Elevated Plasma Complement Factors in CRB1-Associated Inherited Retinal Dystrophies
Investigative Ophthalmology & Visual Science, vol. 66, pp. 55
Abstract
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.
Authors 34
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Lude Moekotte corresponding
University Medical Center Utrecht
Affiliation as printed
Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
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Radboud University Medical Center
Affiliation as printed
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands
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Affiliation as printed
Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
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University of Leeds · St James's University Hospital
Affiliation as printed
Department of Ophthalmology, St. James's University Hospital, Leeds, United Kingdom
Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
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The University of Western Australia
Affiliation as printed
Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Western Australia, Australia
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Affiliation as printed
Australian Inherited Retinal Disease Registry & DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
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The University of Western Australia · Sir Charles Gairdner Hospital
Affiliation as printed
Australian Inherited Retinal Disease Registry & DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Western Australia, Australia
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The University of Western Australia · Sir Charles Gairdner Hospital
Affiliation as printed
Australian Inherited Retinal Disease Registry & DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Western Australia, Australia
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St John of Jerusalem Eye Hospital Group
Affiliation as printed
St. John of Jerusalem Eye Hospital Group, East Jerusalem, Palestine
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
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University of Campania "Luigi Vanvitelli" · Telethon Institute Of Genetics And Medicine
Affiliation as printed
Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
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Inserm · Université de Montpellier · Institute for Neurosciences of Montpellier
Affiliation as printed
Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France
National Reference Center for Inherited Sensory Diseases, University of Montpellier, CHU, Montpellier, France
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Inserm · Université de Montpellier · Institute for Neurosciences of Montpellier
Affiliation as printed
Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France
National Reference Center for Inherited Sensory Diseases, University of Montpellier, CHU, Montpellier, France
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Ghent University Hospital · Ghent University
Affiliation as printed
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
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McGill University Health Centre · Research Institute of the McGill University Health Centre · McGill University
Affiliation as printed
Departments of Paediatric Surgery, Human Genetics, and Adult Ophthalmology, McGill University Health Center, Montreal, QC, Canada
McGill University Health Center (MUHC) Research Institute, Montreal, QC, Canada
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Affiliation as printed
Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland
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University of Leicester · University of Basel · Institute of Molecular and Clinical Ophthalmology Basel
Affiliation as printed
Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom
Department of Ophthalmology, University of Basel, Basel, Switzerland
Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
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University of Cape Town · Institute of Infectious Disease and Molecular Medicine
Affiliation as printed
UCT/MRC Precision and Genomic Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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University of Cape Town · Institute of Infectious Disease and Molecular Medicine
Affiliation as printed
UCT/MRC Precision and Genomic Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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Affiliation as printed
Center of Eye Diseases, Clinic of Ear, Nose, Throat, and Eye Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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Affiliation as printed
Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
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Affiliation as printed
The School of Genetics & Microbiology, The University of Dublin Trinity College, Dublin, Ireland
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University Medical Center Utrecht
Affiliation as printed
Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
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Affiliation as printed
Het Oogziekenhuis Rotterdam, Rotterdam, the Netherlands
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Leiden University Medical Center · Amsterdam University Medical Centers
Affiliation as printed
Department of Ophthalmology, Amsterdam UMC, Amsterdam, the Netherlands
Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
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University Medical Center Utrecht · Bartiméus
Affiliation as printed
Bartiméus, Diagnostic Centre for complex visual disorders, Zeist, the Netherlands
Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Ophthalmology, University Medical Center Utrecht, Utrecht, the Netherlands
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