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A locus in the complement factor H (CFH) gene is linked with the development idiopathic multifocal choroiditis (MFC), research published today in JAMA Ophthalmology suggests. Findings of the case-control study also showed complement and coagulation pathways may hold potential as key targets for the treatment of idiopathic MFC.
MFC is a poorly understood, rare condition, explained corresponding author Jonas J. W. Kuiper, Ph.D., of Utrecht University in the Netherlands, and colleagues. The condition is characterized by the loss of retinal pigment epithelium and outer retinal ischemia, along with other symptoms, and is most commonly reported among Western European populations. Idiopathic MFC also predominately occurs in young women with myopia.
Little research exists on the molecular profiling of idiopathic MFC. “Better understanding of the key disease pathways driving idiopathic MFC and a molecular basis in support of the clinical categories are needed to improve disease management,” wrote Kuiper and colleagues.
To address this knowledge gap, they conducted a genome-wide association study (GWAS) using a Dutch cohort. Researchers also assessed participants’ protein and blood plasma samples.
The multicenter study was carried out between March 2006 and February 2022 and included six Dutch universities. Participants were divided into two cohorts. A total of 170 patients with idiopathic MFC and 4267 controls made up cohort one, while cohort two consisted of 52 patients with MFC and 1292 controls.
Investigators set out to identify both genetic variants linked with idiopathic MFC in addition to risk variants linked with plasma protein concentrations.
No genome-wide significant association was found with classical human leukocyte antigen (HLA) alleles. However, “the primary GWAS association mapped to the CFH gene with genome-wide significance,” authors wrote.
This association revealed consistent direction of effect in a group of 52 cases along with 1,292 control samples, authors added.
When Kuiper and colleagues carried out a proteomic analysis of 87 patients, they found the risk of allele G of rs7535263 in the CFHgene was significantly linked with heightened plasma concentrations of factor H–related (FHR) proteins. Risk of allele G of rs7535263 in the CFH gene was also associated with proteins that play a role in platelet activation and the complement cascade.
“Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC,” Kuiper and colleagues wrote.
Cases of idiopathic MFC that do not involve the peripheral retina and lack cells in the anterior or vitreous cavity can be classified as punctate inner choroidopathy (PIC), but whether MFC and PIC are actually separate diseases remains a matter of debate.
Although the current findings indicate both MFC and PIC share a similar molecular basis, more GWAS with larger sample sizes are warranted to carry out a comprehensive assessment of the genetic correlation between the subtypes, researchers noted.
The small number of idiopathic MFC cases included in their study was one of its limitation, noted Kuiper and his colleagues.
Elisabeth J. Rossin, M.D., is a co-author of an accompanying editorial about a study of idiopathiic multifocal choroiditis and the CFH gene published today in JAMA Ophthalmology.
In an accompanying editorial, Elizabeth J. Rossin, M.D., an assistant professor of ophthalmology at Harvard Medical School and Lucia Sobrin, M.D., MPH, a clinician scientist with Mass Eye and Ear's Retina and Uveitis Services, expand on the role of CFH in ocular diseases.
“Though the exact mechanism through which genetic variants in the region of CFH exert their effect is not fully understood, it likely involves dysregulation of the complement system leading to a state of chronic inflammation and maladaptive healing, slowly driving select tissues toward atrophy and disease,” Rossin and Sobrin wrote.
When it comes to MFC, Rossin and Sobrin acknowledge the small sample size of the current study but highlight the significant association found between CFH and the condition.
“Given the rarity of this diagnosis, we applaud the authors for collecting such a substantial cohort of patients with pure idiopathic MFC and PIC and for highlighting an important pathophysiologic mechanism that may hold therapeutic implications in the future,” they concluded.