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Published on: July 14, 2016
Functional Analysis of Rare Genetic Variants in Complement Factor I (CFI) using a Serum-Based Assay in Advanced
Anuja Java1, Peter Baciu2, Rafael Widjajahakim3
1Divisions of Nephrology and Rheumatology, Department of Medicine, Washington University, St. Louis, MO, USA.
Insights
Rare genetic variants in Factor I (CFI) impact its function and are linked to advanced age-related macular degeneration (AAMD). This study functionally assessed these variants, revealing most have reduced levels or impaired activity, confirming CFI's role in AAMD.
Area of Science:
- Immunology
- Genetics
- Ophthalmology
Background:
- Factor I (FI) is a crucial regulator of the complement system.
- Genetic variants in the *CFI* gene are associated with advanced age-related macular degeneration (AAMD).
- The functional and clinical impact of rare *CFI* variants remains largely uncharacterized.
Purpose of the Study:
- To assess the functional significance of rare *CFI* genetic variants using a serum-based assay.
- To investigate the impact of these variants on Factor I (FI) function in patients with and without AMD.
- To establish the role of FI dysfunction in the pathogenesis of AAMD.
Main Methods:
- Evaluated carriers of rare *CFI* variants with and without AAMD, alongside noncarriers.
- Measured FI function by quantifying the proteolytic cleavage of C3b to iC3b, utilizing Factor H as a cofactor.
- Categorized *CFI* variants based on serum FI levels and functional activity.
Main Results:
- *CFI* variants were classified into three types based on antigenic and functional assessments.
- Type 1 variants (n=18) showed low serum FI levels and reduced FI function.
- Type 2 and 3 variants (n=6 and n=15, respectively) exhibited normal antigenic levels but impaired C3b cleavage to iC3b, indicating reduced functional capacity.
Conclusions:
- This study provides the first comprehensive serum-based functional assessment of rare *CFI* genetic variants.
- The findings confirm the critical role of FI in the pathogenesis of AAMD.
- Stratifying patients by *CFI* variant type can aid in screening and targeting complement therapies.
Purpose:
Factor I (FI) is a serine protease regulator of the complement system. Genetic variants in CFI are associated with advanced age-related macular degeneration (AAMD). However, the clinical and functional impact of these variants is unknown. This study assessed the functional significance of rare CFI variants using a serum-based assay.
Methods:
Carriers of rare variants with (n = 78) and without AAMD (n = 28), and noncarriers with (n = 49) and without AMD (n = 44) were evaluated. Function of FI was determined by measuring the proteolytic cleavage of C3b to iC3b, using the cofactor protein, Factor H.
Results:
CFI variants were categorized into three groups based on antigenic and functional assessments. Type 1 variants (n = 18) in 35 patients with AAMD demonstrated low serum FI levels and a corresponding decrease in FI function. Type 2 variants (n = 6) in 7 individuals demonstrated normal serum FI antigenic levels but reduced degradation of C3b to iC3b. Type 3 variants (n = 15) in 64 individuals demonstrated normal antigenic levels and degradation of C3b to iC3b. However, iC3b generation was low when measured per unit of FI. Thus most rare CFI variants demonstrate either low antigenic levels (type 1) or normal levels but reduced function (types 2 or 3).
Conclusions:
Results provide for the first time a comprehensive functional assessment in serum of CFI rare genetic variants and further establish FI's key role in the pathogenesis of AAMD.
Translational Relevance:
Stratifying patients in the clinic with a rare CFI variant will facilitate screening and targeting patients most likely to benefit from complement therapies.
