Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease.

High-Temperature Requirement A Serine Peptidase 1 / genetics Humans Ischemic Stroke / genetics Coronary Artery Disease / genetics Genetic Predisposition to Disease Genome-Wide Association Study Female Male Middle Aged Japan / epidemiology Risk Assessment Aged Risk Factors Polymorphism, Single Nucleotide Phenotype United Kingdom / epidemiology Loss of Function Mutation

Journal

Nature cardiovascular research
ISSN: 2731-0590
Titre abrégé: Nat Cardiovasc Res
Pays: England
ID NLM: 9918284280206676

Informations de publication

Date de publication:
Jun 2024
Historique:
received: 31 10 2023
accepted: 23 04 2024
medline: 28 8 2024
pubmed: 28 8 2024
entrez: 28 8 2024
Statut: ppublish

Résumé

Genetic variants in HTRA1 are associated with stroke risk. However, the mechanisms mediating this remain largely unknown, as does the full spectrum of phenotypes associated with genetic variation in HTRA1. Here we show that rare HTRA1 variants are linked to ischemic stroke in the UK Biobank and BioBank Japan. Integrating data from biochemical experiments, we next show that variants causing loss of protease function associated with ischemic stroke, coronary artery disease and skeletal traits in the UK Biobank and MyCode cohorts. Moreover, a common variant modulating circulating HTRA1 mRNA and protein levels enhances the risk of ischemic stroke and coronary artery disease while lowering the risk of migraine and macular dystrophy in genome-wide association study, UK Biobank, MyCode and BioBank Japan data. We found no interaction between proxied HTRA1 activity and levels. Our findings demonstrate the role of HTRA1 for cardiovascular diseases and identify two mechanisms as potential targets for therapeutic interventions.

Identifiants

DOI: 10.1038/s44161-024-00475-3 PMID: 39196222
pubmed: 39196222
doi: 10.1038/s44161-024-00475-3
pii: 10.1038/s44161-024-00475-3
doi:

Substances chimiques

High-Temperature Requirement A Serine Peptidase 1 EC 3.4.21.-
HTRA1 protein, human EC 3.4.21.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

701-713

Informations de copyright

© 2024. The Author(s), under exclusive licence to Springer Nature Limited.

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Auteurs

Rainer Malik (R)

Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.

Nathalie Beaufort (N)

Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.

Jiang Li (J)

Department of Molecular and Functional Genomics, Geisinger Health System, Danville, PA, USA.

Koki Tanaka (K)

Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.

Marios K Georgakis (MK)

Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.
ORCID: 0000-0003-3507-3659

Yunye He (Y)

Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
ORCID: 0000-0001-8581-7826

Masaru Koido (M)

Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
ORCID: 0000-0002-0348-0666

Chikashi Terao (C)

Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
ORCID: 0000-0002-6452-4095

BioBank Japan (B)

Institute of Medical Science, University of Tokyo, Tokyo, Japan.

Christopher D Anderson (CD)

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA.
McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA.
Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.

Yoichiro Kamatani (Y)

Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.

Ramin Zand (R)

Department of Neurology, Pennsylvania State University, Hershey, PA, USA.
Department of Neurology, Neuroscience Institute, Geisinger Health System, Danville, PA, USA.

Martin Dichgans (M)

Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University of Munich, Munich, Germany. martin.dichgans@med.uni-muenchen.de.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. martin.dichgans@med.uni-muenchen.de.
German Center for Cardiovascular Research (DZHK), Munich, Germany. martin.dichgans@med.uni-muenchen.de.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. martin.dichgans@med.uni-muenchen.de.
ORCID: 0000-0002-0654-387X

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Protéases à sérine › Serine endopeptidases › High-temperature requirement A serine peptidase 1 › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Angiopathies intracrâniennes › Accident vasculaire cérébral › Accident vasculaire cérébral ischémique › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Ischémie myocardique › Maladie coronarienne › Maladie des artères coronaires › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Régions géographiques › Iles › Japon › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Appréciation des risques › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de risque › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Régions géographiques › Europe › Royaume-Uni › Genetically proxied HTRA1 protease activity...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation perte de fonction › Genetically proxied HTRA1 protease activity...