Research uncovers link between complement factor H gene and idiopathic MFC

fgnoppornstock.adobe.com

A locus in complement factor H (CFH extension) gene is linked to the development of idiopathic multifocal choroiditis (MFC), research published today in JAMA Ophthalmology suggest. The results of the case-control study also showed that the complement and coagulation pathways may represent potential key targets for the treatment of idiopathic MFC.

MFC is a rare and poorly understood condition, explained corresponding author Jonas JW Kuiper, Ph.D., of Utrecht University in the Netherlands, and colleagues. The condition is characterized by loss of the retinal pigment epithelium and external retinal ischemia, along with other symptoms, and is most commonly reported among Western European populations. Idiopathic MFC also occurs predominantly in young women with myopia.

There is little research on the molecular profiling of idiopathic MFC. Improved disease management requires a better understanding of the key disease pathways that drive idiopathic MFC and a molecular basis supporting clinical categories, wrote Kuiper and colleagues.

To address this knowledge gap, they conducted a genome-wide association study (GWAS) using a Dutch cohort. The researchers also evaluated the participants’ protein and blood plasma samples.

The multi-centre study was conducted 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 constituted the first cohort, while the second consisted of 52 patients with MFC and 1292 controls.

The investigators set out to identify both genetic variants linked to idiopathic MFC in addition to risk variants linked to plasma protein concentrations.

No significant genome-wide associations were found with classical human leukocyte antigen (HLA) alleles. However, the primary GWAS association maps to the CFH gene with genome-wide significance, the authors wrote.

This association revealed a consistent direction of effect in a cohort of 52 cases along with 1,292 control samples, the authors added.

When Kuiper and colleagues performed a proteomic analysis of 87 patients, they found that the risk of the G allele of rs7535263 in the CFH gene was significantly linked to increased plasma concentrations of factor H-related proteins (FHR). The risk of the G allele of rs7535263 in the CFH gene has also been associated with proteins that play a role in platelet activation and the complement cascade.

The results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC, wrote Kuiper and colleagues.

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 internal choroidopathy (PIC), but whether MFC and PIC are indeed separate diseases remains a matter of debate.

Although the current results indicate that MFC and PIC share a similar molecular basis, multiple GWAS with larger sample sizes are warranted for making a comprehensive assessment of the genetic relatedness between subtypes, the researchers noted.

The small number of idiopathic MFC cases included in their study was one of its limitations, noted Kuiper and his colleagues.

Elisabeth J. Rossin, MD, co-authored an accompanying editorial on a study of idiopathic multifocal choroiditis and the CFH gene published today in JAMA Ophthalmology.

In an accompanying editorial, Elizabeth J. Rossin, MD, assistant professor of ophthalmology at Harvard Medical School, and Lucia Sobrin, MD, MPH, a clinical scientist with Mass Eye and Ear’s Retina and Uveitis Services, expand the role of CFH in ocular illnesses.

Although the exact mechanism by which genetic variants in the CFH region exert their effect is not fully understood, it probably involves a dysregulation of the complement system leading to a state of chronic inflammation and maladaptive healing, slowly driving selected tissues towards 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 large cohort of pure idiopathic MFC and PIC patients and for highlighting an important pathophysiological mechanism that may have future therapeutic implications, they concluded.