Format

Send to

Choose Destination
PLoS Genet. 2013;9(8):e1003585. doi: 10.1371/journal.pgen.1003585. Epub 2013 Aug 22.

Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels.

Author information

1
Swiss Tropical and Public Health Institute, Basel, Switzerland.

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.

PMID:
23990791
PMCID:
PMC3749935
DOI:
10.1371/journal.pgen.1003585
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

I have read the journal's policy and have the following conflicts: NMPH has received an unrestricted research grant from Talecris GmbH. The grant money was applied to covering part of the salary costs for GAT. IF has received educational and consultancy fees, research grant (eALTA Award), and travel support from Talecris Biotherapeutics GmbH and Kedrion S.p.A. TR has received fees for consulting once in 2011 by Talecris Biotherapeutics GmbH. ML travels to European Respiratory Society and American Thoracic Society congresses have been funded by Talecris Biotherapeutics GmbH, has performed paid lectures for Kedrion S.p.A., has obtained research funds by Talecris Biotherapeutics GmbH, as well as funds for staff members. All other authors declare no conflict of interest.

Publication types, MeSH terms, Substances, Supplementary concept, Grant support

Publication types

MeSH terms

Substances

Supplementary concept

Grant support

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center