A common coding variant in SERPINA1 increases the risk for large artery stroke

Rainer Malik, Therese Dau, Maria Gonik, Anirudh Sivakumar, Daniel J Deredge, Evgeniia V. Edeleva, Jessica Götzfried, Sander W. van der Laan, Gerard Pasterkamp, Nathalie Beaufort, Susana Seixas, Steve Bevan, Lisa F. Lincz, Elizabeth G. Holliday, Annette I. Burgess, Kristiina Rannikmäe, Jens Minnerup, Jennifer Kriebel, Melanie Waldenberger, Martina Müller-NurasyidPeter Lichtner, Danish Saleheen, International Stroke Genetics Consortium, Peter M. Rothwell, Christopher Levi, John R Attia, Cathie L. M. Sudlow, Dieter Braun, Hugh S. Markus, Patrick L. Wintrode, Klaus Berger, Dieter E. Jenne, Martin Dichgans

Research output: Contribution to journalArticlepeer-review


Common single-amino acid variations of proteins are traditionally regarded as functionally neutral polymorphisms because these substitutions are mostly located outside functionally relevant surfaces. In this study, we present an example of a functionally relevant coding sequence variation, which, as we show here, confers risk for large artery atherosclerotic stroke. The single-residue variation M1(A213V) in serpin family A member 1 (SERPINA1) [encoding alpha-1 antitrypsin (AAT)] is situated outside the protease-reactive inhibitory loop and is found in a β-turn on the protein surface. We show that the Ala-to-Val exchange in the gate region of AAT alters its functional dynamics toward neutrophil elastase in the presence of complex lipid-containing plasma and also affects the overall structural flexibility of the protein.
Original languageEnglish
Pages (from-to)3613-3618
Number of pages6
JournalProceedings of the National Academy of Sciences (PNAS)
Issue number14
Early online date6 Mar 2017
Publication statusPublished - 4 Apr 2017


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