uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels
Show others and affiliations
2013 (English)In: PLOS Genetics, ISSN 1553-7404, Vol. 9, no 8, e1003585- p.Article in journal (Refereed) Published
Abstract [en]

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 beta = 20.068 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.

Place, publisher, year, edition, pages
2013. Vol. 9, no 8, e1003585- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-208377DOI: 10.1371/journal.pgen.1003585ISI: 000323830300003OAI: oai:DiVA.org:uu-208377DiVA: diva2:652245
Available from: 2013-09-30 Created: 2013-09-30 Last updated: 2013-09-30Bibliographically approved

Open Access in DiVA

fulltext(2134 kB)182 downloads
File information
File name FULLTEXT01.pdfFile size 2134 kBChecksum SHA-512
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Search in DiVA

By author/editor
Enroth, StefanGyllensten, Ulf
By organisation
GenomicsScience for Life Laboratory, SciLifeLab
In the same journal
PLOS Genetics
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 182 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 238 hits
ReferencesLink to record
Permanent link

Direct link