Genetic Determinants of the Complement and Coagulation Pathways in Invasive Meningococcal Disease

Abstract

Background: The complement and coagulation pathways are implicated in the systemic manifestations of invasive meningococcal disease (MD) However, the genetic landscape of these two interconnected plasma proteolytic pathways has not been systematically explored.

Objective: We investigated how genetic variation in the complement and coagulation pathways contributes to invasive meningococcal disease.

Methods: Whole Exome Sequencing (WES) and high-coverage amplicon-based sequencing were performed in a large series of 229 MD patients. As a control cohort we used 275 patients with other invasive bacterial infections.

Results: Our WES data show 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 to the control infection cohorts. Combining the amplicon panel and the WES datasets, we identified a mild hemophilia A case, five properdin mutated individuals and four digenic complement deficiencies. In addition, we report a significant copy number variant association in the CFH/CFHR1-5 gene cluster. 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.

Conclusion: 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 (CM-TMA) as a key pathophysiologic mechanism involved, particularly in MD.

Clinical implication: Understanding the genetic landscape may enable further exploration of novel complement- and TMA-directed therapies.

Keywords: Coagulation; Complement pathway; Human genetics; Neisseria meningitidis; Sepsis.