RESUMEN
Although genome-wide association studies (GWAS) have successfully linked genetic risk loci to various disorders, identifying underlying cellular biological mechanisms remains challenging due to the complex nature of common diseases. We established a framework using human peripheral blood cells, physical, chemical and pharmacological perturbations, and flow cytometry-based functional readouts to reveal latent cellular processes and performed GWAS based on these evoked traits in up to 2,600 individuals. We identified 119 genomic loci implicating 96 genes associated with these cellular responses and discovered associations between evoked blood phenotypes and subsets of common diseases. We found a population of pro-inflammatory anti-apoptotic neutrophils prevalent in individuals with specific subsets of cardiometabolic disease. Multigenic models based on this trait predicted the risk of developing chronic kidney disease in type 2 diabetes patients. By expanding the phenotypic space for human genetic studies, we could identify variants associated with large effect response differences, stratify patients and efficiently characterize the underlying biology.
Asunto(s)
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/genética , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo/genética , Predisposición Genética a la Enfermedad , Fenotipo , Células Sanguíneas , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Thrombosis is the leading complication of common human disorders including diabetes, coronary heart disease, and infection and remains a global health burden. Current anticoagulant therapies that target the general clotting cascade are associated with unpredictable adverse bleeding effects, because understanding of hemostasis remains incomplete. Here, using perturbational screening of patient peripheral blood samples for latent phenotypes, we identified dysregulation of the major mechanosensory ion channel Piezo1 in multiple blood lineages in patients with type 2 diabetes mellitus (T2DM). Hyperglycemia activated PIEZO1 transcription in mature blood cells and selected high Piezo1expressing hematopoietic stem cell clones. Elevated Piezo1 activity in platelets, red blood cells, and neutrophils in T2DM triggered discrete prothrombotic cellular responses. Inhibition of Piezo1 protected against thrombosis both in human blood and in zebrafish genetic models, particularly in hyperglycemia. Our findings identify a candidate target to precisely modulate mechanically induced thrombosis in T2DM and a potential screening method to predict patient-specific risk. Ongoing remodeling of cell lineages in hematopoiesis is an integral component of thrombotic risk in T2DM, and related mechanisms may have a broader role in chronic disease.
