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Approved research

Identification and validation of causal variants effect on cardiovascular disease through immune-mediated inflammation

Principal Investigator: Professor Jun Li
Approved Research ID: 44482
Approval date: May 14th 2019

Lay summary

Chronic inflammation can contribute the development of cardiovascular diseases (CVDs). Patients with autoimmune disease, such as rheumatoid arthritis and systemic lupus erythematosus, have increased prevalence of CVD. The pathogenesis of CVD is related to environmental factors, such as tobacco, diet, air pollution, and polygenic inheritance, and multiple tissues/cell types involved in the CVD development. Recently, both genome-wide association studies (GWASs) and genomics/proteomics-based methods have identified significant enrichment of inflammatory pathways for CVDs, supporting the hypothesis that proinflammation plays potentially causal role in the development of CVDs. However, the true causal path and underlying mechanism remain elusive. With the accumulation of genetics and functional genomics data of CVD, comprehensive bioinformatics and experimental analysis will be required to unravel the connection between immune-mediated inflammation and CVDs. Borrowing from genotype and phenotype data in the UKBB, our aim is to find the evidence that inflammation would contribute to CVD by medicated causality inference and causal tissues/cell types identification in the matched cohorts. And then, we will integrate tissue/cell type-specific expression quantitative trait loci data, GWAS data and other epigenetic annotation to fine-mapping and co-localize the casual variants. Additionally, we will associate genetic factors with quantitative indicators extracted from Electrocardiogram (ECG) and carotid ultrasound images. By connecting molecular traits with cardiovascular phenotypes, we will investigate the potential biological paths underlying immune-mediated cardiovascular impairment. By performing experimental validations, we will investigate the regulatory effect and potential mechanism of several identified causal regulatory variants conferring CVD susceptibility. We hope that we will finish this project within three years including computational work and experimental validation. Our proposed study could provide an opportunity to reduce cardiovascular disease risk through targeting inflammation or immune-related genes. We also expect that our study could provide new insights into the genetic basis and pathogenesis of CVD and facilitate the new therapeutic strategies related with inflammation-mediated CVD. The ultimate goal of our genetic research is to provide clinical prediction, diagnosis, and prognostic assessment, and to provide individualized treatment strategies for CVD patients.