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

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

Authors :
Gian Andri Thun
Medea Imboden
Ilaria Ferrarotti
Ashish Kumar
Ma'en Obeidat
Michele Zorzetto
Margot Haun
Ivan Curjuric
Alexessander Couto Alves
Victoria E Jackson
Eva Albrecht
Janina S Ried
Alexander Teumer
Lorna M Lopez
Jennifer E Huffman
Stefan Enroth
Yohan Bossé
Ke Hao
Wim Timens
Ulf Gyllensten
Ozren Polasek
James F Wilson
Igor Rudan
Caroline Hayward
Andrew J Sandford
Ian J Deary
Beate Koch
Eva Reischl
Holger Schulz
Jennie Hui
Alan L James
Thierry Rochat
Erich W Russi
Marjo-Riitta Jarvelin
David P Strachan
Ian P Hall
Martin D Tobin
Morten Dahl
Sune Fallgaard Nielsen
Børge G Nordestgaard
Florian Kronenberg
Maurizio Luisetti
Nicole M Probst-Hensch
Source :
PLoS Genetics, Vol 9, Iss 8, p e1003585 (2013)
Publication Year :
2013
Publisher :
Public Library of Science (PLoS), 2013.

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

Subjects

Subjects :
Genetics
QH426-470

Details

Language :
English
ISSN :
15537390 and 15537404
Volume :
9
Issue :
8
Database :
Directory of Open Access Journals
Journal :
PLoS Genetics
Publication Type :
Academic Journal
Accession number :
edsdoj.36501165dac147af9410c1caf6504760
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pgen.1003585