Elevated Plasma Complement Factors in CRB1-Associated Inherited Retinal Dystrophies

Inherited retinal dystrophies (IRDs) caused by mutations in the Crumbs homolog 1 (CRB1) gene are characterized by significant phenotypic variability, even among patients with identical mutations. Because some patients exhibit signs of ocular inflammation, such as cystoid macular edema, researchers hypothesized that systemic immune dysregulation might contribute to the disease's progression and clinical heterogeneity. This study aimed to characterize the plasma proteomic profile of CRB1-IRD patients to identify potential inflammatory pathways involved in the disease.

The researchers performed targeted proteomics using the Olink Explore 384 Inflammation II panel to analyze 370 inflammation-related proteins in the plasma of 30 CRB1-IRD patients and 29 age-matched healthy controls. To account for potential genetic confounding, they also genotyped a specific variant (rs7535263) in the Complement Factor H (CFH) gene, which is located near the CRB1 gene on chromosome 1. This genotyping was extended to a larger validation cohort of 123 patients and 1,292 controls to assess the relationship between the CFH genotype and plasma protein levels.

The study identified a significant enrichment of complement cascade factors in the plasma of CRB1-IRD patients. Specifically, levels of complement factor I, complement factor H (CFH), and complement component 3 (C3) were elevated. Crucially, the researchers discovered that common CRB1 missense variants are in strong linkage disequilibrium with the CFH variant rs7535263. After adjusting for this genetic linkage, they confirmed that plasma levels of CFH-related 2 (CFHR2) protein remained significantly elevated in patients, suggesting that the complement system is intrinsically altered in this patient population.

These findings suggest that CRB1-IRDs are not merely localized retinal conditions but are associated with systemic changes in the innate immune system. The link between CRB1 mutations and the CFH-CFHR locus provides a potential genetic explanation for the observed immune profile and may help explain why clinical phenotypes vary so significantly between patients. This research opens the door to considering complement-modulating therapies or systemic immune monitoring as part of the clinical management for patients with CRB1-associated retinal disease.