Genetic determinants of the complement and coagulation pathways in invasive meningococcal disease.
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Bellos Evangelos, van Leeuwen Karin, Duret Amedine, Hodeib Stephanie, Mashbat Meg, Kohlfuerst Daniela S, Boeddha Navin P, Schlapbach Luregn J, Wright Victoria J, Fink Colin G, van der Flier Michiel, van Deuren Marcel, Sprong Tom, López-Trascasa Margarita, López-Lera Alberto, Martinón-Torres Federico, Salas Antonio, Santillo Dilys, Zenz Werner, Driessen Gertjan J, Anderson Suzanne T, Secka Fatou, Paulus Stephane, de Groot Ronald, Emonts Marieke, Carrol Enitan D, Herberg Jethro, Levin Mike, Sancho-Shimizu Vanessa, Kuijpers Taco, EUCLIDS Consortium
Аннотация
OBJECTIVE: We sought to investigate how genetic variation in the complement and coagulation pathways contributes to invasive MD.
METHODS: Whole-exome sequencing (WES) and high-coverage amplicon-based sequencing were performed in a large series of 229 patients with MD. A group of 275 patients with other invasive bacterial infections was used as a control cohort.
RESULTS: WES data showed an enrichment of rare variants in the complement and coagulation genes in MD, namely, CFP and FCGR2A. In a subcohort of severe MD, CFP and SERPINE1 were enriched for rare variants compared with the control cohort. Combining the amplicon panel and the WES data sets, 1 mild hemophilia A case, 5 properdin mutated individuals, and 4 digenic complement deficiencies were identified. In addition, a significant copy number variant association in the CFH/CFHR1-5 gene cluster was reported. This provides strong support for the role of complement regulation in MD. Furthermore, there are pathogenic variants in VWF, PROS1, and SERPINC1, relevant to coagulation and fibrinolysis.
CONCLUSIONS: The study demonstrates the value of a mechanistic pathway approach to describe the genetic landscape of infectious disease, particularly in understanding its course and outcome. Notably, we identify complement-mediated thrombotic microangiopathy as a key pathophysiologic mechanism involved, particularly in MD.