Purpose

The disease mechanisms underlying central multifocal choroiditis (cMFC) are unknown. This study was undertaken to identify genetic susceptibility loci by genome-wide association study (GWAS) of 228 Dutch cases and 3577 unrelated Dutch controls.

Methods

Genomic DNA from cases with idiopathic multifocal choroiditis (MFC), punctate inner choroidopathy (PIC), serpiginous choroiditis (SC), relentless placoid chorioretinitis (RPC) and controls were genotyped by Infinium OmniExpress-24 BeadChip array. Data were subjected to genome-wide and HLA-specific imputation for association testing.

Results

The primary genetic association mapped to a haplotype spanning the CFH gene (lead variant the A allele of rs7535263; OR[95% CI] = 0.57 [0.46-0.70], P= 1.48 × 10-7). Co-localization analysis showed that this haplotype strongly affects plasma levels of Complement factor H and other immune mediators. Association testing considering the 171 cases with the phenotypically similar subtypes MFC and PIC substantially increased the signal (MFC+PIC versus controls, rs7535263; OR[95% CI] = 0.52 [0.41-0.64]; P= 9.3 × 10-9). We evaluated the association with CFH in independent case-control samples. No association with classical HLA alleles or amino acids positions was observed (lead classical allele; HLA-A*31:01, PMFC+PIC = 0.002).

Conclusions

This study identified the CFH gene as a risk locus for MFC and PIC and implicates a disease mechanism that involves dysregulation of the complement system.