Gibson, Greg and Thun, Gian Andri and Imboden, Medea and Ferrarotti, Ilaria and Kumar, Ashish and Obeidat, Ma'en and Zorzetto, Michele and Haun, Margot and Curjuric, Ivan and Couto Alves, Alexessander and Jackson, Victoria E. and Albrecht, Eva and Ried, Janina S. and Teumer, Alexander and Lopez, Lorna M. and Huffman, Jennifer E. and Enroth, Stefan and Bossé, Yohan and Hao, Ke and Timens, Wim and Gyllensten, Ulf and Polasek, Ozren and Wilson, James F. and Rudan, Igor and Hayward, Caroline and Sandford, Andrew J. and Deary, Ian J. and Koch, Beate and Reischl, Eva and Schulz, Holger and Hui, Jennie and James, Alan L. and Rochat, Thierry and Russi, Erich W. and Jarvelin, Marjo-Riitta and Strachan, David P. and Hall, Ian P. and Tobin, Martin D. and Dahl, Morten and Fallgaard Nielsen, Sune and Nordestgaard, Børge G. and Kronenberg, Florian and Luisetti, Maurizio and Probst-Hensch, Nicole M. (2013) Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels. PLoS Genetics, 9 (8). e1003585. ISSN 1553-7404

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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 b = 20.068 g/L per minor allele (P = 1.20*10212). 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.

Item Type:	Article
Keywords:	Causal; Synthetic; Associations; Variants; SERPINA Gene Cluster; Alpha1-antitrypsin Serum Levels;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17255
Identification Number:	https://doi.org/10.1371/journal.pgen.1003585
Depositing User:	Lorna Lopez
Date Deposited:	29 May 2023 15:47
Journal or Publication Title:	PLoS Genetics
Publisher:	Public Library of Science
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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