Elevated Plasma Complement Factors inCRB1-associated Inherited Retinal Dystrophies

Abstract

ObjectiveTo determine the profile of inflammation-related proteins and complement system factors in serum ofCRB1-associated inherited retinal dystrophies (CRB1-IRDs).DesignA case-control study.Subjects, Participants, and/or ControlsA cohort of 30 DutchCRB1-IRD patients and 29 Dutch healthy controls (HC) (Cohort I), and a second cohort of 123CRB1-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 theCFHgene.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 (Pearson’s 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 × 10-15). An analysis of the genotype ofCFHvariant rs7535263, which is in close physical proximity to theCRB1gene 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 × 10-3), but not in a global case-control cohort (P= 0.12). However,CRB1missense variants that are common in patients display strong linkage disequilibrium (LD) with rs7535263 inCFHin 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 inCRB1-IRD patients. After accounting for theCFHgenotype in the proteomic analyses, we also detected significantly elevated plasma levels of Complement Factor H Related 2 [CFHR2] inCRB1-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 theCFH-CFHRlocus. This indicates that innate immunity is implicated inCRB1-IRDs.