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Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):3613-3618. doi: 10.1073/pnas.1616301114. Epub 2017 Mar 6.

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

Author information

1
Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich 81377, Germany.
2
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.
3
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201.
4
Systems Biophysics, Physics Department, Nanosystems Initiative Munich and Center for NanoScience, Ludwig-Maximilians-Universität Munich, Munich 80799, Germany.
5
Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
6
Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
7
Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal.
8
Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
9
Public Health Research Program, Hunter Medical Research Institute, Newcastle, 2305, Australia.
10
Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, United Kingdom.
11
Division of Clinical Neurosciences, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
12
Institute of Epidemiology and Social Medicine, University of Münster, Muenster 48149, Germany.
13
Department of Neurology, University of Münster, Muenster 48149, Germany.
14
Research Unit Molecular Epidemiology, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg 85764, Germany.
15
Institut für Genetische Epidemiologie, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg 85764, Germany.
16
Institut für Humangenetik, Helmholtz Zentrum München, Munich 85764, Germany.
17
Institut für Humangenetik, Technische Universität München, Munich 85764, Germany.
18
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
19
Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich 81377, Germany; martin.dichgans@med.uni-muenchen.de.
20
Munich Cluster for Systems Neurology, Munich 81377, Germany.

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.

KEYWORDS:

antitrypsin; genetics; ischemic stroke; large artery stroke; variation

Comment in

PMID:
28265093
PMCID:
PMC5389268
DOI:
10.1073/pnas.1616301114
[Indexed for MEDLINE]
Free PMC Article

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