title: Common coding variant inSERPINA1increases the risk for large artery stroke.
abstract: Large artery atherosclerotic stroke (LAS) shows substantial heritability not explained by previous genome-wide association studies. Here, we explore the role of coding variation in LAS by analyzing variants on the HumanExome BeadChip in a total of 3,127 cases and 9,778 controls from Europe, Australia, and South Asia. We report on a nonsynonymous single-nucleotide variant in serpin family A member 1 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A;P= 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 (HDAC9) as a major risk gene for LAS with an association in the 3'-UTR (rs2023938;P= 7.76E-7, OR = 1.28). Using quantitative microscale thermophoresis, we show that M1 (A213) exhibits an almost twofold lower dissociation constant with its primary target human neutrophil elastase (NE) in lipoprotein-containing plasma, but not in lipid-free plasma. Hydrogen/deuterium exchange combined with mass spectrometry further revealed a significant difference in the global flexibility of the two variants. The observed stronger interaction with lipoproteins in plasma and reduced global flexibility of the Val-213 variant most likely improve its local availability and reduce the extent of proteolytic inactivation by other proteases in atherosclerotic plaques. Our results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (357-360). Collectively, our findings point to a functionally relevant balance between lipoproteins, proteases, and AAT in atherosclerosis.
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich 81377, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Malik
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig Maximilians University and Helmholtz Zentrum München, German Center for Lung Research, Munich 81377, Germany.
authors.forename: Therese
authors.initials: T
authors.lastname: Dau
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich 81377, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Gonik
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201.
authors.forename: Anirudh
authors.initials: A
authors.lastname: Sivakumar
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Deredge
authors.affiliation: Systems Biophysics, Physics Department, Nanosystems Initiative Munich and Center for NanoScience, Ludwig-Maximilians-Universität Munich, Munich 80799, Germany.
authors.forename: Evgeniia V
authors.initials: EV
authors.lastname: Edeleva
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig Maximilians University and Helmholtz Zentrum München, German Center for Lung Research, Munich 81377, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Götzfried
authors.affiliation: Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
authors.forename: Sander W
authors.identifier: 0000-0001-6888-1404
authors.initials: SW
authors.lastname: van der Laan
authors.affiliation: Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich 81377, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Beaufort
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.|Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Seixas
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Steve
authors.initials: S
authors.lastname: Bevan
authors.affiliation: Public Health Research Program, Hunter Medical Research Institute, Newcastle, 2305, Australia.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Lincz
authors.affiliation: Public Health Research Program, Hunter Medical Research Institute, Newcastle, 2305, Australia.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Holliday
authors.affiliation: Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, United Kingdom.
authors.forename: Annette I
authors.initials: AI
authors.lastname: Burgess
authors.affiliation: Division of Clinical Neurosciences, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Rannikmäe
authors.affiliation: Institute of Epidemiology and Social Medicine, University of Münster, Muenster 48149, Germany.|Department of Neurology, University of Münster, Muenster 48149, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Minnerup
authors.affiliation: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg 85764, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kriebel
authors.affiliation: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg 85764, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: Institut für Genetische Epidemiologie, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg 85764, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Müller-Nurasyid
authors.affiliation: Institut für Humangenetik, Helmholtz Zentrum München, Munich 85764, Germany.|Institut für Humangenetik, Technische Universität München, Munich 85764, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Danish
authors.initials: D
authors.lastname: Saleheen
authors.affiliation: Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, United Kingdom.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Rothwell
authors.affiliation: Public Health Research Program, Hunter Medical Research Institute, Newcastle, 2305, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Levi
authors.affiliation: Public Health Research Program, Hunter Medical Research Institute, Newcastle, 2305, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Attia
authors.affiliation: Division of Clinical Neurosciences, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Cathie L M
authors.initials: CL
authors.lastname: Sudlow
authors.affiliation: Systems Biophysics, Physics Department, Nanosystems Initiative Munich and Center for NanoScience, Ludwig-Maximilians-Universität Munich, Munich 80799, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Braun
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Wintrode
authors.affiliation: Institute of Epidemiology and Social Medicine, University of Münster, Muenster 48149, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Berger
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, University Hospital, Ludwig Maximilians University and Helmholtz Zentrum München, German Center for Lung Research, Munich 81377, Germany.
authors.forename: Dieter E
authors.initials: DE
authors.lastname: Jenne
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich 81377, Germany; martin.dichgans@med.uni-muenchen.de.|Munich Cluster for Systems Neurology, Munich 81377, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
mesh_terms: D020413:3' Untranslated Regions; D041961:Deuterium Exchange Measurement; D056726:Genetic Association Studies; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D013058:Mass Spectrometry; D058226:Plaque, Atherosclerotic / Q000150:complications* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D020521:Stroke / Q000209:etiology / Q000235:genetics*; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D012097:Repressor Proteins; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase; C486544:HDAC9 protein, human; D006655:Histone Deacetylases
keywords: antitrypsin; genetics; ischemic stroke; large artery stroke; variation