Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

Gian Andri Thun; Medea Imboden; Ilaria Ferrarotti; Ashish Kumar; Ma'en Obeidat; Michele Zorzetto; Margot Haun; Ivan Curjuric; Alexessander Couto Alves; Victoria E Jackson; Eva Albrecht; Janina S Ried; Alexander Teumer; Lorna M Lopez; Jennifer E Huffman; Stefan Enroth; Yohan Bossé; Ke Hao; Wim Timens; Ulf Gyllensten; Ozren Polasek; James Wilson; Igor Rudan; Caroline Hayward; Andrew J Sandford; Ian J Deary; Beate Koch; Eva Reischl; Holger Schulz; Jennie Hui; Alan L James; Thierry Rochat; Erich W Russi; Marjo-Riitta Jarvelin; David P Strachan; Ian P Hall; Martin D Tobin; Morten Dahl; Sune Fallgaard Nielsen; Børge G Nordestgaard; Florian Kronenberg; Maurizio Luisetti; Nicole M Probst-Hensch

doi:10.1371/journal.pgen.1003585

Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

Gian Andri Thun, Medea Imboden, Ilaria Ferrarotti, Ashish Kumar, Ma'en Obeidat, Michele Zorzetto, Margot Haun, Ivan Curjuric, Alexessander Couto Alves, Victoria E Jackson, Eva Albrecht, Janina S Ried, Alexander Teumer, Lorna M Lopez, Jennifer E Huffman, Stefan Enroth, Yohan Bossé, Ke Hao, Wim Timens, Ulf GyllenstenOzren Polasek, James Wilson, Igor Rudan, Caroline Hayward, Andrew J Sandford, Ian J Deary, Beate Koch, Eva Reischl, Holger Schulz, Jennie Hui, Alan L James, Thierry Rochat, Erich W Russi, Marjo-Riitta Jarvelin, David P Strachan, Ian P Hall, Martin D Tobin, Morten Dahl, Sune Fallgaard Nielsen, Børge G Nordestgaard, Florian Kronenberg, Maurizio Luisetti, Nicole M Probst-Hensch

Department of Clinical Medicine

34 Citations (Scopus)

Abstract

Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = -0.068 g/L per minor allele (P = 1.20*10^-12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.

Original language	English
Article number	e1003585
Journal	P L o S Genetics (Online)
Volume	9
Issue number	8
Pages (from-to)	1-16
Number of pages	16
ISSN	1553-7404
DOIs	https://doi.org/10.1371/journal.pgen.1003585
Publication status	Published - Aug 2013

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Thun, G. A., Imboden, M., Ferrarotti, I., Kumar, A., Obeidat, M., Zorzetto, M., Haun, M., Curjuric, I., Couto Alves, A., Jackson, V. E., Albrecht, E., Ried, J. S., Teumer, A., Lopez, L. M., Huffman, J. E., Enroth, S., Bossé, Y., Hao, K., Timens, W., ... Probst-Hensch, N. M. (2013). Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels. P L o S Genetics (Online), 9(8), 1-16. Article e1003585. https://doi.org/10.1371/journal.pgen.1003585

Thun, GA, Imboden, M, Ferrarotti, I, Kumar, A, Obeidat, M, Zorzetto, M, Haun, M, Curjuric, I, Couto Alves, A, Jackson, VE, Albrecht, E, Ried, JS, Teumer, A, Lopez, LM, Huffman, JE, Enroth, S, Bossé, Y, Hao, K, Timens, W, Gyllensten, U, Polasek, O, Wilson, J, Rudan, I, Hayward, C, Sandford, AJ, Deary, IJ, Koch, B, Reischl, E, Schulz, H, Hui, J, James, AL, Rochat, T, Russi, EW, Jarvelin, M-R, Strachan, DP, Hall, IP, Tobin, MD, Dahl, M, Fallgaard Nielsen, S, Nordestgaard, BG, Kronenberg, F, Luisetti, M & Probst-Hensch, NM 2013, 'Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels', P L o S Genetics (Online), vol. 9, no. 8, e1003585, pp. 1-16. https://doi.org/10.1371/journal.pgen.1003585

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title = "Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels",

abstract = "Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = -0.068 g/L per minor allele (P = 1.20*10-12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.",

author = "Thun, {Gian Andri} and Medea Imboden and Ilaria Ferrarotti and Ashish Kumar and Ma'en Obeidat and Michele Zorzetto and Margot Haun and Ivan Curjuric and {Couto Alves}, Alexessander and Jackson, {Victoria E} and Eva Albrecht and Ried, {Janina S} and Alexander Teumer and Lopez, {Lorna M} and Huffman, {Jennifer E} and Stefan Enroth and Yohan Boss{\'e} and Ke Hao and Wim Timens and Ulf Gyllensten and Ozren Polasek and James Wilson and Igor Rudan and Caroline Hayward and Sandford, {Andrew J} and Deary, {Ian J} and Beate Koch and Eva Reischl and Holger Schulz and Jennie Hui and James, {Alan L} and Thierry Rochat and Russi, {Erich W} and Marjo-Riitta Jarvelin and Strachan, {David P} and Hall, {Ian P} and Tobin, {Martin D} and Morten Dahl and {Fallgaard Nielsen}, Sune and Nordestgaard, {B{\o}rge G} and Florian Kronenberg and Maurizio Luisetti and Probst-Hensch, {Nicole M}",

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doi = "10.1371/journal.pgen.1003585",

language = "English",

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T1 - Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

AU - Thun, Gian Andri

AU - Imboden, Medea

AU - Ferrarotti, Ilaria

AU - Kumar, Ashish

AU - Obeidat, Ma'en

AU - Zorzetto, Michele

AU - Haun, Margot

AU - Curjuric, Ivan

AU - Couto Alves, Alexessander

AU - Jackson, Victoria E

AU - Albrecht, Eva

AU - Ried, Janina S

AU - Teumer, Alexander

AU - Lopez, Lorna M

AU - Huffman, Jennifer E

AU - Enroth, Stefan

AU - Bossé, Yohan

AU - Hao, Ke

AU - Timens, Wim

AU - Gyllensten, Ulf

AU - Polasek, Ozren

AU - Wilson, James

AU - Rudan, Igor

AU - Hayward, Caroline

AU - Sandford, Andrew J

AU - Deary, Ian J

AU - Koch, Beate

AU - Reischl, Eva

AU - Schulz, Holger

AU - Hui, Jennie

AU - James, Alan L

AU - Rochat, Thierry

AU - Russi, Erich W

AU - Jarvelin, Marjo-Riitta

AU - Strachan, David P

AU - Hall, Ian P

AU - Tobin, Martin D

AU - Dahl, Morten

AU - Fallgaard Nielsen, Sune

AU - Nordestgaard, Børge G

AU - Kronenberg, Florian

AU - Luisetti, Maurizio

AU - Probst-Hensch, Nicole M

PY - 2013/8

Y1 - 2013/8

N2 - Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = -0.068 g/L per minor allele (P = 1.20*10-12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.

AB - Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = -0.068 g/L per minor allele (P = 1.20*10-12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.

U2 - 10.1371/journal.pgen.1003585

DO - 10.1371/journal.pgen.1003585

M3 - Journal article

C2 - 23990791

SN - 1553-7404

VL - 9

SP - 1

EP - 16

JO - P L o S Genetics (Online)

JF - P L o S Genetics (Online)

IS - 8

M1 - e1003585

ER -

Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

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