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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. ; Müller-Nurasyid, M. ; Lichtner, P. ; Saleheen, D.* ; Rothwell, P.M.* ; Levi, C.* ; Attia, J.* ; Sudlow, C.L.* ; Braun, D.* ; Markus, H.S.* ; Wintrode, P.L.* ; Berger, K.* ; Jenne, D. ; Dichgans, M.*

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

Proc. Natl. Acad. Sci. U.S.A. 114, 3613-3618 (2017)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Antitrypsin ; Genetics ; Ischemic Stroke ; Large Artery Stroke ; Variation
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 114, Issue: 14, Pages: 3613-3618 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
Institute of Epidemiology (EPI)
Institute of Genetic Epidemiology (IGE)
Institute of Human Genetics (IHG)
POF-Topic(s) 30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Lung Research
Genetics and Epidemiology
PSP Element(s) G-501600-005
G-504091-001
G-504100-001
G-500700-001
DOI 10.1073/pnas.1616301114
WOS ID WOS:000398159000040
Scopus ID 85016951331
PubMed ID 28265093
Erfassungsdatum 2017-04-28
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