title: Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels.
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.
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.
authors.forename: Gian Andri
authors.initials: GA
authors.lastname: Thun
authors.forename: Medea
authors.initials: M
authors.lastname: Imboden
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ferrarotti
authors.forename: Ashish
authors.initials: A
authors.lastname: Kumar
authors.forename: Ma'en
authors.initials: M
authors.lastname: Obeidat
authors.forename: Michele
authors.initials: M
authors.lastname: Zorzetto
authors.forename: Margot
authors.initials: M
authors.lastname: Haun
authors.forename: Ivan
authors.initials: I
authors.lastname: Curjuric
authors.forename: Alexessander
authors.initials: A
authors.lastname: Couto Alves
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Jackson
authors.forename: Eva
authors.initials: E
authors.lastname: Albrecht
authors.forename: Janina S
authors.initials: JS
authors.lastname: Ried
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.forename: Lorna M
authors.initials: LM
authors.lastname: Lopez
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Huffman
authors.forename: Stefan
authors.initials: S
authors.lastname: Enroth
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.forename: Ozren
authors.initials: O
authors.lastname: Polasek
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sandford
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.forename: Beate
authors.initials: B
authors.lastname: Koch
authors.forename: Eva
authors.initials: E
authors.lastname: Reischl
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz
authors.forename: Jennie
authors.initials: J
authors.lastname: Hui
authors.forename: Alan L
authors.initials: AL
authors.lastname: James
authors.forename: Thierry
authors.initials: T
authors.lastname: Rochat
authors.forename: Erich W
authors.initials: EW
authors.lastname: Russi
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.forename: David P
authors.initials: DP
authors.lastname: Strachan
authors.forename: Ian P
authors.initials: IP
authors.lastname: Hall
authors.forename: Martin D
authors.initials: MD
authors.lastname: Tobin
authors.forename: Morten
authors.initials: M
authors.lastname: Dahl
authors.forename: Sune
authors.initials: S
authors.lastname: Fallgaard Nielsen
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.forename: Maurizio
authors.initials: M
authors.lastname: Luisetti
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Probst-Hensch
mesh_terms: D003718:Denmark; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008168:Lung / Q000473:pathology; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000235:genetics* / Q000473:pathology; D000515:alpha 1-Antitrypsin / Q000097:blood* / Q000235:genetics
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin