Abstract Text: The Sanofi Genetic Data Lake (SGDL) is a comprehensive platform integrating various genome-centricdata, including genome-wide association studies, single cell eQTL, and epigenetic data, to uncover relationships between immune diseases, cell types, and therapeutic targets. This integration aims to strategically position therapeutic targets in immune diseases, enhancing probability of technical and regualory success of clinical trials. Specifically, the platform identifies targets with broad associations, facilitating multi-indication drug development. We applied SGDL to explore new indications for IL6-targeted therapies, focusing on IL6, IL6ST, and IL6R genes. Through Mendelian randomization and colocalization analysis, combining disease GWAS and eQTL data from multiple tissues and immune cell types, we discovered causal links between IL6 expression in CD16 monocytes and various cardiovascular diseases, contrasting with decreased allergic asthma risk. Similarly, IL6R and IL6ST expressions were associated with distinct risks across cardiovascular, respiratory, and autoimmune diseases. Notably, IL6ST expression in T cells and whole blood was strongly linked to both rheumatoid arthritis and polymyalgia rheumatica. Our findings not only reaffirmed known associations of the IL-6R pathway with cardiovascular and immune diseases but also revealed a new link between IL6ST and polymyalgia rheumatica. This discovery is supported by the recent US approval of Sarilumab, an IL-6R inhibitor, for treating polymyalgia rheumatica. Overall, SGDL, utilizing multiomics data, machine intelligence, and large language models-based technologies, proves to be useful to deepen understanding of immune target biology.
