Genetically Proxied HTRA1 Protease Activity and Circulating Levels Independently Predict Risk of Ischemic Stroke and Coronary Artery Disease

Overview

Journal Nat Cardiovasc Res

Publisher Springer Nature

Specialty Cardiology & Vascular Diseases

Date 2024 Aug 28

PMID 39196222

Authors

Rainer Malik

Nathalie Beaufort

Jiang Li

Koki Tanaka

Marios K Georgakis

Yunye He

Masaru Koido

Chikashi Terao

BioBank Japan

Christopher D Anderson

Yoichiro Kamatani

Ramin Zand

Martin Dichgans

Affiliations

Soon will be listed here.

Abstract

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.

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