Genetic determinants of the complement and coagulation pathways in invasive meningococcal disease

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Bellos, E ORCID: 0000-0002-3389-5715, van Leeuwen, K, Duret, A, Hodeib, S, Mashbat, M, Kohlfuerst, DS, Boeddha, NP, Schlapbach, LJ, Wright, VJ, Fink, CG et al (show 20 more authors) , van der Flier, M, van Deuren, M, Sprong, T, López-Trascasa, M, López-Lera, A, Martinón-Torres, F, Salas, A, Santillo, D, Zenz, W, Driessen, GJ, Anderson, ST, Secka, F, Paulus, S, de Groot, R, Emonts, M, Carrol, ED ORCID: 0000-0001-8357-7726, Herberg, J, Levin, M, Sancho-Shimizu, V and Kuijpers, T (2025) Genetic determinants of the complement and coagulation pathways in invasive meningococcal disease Journal of Allergy and Clinical Immunology, 156 (6). 1743-1751.e4. ISSN 0091-6749, 1097-6825

Text Genetic Determinants of the Complement and Coagulation Pathways in IMD bellos 2025.pdf - Author Accepted Manuscript Available under License Creative Commons Attribution. Download (2MB) | Preview

Abstract

Background: The complement and coagulation pathways are implicated in the systemic manifestations of invasive meningococcal disease (MD). However, the genetic landscape of these 2 interconnected plasma proteolytic pathways has not been systematically explored. 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.

Item Type:	Article
Uncontrolled Keywords:	Complement pathway, coagulation, Neisseria meningitidis, sepsis, human genetics
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Infection, Vet & Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	29 Sep 2025 08:20
Last Modified:	13 Mar 2026 23:32
DOI:	10.1016/j.jaci.2025.09.011
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3194640
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