Elevated Plasma Complement Factors in CRB1-Associated Inherited Retinal Dystrophies
Lude Moekotte1, Joke H de Boer1, Sanne Hiddingh1
1Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands.
Insights
Inflammation and complement factors are altered in CRB1-associated inherited retinal dystrophies (CRB1-IRDs). Genetic links between CRB1 and CFH genes suggest their variants influence disease.
Area of Science:
- Ophthalmology
- Immunology
- Genetics
Background:
- Inherited retinal dystrophies (IRDs) encompass a group of genetic disorders affecting vision.
- CRB1-associated IRDs (CRB1-IRDs) are a subset of these conditions with specific genetic underpinnings.
- Understanding the molecular mechanisms, including immune responses, is crucial for CRB1-IRDs.
Purpose of the Study:
- To profile inflammation-related proteins in CRB1-IRDs.
- To investigate complement system factors in CRB1-IRDs.
- To identify immune pathways implicated in CRB1-IRDs.
Main Methods:
- Targeted proteomics using the Olink Explore 384 Inflammation II panel.
- Analysis of plasma samples from CRB1-IRD patients and controls.
- Genotyping of patients and controls across two cohorts.
Main Results:
- Significant enrichment of complement cascade factors in CRB1-IRD plasma proteomes.
- Elevated plasma levels of complement factor I and complement factor H (CFH).
- Linkage disequilibrium between CRB1 variants and a common CFH variant (rs7535263), associated with altered CFH-related protein levels.
Conclusions:
- CRB1-IRDs exhibit altered plasma levels of complement factors and innate immune proteins.
- Genetic linkage between CRB1 and CFH genes suggests a role for CFH-CFHR locus variants.
- Functional variants in the CFH-CFHR locus may interact with specific pathogenic CRB1 variants in CRB1-IRDs.
Purpose:
To determine the profile of inflammation-related proteins and complement system factors in the plasma of CRB1-associated inherited retinal dystrophies (CRB1-IRDs).
Methods:
We used the Olink Explore 384 Inflammation II panel for targeted proteomics in 30 cases and 29 controls (cohort I) to identify immune pathways involved in CRB1-IRDs. Genotyping was performed in cohort I and a second cohort of 123 patients from 14 countries and 1292 controls (cohort II).
Results:
A significant shift in complement cascade factors was observed in plasma proteomes of CRB1-IRD patients (enrichment for complement cascade, Padj = 3.03 × 10-15). We detected higher plasma levels of complement factor I and complement factor H [CFH] (q = 0.008 and q = 0.046, respectively, adjusted for age and sex), inhibitors of complement component 3 (C3), which correlated significantly (Pearson's coefficient >0.6) with elevated levels of C3 (q = 0.064). The CRB1 missense variants frequently found in patients showed a strong linkage disequilibrium with the common CFH variant rs7535263 (D' = 0.97 for p.(Cys948Tyr); D' = 1.0 for p.(Arg764Cys)), known to be linked with altered plasma CFH-related protein levels. Correction for the CFH genotype revealed significantly elevated plasma levels of CFH-related 2 (CFHR2) in CRB1-IRD patients (q = 0.041).
Conclusions:
CRB1-IRDs are characterized by changes in plasma levels of complement factors and proteins of the innate immune system, and linkage between CRB1 and CFH genes implicates functional variants of the CFH-CFHR locus with specific pathogenic variants of CRB1.
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