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

Abstract

ImportanceIdiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients.ObjectiveTo identify the genes and pathways associated with idiopathic MFC.Design, Setting, and ParticipantsThis 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 measuresGenetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients.ResultsThis 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 relevanceResults 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.

Serum Biomarkers of Vascular Involvement in Childhood Uveitis

“…Genetic variants in chromosome 1 lead to an increased risk of developing age-related macular degeneration driven predominantly by dysregulation of the complement system and are also associated with central serous chorioretinopathy and multifocal choroiditis. 27 , 34 , 35 CFH -rs1065489 polymorphism was associated with anterior uveitis, as well as uveitis recurrence. 36 There are many genetic variants or polymorphisms of the CFH gene in the general population; therefore, it would be interesting for future research to investigate whether these polymorphisms in the CFH gene are associated with retinal vascular involvement in idiopathic pediatric uveitis.…”

“… 25 Similarly, in adult patients with intermediate uveitis, elevated levels of complement cascade effectors and the coagulation system have been reported. 26 A recent study by de Groot et al 27 identified a key role of the complement and coagulation cascades in the underlying disease mechanisms of idiopathic multifocal choroiditis. Platelets are well known for their essential role in thrombus formation in response to vessel injuries.…”