Dichgans Martin, Malik Rainer, Beaufort Nathalie, Tanaka Koki, Georgakis Marios, He Yunye, Koido Masaru, Terao Chikashi, Anderson Christopher, Kamatani Yoichiro
LMU Munich.
Institute for Stroke and Dementia Research.
Res Sq. 2023 Nov 7:rs.3.rs-3523612. doi: 10.21203/rs.3.rs-3523612/v1.
has emerged as a major risk gene for stroke and cerebral small vessel disease with both rare and common variants contributing to disease risk. However, the precise mechanisms mediating this risk remain largely unknown as does the full spectrum of phenotypes associated with genetic variation in in the general population. Using a family-history informed approach, we first show that rare variants in are linked to ischemic stroke in 425,338 European individuals from the UK Biobank with replication in 143,149 individuals from the Biobank Japan. Integrating data from biochemical experiments on 76 mutations occurring in the UK Biobank, we next show that rare variants causing loss of protease function associate with ischemic stroke, coronary artery disease, and skeletal traits. In addition, a common causal variant (rs2672592) modulating circulating HTRA1 mRNA and protein levels enhances the risk of ischemic stroke, small vessel stroke, and coronary artery disease while lowering the risk of migraine and age-related macular dystrophy in GWAS and UK Biobank data from > 2,000,000 individuals. There was no evidence of an interaction between genetically proxied HTRA1 activity and levels. Our findings demonstrate a central role of HTRA1 for human disease including stroke and coronary artery disease and identify two independent mechanisms that might qualify as targets for future therapeutic interventions.
已成为中风和脑小血管疾病的主要风险基因，罕见和常见变异均会增加疾病风险。然而，介导这种风险的精确机制在很大程度上仍不清楚，一般人群中与基因变异相关的全部表型也是如此。采用基于家族史的方法，我们首先表明，在英国生物银行的425338名欧洲个体中，罕见变异与缺血性中风相关，并在日本生物银行的143149名个体中得到验证。整合来自英国生物银行中发生的76种突变的生化实验数据，我们接下来表明，导致蛋白酶功能丧失的罕见变异与缺血性中风、冠状动脉疾病和骨骼特征相关。此外，一个调节循环HTRA1 mRNA和蛋白质水平的常见因果变异（rs2672592）在来自超过200万个体的全基因组关联研究（GWAS）和英国生物银行数据中，增加了缺血性中风、小血管中风和冠状动脉疾病的风险，同时降低了偏头痛和年龄相关性黄斑营养不良的风险。没有证据表明遗传代理的HTRA1活性和水平之间存在相互作用。我们的研究结果证明了HTRA1在包括中风和冠状动脉疾病在内的人类疾病中的核心作用，并确定了两种可能成为未来治疗干预靶点的独立机制。
