Risk variants in the CFH gene associate with elevated levels of coagulation and complement factors in idiopathic multifocal choroiditis

Abstract

Purpose : Idiopathic multifocal choroiditis (MFC) is poorly understood, hindering optimal treatment and monitoring of patients. The aim of this study was to identify genes and pathways involved in idiopathic MFC.

Methods : This was a multicenter study involving six Dutch universities and included 170 Dutch idiopathic MFC cases and 4267 controls (cohort 1), and 52 cases and 1292 controls (cohort 2). Idiopathic MFC was diagnosed according to the SUN working group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. A genome-wide association study (GWAS) in cases and controls was performed to expose genetic variants associated with idiopathic MFC. Additionally, plasma samples from 87 treatment-free idiopathic MFC cases were subjected to targeted proteomics to explore if risk variants were associated with plasma protein concentrations in patients.

Results : The primary GWAS association mapped to the complement factor H (CFH) gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio (OR) [95% confidence interval (95%CI)] = 0.52 [0.41-0.64]; P= 9.3 × 10^-9). There was no significant association with classical HLA alleles (lead classical allele; HLA-A*31:01, P = 0.002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR [95%CI] = 0.58 [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 (e.g., FHR-2, likelihood ratio test, P_adj = 1.1 × 10⁻³) and proteins involved in platelet activation and the complement cascade.

Conclusions : CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. In conclusion, these results indicate that the complement and coagulation pathways are key targets for the treatment of idiopathic MFC.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.