Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Java A

PROVIDER: S-EPMC7453046 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Java Anuja A Baciu Peter P Widjajahakim Rafael R Sung Yun Ju YJ Yang Jae J Kavanagh David D Atkinson John J Seddon Johanna J

Translational vision science & technology 20200824 9

<h4>Purpose</h4>Factor I (FI) is a serine protease regulator of the complement system. Genetic variants in <i>CFI</i> 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 <i>CFI</i> variants using a serum-based assay.<h4>Methods</h4>Carriers of rare variants with (n = 78) and without AAMD (n = 28), and noncarriers with (n = 49) and without AMD (n = 44 ...[more]

PMID: 32908800

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Project description:Purpose To evaluate associations between rare dysfunctional complement factor I (CFI) genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA), and neovascular disease (NV). Design Prospective, longitudinal study Participants Patients aged 55 to 80 years at baseline identifying as White with non-AAMD in 1 or both eyes at baseline were included. Follow-up grades were assigned as early, intermediate, or AAMD (GA or NV). CFI variants were categorized using genotyping and sequencing platforms. Methods Analyses were performed using the Seddon Longitudinal Cohort Study (N = 2116 subjects, 3901 eyes, and mean follow-up of 8.3 years) and the Age-Related Eye Disease Study (N = 2837 subjects, 5200 eyes, and mean follow-up of 9.2 years). CFI rare variants associated with low serum factor I (FI) protein levels and decreased FI function (type 1), other AMD genetic variants, and demographic, behavioral, and ocular factors were evaluated. Generalized estimating equations methods were used to assess the association between CFI rare variants and progression, independent of other genetic variants and covariates. Main Outcome Measures Progression to AAMD, GA, or NV. Results In the prospective cohort of 4953 subjects (9101 eyes with non-AAMD at baseline), 1% were type 1 rare CFI carriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for noncarriers (P < 0.001), 30% of carriers versus 10% of noncarriers progressed to GA (P < 0.001), and 18% of carriers compared with 11% of noncarriers progressed to NV (P = 0.049). CFI carriers were more likely to have a family history of AMD (P for trend = 0.035) and a higher baseline AMD grade (P < 0.001). After adjusting for all covariates, CFI carrier status was associated with progression to GA (odds ratio [OR] = 1.91; 95% confidence interval [CI] = 1.03, 3.52) but not NV (OR = 0.96). Higher body mass index was associated with progression among CFI carriers (body mass index ≥ 25 vs. < 25; OR = 5.8; 95% CI 1.5, 22.3) but not for noncarriers (OR = 1.1; 95% CI = 0.9, 1.3), with P_interaction = 0.011. Conclusions Results suggest that carriers of rare dysfunctional type 1 CFI variants are at higher risk for progression to AAMD with GA. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Dataset Information

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

Publications

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

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