Blood. 2023 Dec 14:blood.2023021231. doi: 10.1182/blood.2023021231. Online ahead of print.
ABSTRACT
Extreme disease phenotypes can provide key insights into the pathophysiology of common conditions, but studying these patients is challenging due to their rarity and the limited statistical power of existing methods. Herein, we used a novel approach to pathway-based mutational burden testing, the rare variant trend test (RVTT), to investigate genetic risk factors for an extreme form of sepsis-induced coagulopathy, infectious purpura fulminans (PF). In addition to prospective patient sample collection, we electronically screened over 10.4 million medical records from four large hospital systems and identified historical cases of PF for which archived specimens were available to perform germline whole exome sequencing. We found a significantly increased burden of rare, putatively function-altering variants in the complement system in patients with PF compared to unselected patients with sepsis (p=0.01). A multivariable logistic regression analysis found that the number of complement system variants per patient was independently associated with PF after controlling for age, sex, and disease acuity (p=0.01). Functional characterization of PF-associated variants in the immunomodulatory complement receptors CR3 and CR4 revealed that they result in partial or complete loss of anti-inflammatory CR3 function and/or gain of pro-inflammatory CR4 function. Taken together, these findings suggest that inherited defects in CR3 and CR4 predispose to the maladaptive hyperinflammation that characterizes severe sepsis with coagulopathy.
PMID:38096369 | DOI:10.1182/blood.2023021231
