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WFRF:(Lopez Lorna M.)
 

Sökning: WFRF:(Lopez Lorna M.) > Causal and Syntheti...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00005098naa a22008893a 4500
00122081039
003SE-LIBR
00520171207151652.0
007cr||||||||||||
008171207s2013 sw |||| o |||| ||eng c
0247 a http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2083772 uri
0247 a urn:nbn:se:uu:diva-2083772 urn
0247 a 10.1371/journal.pgen.10035852 doi
040 a S
0410 a eng
042 9 EPLK
1001 a Thun, Gian Andri4 aut
2451 0a Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levelsh [Elektronisk resurs]
260 c 2013
500 a Published
5060 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 7a Medical and Health Sciences2 hsv
650 7a Medicin och hälsovetenskap2 hsv
7001 a Imboden, Medea4 aut
7001 a Ferrarotti, Ilaria4 aut
7001 a Kumar, Ashish4 aut
7001 a Obeidat, Ma'en4 aut
7001 a Zorzetto, Michele4 aut
7001 a Haun, Margot4 aut
7001 a Curjuric, Ivan4 aut
7001 a Alves, Alexessander Couto4 aut
7001 a Jackson, Victoria E.4 aut
7001 a Albrecht, Eva4 aut
7001 a Ried, Janina S.4 aut
7001 a Teumer, Alexander4 aut
7001 a Lopez, Lorna M.4 aut
7001 a Huffman, Jennifer E.4 aut
7001 a Enroth, Stefan4 aut
7001 a Bosse, Yohan4 aut
7001 a Hao, Ke4 aut
7001 a Timens, Wim4 aut
7001 a Gyllensten, Ulf4 aut
7001 a Polasek, Ozren4 aut
7001 a Wilson, James F.4 aut
7001 a Rudan, Igor4 aut
7001 a Hayward, Caroline4 aut
7001 a Sandford, Andrew J.4 aut
7001 a Deary, Ian J.4 aut
7001 a Koch, Beate4 aut
7001 a Reischl, Eva4 aut
7001 a Schulz, Holger4 aut
7001 a Hui, Jennie4 aut
7001 a James, Alan L.4 aut
7001 a Rochat, Thierry4 aut
7001 a Russi, Erich W.4 aut
7001 a Jarvelin, Marjo-Riitta4 aut
7001 a Strachan, David P.4 aut
7001 a Hall, Ian P.4 aut
7001 a Tobin, Martin D.4 aut
7001 a Dahl, Morten4 aut
7001 a Nielsen, Sune Fallgaard4 aut
7001 a Nordestgaard, Borge G.4 aut
7001 a Kronenberg, Florian4 aut
7001 a Luisetti, Maurizio4 aut
7001 a Probst-Hensch, Nicole M.4 aut
7101 2a Uppsala universitetb Medicinska och farmaceutiska vetenskapsområdet4 pbl
7101 2a Uppsala universitetb Science for Life Laboratory, SciLifeLab4 pbl
7721 8i channel recordw 19753896
7730 8i Värdpublikationt PLOS Geneticsg 9:8, e1003585x 1553-7390
8564 0u http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-208377
8564 0u http://dx.doi.org/10.1371/journal.pgen.1003585
8564 0u http://uu.diva-portal.org/smash/get/diva2:652245/FULLTEXT01
841 5 APISa x ab 171210||0000|||||001||||||000000e 1
0247 5 APISa urn:nbn:se:uu:diva-2083772 urn
852 5 APISb APIS
8564 05 APISu http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-208377

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