Elevated Plasma Complement Factors in CRB1 -associated Inherited Retinal Dystrophies
Abstract
Abstract Objective To determine the profile of inflammation-related proteins and complement system factors in serum of CRB1 -associated inherited retinal dystrophies ( CRB1 -IRDs). Design A case-control study. Subjects, Participants, and/or Controls A 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. Methods Quantitative 370-plex targeted proteomics in blood plasma and genotyping of the single nucleotide variant (SNV) rs7535263 in the CFH gene. Main Outcome Measures Plasma concentrations of inflammation-related proteins and the genotype of the SNV rs7535263. Results CRB1 -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 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 × 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). Conclusions CRB1 -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.
Authors 33
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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
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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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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
Department of Ophthalmology, 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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