Elevated Plasma Complement Factors in CRB1-associated Inherited Retinal Dystrophies

ObjectiveTo determine the profile of inflammation-related proteins and complement system factors in serum of CRB1-associated inherited retinal dystrophies (CRB1-IRDs). DesignA case-control study. Subjects, Participants, and/or ControlsA cohort of 30 Dutch CRB1-IRD patients and 29 Dutch healthy controls (HC) (Cohort I), and a second cohort of 123 CRB1-IRD patients from 14 countries and 1292 controls (Cohort II) were used in this study. MethodsQuantitative 370-plex targeted proteomics in blood plasma and genotyping of the single nucleotide variant (SNV) rs7535263 in the CFH gene. Main Outcome MeasuresPlasma concentrations of inflammation-related proteins and the genotype of the SNV rs7535263. ResultsCRB1-IRD patients showed increased plasma levels of complement system and coagulation cascade proteins compared to healthy controls. Complement Factor I [CFI], Serpin Family D1 [SERPIND1], and Complement Factor H [CFH] were significantly elevated (q<0.05, adjusted for age and sex), which correlated (Pearsons correlation coefficient >0.6) with higher levels of plasma Complement Component 3 [C3] (q = 0.064). The most enriched pathway in patients was the "Complement cascade" (R-HSA-166658, Padj = P = 3.03 x 10-15). An analysis of the genotype of CFH variant rs7535263, which is in close physical proximity to the CRB1 gene and is associated with other retinal conditions by influencing plasma complement levels, revealed significantly skewed allele distribution specifically in Dutch patients (A allele of rs7535263, odds ratio (OR) [95%CI = 2.85 [1.35-6.02], P = 6.19 x 10-3), but not in a global case-control cohort (P = 0.12). However, CRB1 missense variants that are common in patients display strong linkage disequilibrium (LD) with rs7535263 in CFH in the UK Biobank (D = 0.97 for p.(Cys948Tyr); D = 1.0 for p.(Arg764Cys)), indicating that genetic linkage may influence plasma complement factor levels in CRB1-IRD patients. After accounting for the CFH genotype in the proteomic analyses, we also detected significantly elevated plasma levels of Complement Factor H Related 2 [CFHR2] in CRB1-IRD patients (q = 0.04). ConclusionsCRB1-IRDs are characterized by changes in plasma levels of complement factors and proteins of the innate immune system, which is influenced by common functional variants in the CFH-CFHR locus. This indicates that innate immunity is implicated in CRB1-IRDs.