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

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  • 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
  • Andrew J Sandford
  • 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

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    Rights statement: 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.

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    Licence: Creative Commons: Attribution (CC-BY)

Original languageEnglish
Article numbere1003585
Number of pages16
JournalPLoS Genetics
Issue number8
Publication statusPublished - Aug 2013


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

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