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-Nurasyid; Peter 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

doi:10.1073/pnas.1616301114

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 journal › Article › peer-review

Abstract

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 language	English
Pages (from-to)	3613-3618
Number of pages	6
Journal	Proceedings of the National Academy of Sciences (PNAS)
Volume	114
Issue number	14
Early online date	6 Mar 2017
DOIs	https://doi.org/10.1073/pnas.1616301114
Publication status	Published - 4 Apr 2017

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10.1073/pnas.1616301114

A common coding variant in SERPINA1 increases the risk for large artery stroke
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Catherine Sudlow
- cathie.sudlowed.acuk
- Deanery of Molecular, Genetic and Population Health Sciences - Personal Chair of Neurology and Clinical Epidemiology
- Usher Institute
- Edinburgh Neuroscience
- Centre for Clinical Brain Sciences - Chair of Neurology and Clinical Epidemiology
- Centre for Medical Informatics
- Cerebrovascular Research Group
Person: Academic: Research Active

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Malik, R., Dau, T., Gonik, M., Sivakumar, A., Deredge, D. J., Edeleva, E. V., Götzfried, J., van der Laan, S. W., Pasterkamp, G., Beaufort, N., Seixas, S., Bevan, S., Lincz, L. F., Holliday, E. G., Burgess, A. I., Rannikmäe, K., Minnerup, J., Kriebel, J., Waldenberger, M., ... Dichgans, M. (2017). A common coding variant in SERPINA1 increases the risk for large artery stroke. Proceedings of the National Academy of Sciences (PNAS), 114(14), 3613-3618. https://doi.org/10.1073/pnas.1616301114

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title = "A common coding variant in SERPINA1 increases the risk for large artery stroke",

abstract = "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.",

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

year = "2017",

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doi = "10.1073/pnas.1616301114",

language = "English",

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Malik, R, Dau, T, Gonik, M, Sivakumar, A, Deredge, DJ, Edeleva, EV, Götzfried, J, van der Laan, SW, Pasterkamp, G, Beaufort, N, Seixas, S, Bevan, S, Lincz, LF, Holliday, EG, Burgess, AI, Rannikmäe, K, Minnerup, J, Kriebel, J, Waldenberger, M, Müller-Nurasyid, M, Lichtner, P, Saleheen, D, International Stroke Genetics Consortium, Rothwell, PM, Levi, C, Attia, JR, Sudlow, CLM, Braun, D, Markus, HS, Wintrode, PL, Berger, K, Jenne, DE & Dichgans, M 2017, 'A common coding variant in SERPINA1 increases the risk for large artery stroke', Proceedings of the National Academy of Sciences (PNAS), vol. 114, no. 14, pp. 3613-3618. https://doi.org/10.1073/pnas.1616301114

TY - JOUR

T1 - A common coding variant in SERPINA1 increases the risk for large artery stroke

AU - Malik, Rainer

AU - Dau, Therese

AU - Gonik, Maria

AU - Sivakumar, Anirudh

AU - Deredge, Daniel J

AU - Edeleva, Evgeniia V.

AU - Götzfried, Jessica

AU - van der Laan, Sander W.

AU - Pasterkamp, Gerard

AU - Beaufort, Nathalie

AU - Seixas, Susana

AU - Bevan, Steve

AU - Lincz, Lisa F.

AU - Holliday, Elizabeth G.

AU - Burgess, Annette I.

AU - Rannikmäe, Kristiina

AU - Minnerup, Jens

AU - Kriebel, Jennifer

AU - Waldenberger, Melanie

AU - Müller-Nurasyid, Martina

AU - Lichtner, Peter

AU - Saleheen, Danish

AU - International Stroke Genetics Consortium

AU - Rothwell, Peter M.

AU - Levi, Christopher

AU - Attia, John R

AU - Sudlow, Cathie L. M.

AU - Braun, Dieter

AU - Markus, Hugh S.

AU - Wintrode, Patrick L.

AU - Berger, Klaus

AU - Jenne, Dieter E.

AU - Dichgans, Martin

PY - 2017/4/4

Y1 - 2017/4/4

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1616301114

DO - 10.1073/pnas.1616301114

M3 - Article

SN - 0027-8424

VL - 114

SP - 3613

EP - 3618

JO - Proceedings of the National Academy of Sciences (PNAS)

JF - Proceedings of the National Academy of Sciences (PNAS)

IS - 14

ER -

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

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