Sökning: WFRF:(Ferrarotti Ilaria) > Teumer Alexander > Causal and Syntheti...
Fältnamn | Indikatorer | Metadata |
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000 | 05098naa a22008893a 4500 | |
001 | 22081039 | |
003 | SE-LIBR | |
005 | 20171207151652.0 | |
007 | cr|||||||||||| | |
008 | 171207s2013 sw |||| o |||| ||eng c | |
024 | 7 | a http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2083772 uri |
024 | 7 | a urn:nbn:se:uu:diva-2083772 urn |
024 | 7 | a 10.1371/journal.pgen.10035852 doi |
040 | a S | |
041 | 0 | a eng |
042 | 9 EPLK | |
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 Levelsh [Elektronisk resurs] |
260 | c 2013 | |
500 | a Published | |
506 | 0 | a gratis |
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. | |
650 | 7 | a Medical and Health Sciences2 hsv |
650 | 7 | a Medicin och hälsovetenskap2 hsv |
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, Stefan4 aut |
700 | 1 | a Bosse, Yohan4 aut |
700 | 1 | a Hao, Ke4 aut |
700 | 1 | a Timens, Wim4 aut |
700 | 1 | a Gyllensten, Ulf4 aut |
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 | 1 2 | a Uppsala universitetb Medicinska och farmaceutiska vetenskapsområdet4 pbl |
710 | 1 2 | a Uppsala universitetb Science for Life Laboratory, SciLifeLab4 pbl |
772 | 1 8 | i channel recordw 19753896 |
773 | 0 8 | i Värdpublikationt PLOS Geneticsg 9:8, e1003585x 1553-7390 |
856 | 4 0 | u http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-208377 |
856 | 4 0 | u http://dx.doi.org/10.1371/journal.pgen.1003585 |
856 | 4 0 | u http://uu.diva-portal.org/smash/get/diva2:652245/FULLTEXT01 |
841 | 5 APISa x ab 171210||0000|||||001||||||000000e 1 | |
024 | 7 | 5 APISa urn:nbn:se:uu:diva-2083772 urn |
852 | 5 APISb APIS | |
856 | 4 0 | 5 APISu http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-208377 |
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