Systemic complement levels in patients with age-related macular degeneration carrying rare or low-frequency variants...

Area of Science:

• Genetics
• Ophthalmology
• Immunology

Background:

• Age-related macular degeneration (AMD) is a leading cause of vision loss in older adults.
• Genetic variants in the complement factor H (CFH) gene are linked to AMD, but their functional effects are often unclear.
• Factor H (FH) plays a crucial role in regulating the complement system, a key immune pathway implicated in AMD pathogenesis.

Purpose of the Study:

• To investigate the functional consequences of 64 rare and low-frequency variants in the CFH gene.
• To assess the impact of these variants on systemic levels of factor H (FH) and the complement activation marker C3bBbP.
• To enhance the clinical interpretation of rare CFH variants in patients with AMD.

Main Methods:

• Analysis of plasma samples from 252 carriers and 159 non-carriers of CFH variants.
• Quantification of factor H (FH) and C3bBbP levels in plasma.
• Comparison of FH and C3bBbP levels between carriers and non-carriers across different AMD stages and within AMD families.

Main Results:

• Individuals with CFH variants showed significantly decreased FH levels and significantly increased C3bBbP levels compared to non-carriers.
• FH and C3bBbP levels remained relatively stable over time.
• While decreased FH and increased C3bBbP were observed across AMD stages, C3bBbP levels were similarly high in carriers and non-carriers with advanced AMD.

Conclusions:

• Rare CFH variants can lead to reduced FH levels or impaired FH function, indicated by increased C3bBbP.
• These findings improve the understanding and clinical interpretation of rare and low-frequency CFH variants in AMD patients.
• The study highlights the importance of complement system dysregulation in AMD pathogenesis.