Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

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Fältnamn	Indikatorer	Metadata
000		05048naa a2200793 4500
001		oai:DiVA.org:uu-208377
003		SwePub
008		130930s2013 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2083772 URI
024	7	a https://doi.org/10.1371/journal.pgen.10035852 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Thun, Gian Andri4 aut
245	1 0	a Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels
264		c 2013-08-22
264	1	b Public Library of Science (PLoS),c 2013
338		a electronic2 rdacarrier
520		a 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.
700	1	a Imboden, Medea4 aut
700	1	a Ferrarotti, Ilaria4 aut
700	1	a Kumar, Ashish4 aut
700	1	a Obeidat, Ma'en4 aut
700	1	a Zorzetto, Michele4 aut
700	1	a Haun, Margot4 aut
700	1	a Curjuric, Ivan4 aut
700	1	a Alves, Alexessander Couto4 aut
700	1	a Jackson, Victoria E.4 aut
700	1	a Albrecht, Eva4 aut
700	1	a Ried, Janina S.4 aut
700	1	a Teumer, Alexander4 aut
700	1	a Lopez, Lorna M.4 aut
700	1	a Huffman, Jennifer E.4 aut
700	1	a Enroth, Stefanu Uppsala universitet,Genomik,Science for Life Laboratory, SciLifeLab4 aut0 (Swepub:uu)stenr451
700	1	a Bosse, Yohan4 aut
700	1	a Hao, Ke4 aut
700	1	a Timens, Wim4 aut
700	1	a Gyllensten, Ulfu Uppsala universitet,Genomik,Science for Life Laboratory, SciLifeLab4 aut0 (Swepub:uu)ulfgyll
700	1	a Polasek, Ozren4 aut
700	1	a Wilson, James F.4 aut
700	1	a Rudan, Igor4 aut
700	1	a Hayward, Caroline4 aut
700	1	a Sandford, Andrew J.4 aut
700	1	a Deary, Ian J.4 aut
700	1	a Koch, Beate4 aut
700	1	a Reischl, Eva4 aut
700	1	a Schulz, Holger4 aut
700	1	a Hui, Jennie4 aut
700	1	a James, Alan L.4 aut
700	1	a Rochat, Thierry4 aut
700	1	a Russi, Erich W.4 aut
700	1	a Jarvelin, Marjo-Riitta4 aut
700	1	a Strachan, David P.4 aut
700	1	a Hall, Ian P.4 aut
700	1	a Tobin, Martin D.4 aut
700	1	a Dahl, Morten4 aut
700	1	a Nielsen, Sune Fallgaard4 aut
700	1	a Nordestgaard, Borge G.4 aut
700	1	a Kronenberg, Florian4 aut
700	1	a Luisetti, Maurizio4 aut
700	1	a Probst-Hensch, Nicole M.4 aut
710	2	a Uppsala universitetb Genomik4 org
773	0	t PLOS Geneticsd : Public Library of Science (PLoS)g 9:8, s. e1003585-q 9:8<e1003585-x 1553-7390x 1553-7404
856	4	u https://uu.diva-portal.org/smash/get/diva2:652245/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
856	4	u https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003585&type=printable
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-208377
856	4 8	u https://doi.org/10.1371/journal.pgen.1003585

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Av författaren/redakt...: Thun, Gian Andri; Imboden, Medea; Ferrarotti, Ilar ...; Kumar, Ashish; Obeidat, Ma'en; Zorzetto, Michel ...; visa fler...; Haun, Margot; Curjuric, Ivan; Alves, Alexessan ...; Jackson, Victori ...; Albrecht, Eva; Ried, Janina S.; Teumer, Alexande ...; Lopez, Lorna M.; Huffman, Jennife ...; Enroth, Stefan; Bosse, Yohan; Hao, Ke; Timens, Wim; Gyllensten, Ulf; Polasek, Ozren; Wilson, James F.; Rudan, Igor; Hayward, Carolin ...; Sandford, Andrew ...; Deary, Ian J.; Koch, Beate; Reischl, Eva; Schulz, Holger; Hui, Jennie; James, Alan L.; Rochat, Thierry; Russi, Erich W.; Jarvelin, Marjo- ...; Strachan, David ...; Hall, Ian P.; Tobin, Martin D.; Dahl, Morten; Nielsen, Sune Fa ...; Nordestgaard, Bo ...; Kronenberg, Flor ...; Luisetti, Mauriz ...; Probst-Hensch, N ...; visa färre...

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