Common coding variant in SERPINA1 increases the risk for large artery stroke

• DOI: 10.1073/pnas.1616301114
• Publication Date: 2017-03-07T02:00:34Z
• Authors: Rainer Malik; Therese Dau; Maria Gonik; Anirudh Sivakumar; Daniel J. Deredge; Evgeniia V. Edeleva; Jessica Götzfried; Sander W. van der...; Gerard Pasterkamp; Nathalie Beaufort; Susana Seixas; Steve Bevan; Lisa F. Lincz; Elizabeth G. Holl...; Annette I. Burgess; Kristiina Rannikmäe; Jens Minnerup; Jennifer Kriebel; Melanie Waldenberger; Martina Müller-Nu...; Peter Lichtner; Danish Saleheen; ; Peter M. Rothwell; Christopher Levi; John Attia; Cathie L. M. Sudlow; Dieter Braun; Hugh S. Markus; Patrick L. Wintrode; Klaus Berger; Dieter E. Jenne; Martin Dichgans; Daniel Woo; Stephanie Debette; Jane Maguire; John W. Cole; Jennifer Majersik; Steve Bevan; Jordi Jimenez-Conde; Jin-Moo Lee; Natalia Rost; Guillaume Pare; Christina Jern; Arne G Lindgren; Israel Fernandez ...
• Keywords: 0301 basic medicine; large artery stroke; C420 - Human genetics; 610; Variation; C431 - Medical genetics; Polymorphism, Single Nucleotide; Histone Deacetylases; Mass Spectrometry; 03 medical and health sciences; XXXXXX - Unknown; Genetics; ischemic stroke; Journal Article; Humans; genetics; Large artery stroke; antitrypsin; C440 Molecular Genetics; 3' Untranslated Regions; Genetic Association Studies; Antitrypsin ; Genetics ; Ischemic Stroke ; Large Artery Stroke ; Variation; 0303 health sciences; alpha 1 antitrypsin; 500; Deuterium Exchange Measurement; C400 - Genetics; stroke; C440 - Molecular genetics; C420 Human Genetics; Plaque, Atherosclerotic; Repressor Proteins; Stroke; C431 Medical Genetics; alpha 1-Antitrypsin; C400 Genetics; variation; Leukocyte Elastase

Significance

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.