Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis.

Autor:	de Groot EL; Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, the Netherlands., Ossewaarde-van Norel J; Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, the Netherlands., de Boer JH; Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, the Netherlands., Hiddingh S; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Bakker B; Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands., van Huet RAC; Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands., Ten Dam-van Loon NH; Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, the Netherlands., Thiadens AAHJ; Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, the Netherlands., Meester-Smoor MA; Department of Ophthalmology, Erasmus Medical Centre, Rotterdam, the Netherlands., de Jong-Hesse Y; Department of Ophthalmology, Amsterdam University Medical Centre, Amsterdam, the Netherlands.; Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands., Los LI; Department of Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., den Hollander AI; Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.; AbbVie, Genomics Research Center, Cambridge, Massachusetts., Boon CJF; Department of Ophthalmology, Amsterdam University Medical Centre, Amsterdam, the Netherlands.; Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands., Kiemeney LA; Department of Health Evidence, Radboud University Medical Centre, Nijmegen, the Netherlands., van Eijk KR; Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Bakker MK; Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Hoyng CB; Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands., Kuiper JJW; Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, the Netherlands.; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Jazyk:	angličtina
Zdroj:	JAMA ophthalmology [JAMA Ophthalmol] 2023 Aug 01; Vol. 141 (8), pp. 737-745.
DOI:	10.1001/jamaophthalmol.2023.2557
Abstrakt:	Importance: Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. Objective: To identify the genes and pathways associated with idiopathic MFC. Design, Setting, and Participants: This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Main Outcomes and Measures: Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. Results: This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10-8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Conclusions and Relevance: Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.
Databáze:	MEDLINE
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