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

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; Woo, D; Debette, S; Maguire, J; Cole, JW; Majersik, J; Jimenez-Conde, J; Lee, JM; Rost, N; Pare, G; Jern, C; Lindgren, AG; Cardenas, IF; Rothwell, PM; Levi, C; Attia, J; Sudlow, CLM; Braun, D; Markus, HS; Wintrode, PL; Berger, K; Jenne, DE; Dichgans, M

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

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 Woo, D Debette, S Maguire, J

Cole, JW Majersik, J Jimenez-Conde, J Lee, JM Rost, N Pare, G Jern, C Lindgren, AG Cardenas, IF Rothwell, PM Levi, C Attia, J Sudlow, CLM Braun, D Markus, HS Wintrode, PL Berger, K Jenne, DE Dichgans, M

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Publication Type:: Journal Article
Citation:: Proceedings of the National Academy of Sciences of the United States of America, 2017, 114 (14), pp. 3613 - 3618
Issue Date:: 2017-04-04

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Field	Value	Language
dc.contributor.author	Malik, R	en_US
dc.contributor.author	Dau, T	en_US
dc.contributor.author	Gonik, M	en_US
dc.contributor.author	Sivakumar, A	en_US
dc.contributor.author	Deredge, DJ	en_US
dc.contributor.author	Edeleva, EV	en_US
dc.contributor.author	Götzfried, J	en_US
dc.contributor.author	Van Der Laan, SW	en_US
dc.contributor.author	Pasterkamp, G	en_US
dc.contributor.author	Beaufort, N	en_US
dc.contributor.author	Seixas, S	en_US
dc.contributor.author	Bevan, S	en_US
dc.contributor.author	Lincz, LF	en_US
dc.contributor.author	Holliday, EG	en_US
dc.contributor.author	Burgess, AI	en_US
dc.contributor.author	Rannikmäe, K	en_US
dc.contributor.author	Minnerup, J	en_US
dc.contributor.author	Kriebel, J	en_US
dc.contributor.author	Waldenberger, M	en_US
dc.contributor.author	Müller-Nurasyid, M	en_US
dc.contributor.author	Lichtner, P	en_US
dc.contributor.author	Saleheen, D	en_US
dc.contributor.author	Woo, D	en_US
dc.contributor.author	Debette, S	en_US
dc.contributor.author	Maguire, J https://orcid.org/0000-0001-5722-8311	en_US
dc.contributor.author	Cole, JW	en_US
dc.contributor.author	Majersik, J	en_US
dc.contributor.author	Jimenez-Conde, J	en_US
dc.contributor.author	Lee, JM	en_US
dc.contributor.author	Rost, N	en_US
dc.contributor.author	Pare, G	en_US
dc.contributor.author	Jern, C	en_US
dc.contributor.author	Lindgren, AG	en_US
dc.contributor.author	Cardenas, IF	en_US
dc.contributor.author	Rothwell, PM	en_US
dc.contributor.author	Levi, C	en_US
dc.contributor.author	Attia, J	en_US
dc.contributor.author	Sudlow, CLM	en_US
dc.contributor.author	Braun, D	en_US
dc.contributor.author	Markus, HS	en_US
dc.contributor.author	Wintrode, PL	en_US
dc.contributor.author	Berger, K	en_US
dc.contributor.author	Jenne, DE	en_US
dc.contributor.author	Dichgans, M	en_US
dc.date.issued	2017-04-04	en_US
dc.identifier.citation	Proceedings of the National Academy of Sciences of the United States of America, 2017, 114 (14), pp. 3613 - 3618	en_US
dc.identifier.issn	0027-8424	en_US
dc.identifier.uri	http://hdl.handle.net/10453/126735
dc.description.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.	en_US
dc.relation.ispartof	Proceedings of the National Academy of Sciences of the United States of America	en_US
dc.relation.isbasedon	10.1073/pnas.1616301114	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Histone Deacetylases	en_US
dc.subject.mesh	Leukocyte Elastase	en_US
dc.subject.mesh	alpha 1-Antitrypsin	en_US
dc.subject.mesh	Repressor Proteins	en_US
dc.subject.mesh	3' Untranslated Regions	en_US
dc.subject.mesh	Deuterium Exchange Measurement	en_US
dc.subject.mesh	Polymorphism, Single Nucleotide	en_US
dc.subject.mesh	Mass Spectrometry	en_US
dc.subject.mesh	Stroke	en_US
dc.subject.mesh	Genetic Association Studies	en_US
dc.subject.mesh	Plaque, Atherosclerotic	en_US
dc.title	Common coding variant in SERPINA1 increases the risk for large artery stroke	en_US
dc.type	Journal Article
utslib.citation.volume	14	en_US
utslib.citation.volume	114	en_US
utslib.for	1102 Cardiorespiratory Medicine and Haematology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Nursing
utslib.copyright.status	open_access
pubs.issue	14	en_US
pubs.publication-status	Published	en_US
pubs.volume	114	en_US

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/126735