zorzetto, Michele ; Ottaviani, Stefania ; Russi, Erich W. ; Luisetti, Maurizio ; Probst-Hensch, Nicole M. / SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort. In: PLoS One. 2012 ; Vol. 7, No. 8.
@article{8e25620c515f4f0cb630a3e4722f025e,
title = "SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort",
abstract = "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. Methodology and Principal Findings: 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.",
author = "Thun, {Gian Andri} and Ilaria Ferrarotti and Medea Imboden and Thierry Rochat and Margaret Gerbase and Florian Kronenberg and Bridevaux, {Pierre Olivier} and Elisabeth Zemp and Michele Zorzetto and Stefania Ottaviani and Russi, {Erich W.} and Maurizio Luisetti and Probst-Hensch, {Nicole M.}",
year = "2012",
month = "8",
day = "13",
doi = "10.1371/journal.pone.0042728",
language = "English",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort

AU - Thun, Gian Andri

AU - Ferrarotti, Ilaria

AU - Imboden, Medea

AU - Rochat, Thierry

AU - Gerbase, Margaret

AU - Kronenberg, Florian

AU - Bridevaux, Pierre Olivier

AU - Zemp, Elisabeth

AU - Zorzetto, Michele

AU - Ottaviani, Stefania

AU - Russi, Erich W.

AU - Luisetti, Maurizio

AU - Probst-Hensch, Nicole M.

PY - 2012/8/13

Y1 - 2012/8/13

N2 - 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. Methodology and Principal Findings: 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.

AB - 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. Methodology and Principal Findings: 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.

UR - http://www.scopus.com/inward/record.url?scp=84865057815&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865057815&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0042728

DO - 10.1371/journal.pone.0042728

M3 - Article

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 8

M1 - e42728

ER -