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Title: Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels
Authors: 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.
Gyllensten, U.
Polasek, O.
Wilson, J. F.
Rudan, I.
Hayward, C.
Sandford, A. J.
Deary, I. J.
Koch, B.
Reischl, E.
Schulz, H.
Hui, J.
James, A. L.
Rochat, T.
Russi, E. W.
Jarvelin, M. R.
Strachan, D. P.
Hall, I. P.
Tobin, M. D.
Dahl, M.
Fallgaard Nielsen, S.
Nordestgaard, B. G.
Kronenberg, F.
Luisetti, M.
Probst-Hensch, N. M.
First Published: 22-Aug-2013
Publisher: Public Library of Science
Citation: PLoS Genetics, 2013, 9 (8), e1003585
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.
DOI Link: 10.1371/journal.pgen.1003585
ISSN: 1553-7390
eISSN: 1553-7404
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2013 Thun et al. 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 credited.
Appears in Collections:Published Articles, Dept. of Health Sciences

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