Functional Analysis of Rare Genetic Variants in Complement Factor I () using a Serum-Based Assay in Advanced Age-related Macular Degeneration.

Purpose: Factor I (FI) is a serine protease regulator of the complement system. Genetic variants in 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 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: 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 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 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 variant will facilitate screening and targeting patients most likely to benefit from complement therapies.