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Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels
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 c...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749935/ https://www.ncbi.nlm.nih.gov/pubmed/23990791 http://dx.doi.org/10.1371/journal.pgen.1003585 |
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author | Thun, Gian Andri Imboden, Medea Ferrarotti, Ilaria Kumar, Ashish Obeidat, Ma'en Zorzetto, Michele Haun, Margot Curjuric, Ivan Couto Alves, Alexessander Jackson, Victoria E. Albrecht, Eva Ried, Janina S. Teumer, Alexander Lopez, Lorna M. Huffman, Jennifer E. Enroth, Stefan Bossé, Yohan Hao, Ke Timens, Wim Gyllensten, Ulf Polasek, Ozren Wilson, James F. Rudan, Igor Hayward, Caroline Sandford, Andrew J. Deary, Ian J. Koch, Beate Reischl, Eva Schulz, Holger Hui, Jennie James, Alan L. Rochat, Thierry Russi, Erich W. Jarvelin, Marjo-Riitta Strachan, David P. Hall, Ian P. Tobin, Martin D. Dahl, Morten Fallgaard Nielsen, Sune Nordestgaard, Børge G. Kronenberg, Florian Luisetti, Maurizio Probst-Hensch, Nicole M. |
author_facet | Thun, Gian Andri Imboden, Medea Ferrarotti, Ilaria Kumar, Ashish Obeidat, Ma'en Zorzetto, Michele Haun, Margot Curjuric, Ivan Couto Alves, Alexessander Jackson, Victoria E. Albrecht, Eva Ried, Janina S. Teumer, Alexander Lopez, Lorna M. Huffman, Jennifer E. Enroth, Stefan Bossé, Yohan Hao, Ke Timens, Wim Gyllensten, Ulf Polasek, Ozren Wilson, James F. Rudan, Igor Hayward, Caroline Sandford, Andrew J. Deary, Ian J. Koch, Beate Reischl, Eva Schulz, Holger Hui, Jennie James, Alan L. Rochat, Thierry Russi, Erich W. Jarvelin, Marjo-Riitta Strachan, David P. Hall, Ian P. Tobin, Martin D. Dahl, Morten Fallgaard Nielsen, Sune Nordestgaard, Børge G. Kronenberg, Florian Luisetti, Maurizio Probst-Hensch, Nicole M. |
author_sort | Thun, Gian Andri |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3749935 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37499352013-08-29 Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels Thun, Gian Andri Imboden, Medea Ferrarotti, Ilaria Kumar, Ashish Obeidat, Ma'en Zorzetto, Michele Haun, Margot Curjuric, Ivan Couto Alves, Alexessander Jackson, Victoria E. Albrecht, Eva Ried, Janina S. Teumer, Alexander Lopez, Lorna M. Huffman, Jennifer E. Enroth, Stefan Bossé, Yohan Hao, Ke Timens, Wim Gyllensten, Ulf Polasek, Ozren Wilson, James F. Rudan, Igor Hayward, Caroline Sandford, Andrew J. Deary, Ian J. Koch, Beate Reischl, Eva Schulz, Holger Hui, Jennie James, Alan L. Rochat, Thierry Russi, Erich W. Jarvelin, Marjo-Riitta Strachan, David P. Hall, Ian P. Tobin, Martin D. Dahl, Morten Fallgaard Nielsen, Sune Nordestgaard, Børge G. Kronenberg, Florian Luisetti, Maurizio Probst-Hensch, Nicole M. PLoS Genet Research Article 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. Public Library of Science 2013-08-22 /pmc/articles/PMC3749935/ /pubmed/23990791 http://dx.doi.org/10.1371/journal.pgen.1003585 Text en © 2013 Thun et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Thun, Gian Andri Imboden, Medea Ferrarotti, Ilaria Kumar, Ashish Obeidat, Ma'en Zorzetto, Michele Haun, Margot Curjuric, Ivan Couto Alves, Alexessander Jackson, Victoria E. Albrecht, Eva Ried, Janina S. Teumer, Alexander Lopez, Lorna M. Huffman, Jennifer E. Enroth, Stefan Bossé, Yohan Hao, Ke Timens, Wim Gyllensten, Ulf Polasek, Ozren Wilson, James F. Rudan, Igor Hayward, Caroline Sandford, Andrew J. Deary, Ian J. Koch, Beate Reischl, Eva Schulz, Holger Hui, Jennie James, Alan L. Rochat, Thierry Russi, Erich W. Jarvelin, Marjo-Riitta Strachan, David P. Hall, Ian P. Tobin, Martin D. Dahl, Morten Fallgaard Nielsen, Sune Nordestgaard, Børge G. Kronenberg, Florian Luisetti, Maurizio Probst-Hensch, Nicole M. Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels |
title | Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels |
title_full | Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels |
title_fullStr | Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels |
title_full_unstemmed | Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels |
title_short | Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels |
title_sort | causal and synthetic associations of variants in the serpina gene cluster with alpha1-antitrypsin serum levels |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749935/ https://www.ncbi.nlm.nih.gov/pubmed/23990791 http://dx.doi.org/10.1371/journal.pgen.1003585 |
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