Evaluating a Causal Relationship between Complement Factor I Protein Level and Advanced Age-Related Macular...

Area of Science:

• Genetics
• Ophthalmology
• Biochemistry

Background:

• Rare genetic variants in the Complement factor I (CFI) gene are linked to advanced age-related macular degeneration (AAMD) risk.
• These variants are associated with lower circulating CFI protein levels, but the causal relationship remains unclear.

Purpose of the Study:

• To investigate whether genetic factors can establish a causal link between low circulating CFI levels and AAMD risk.
• To quantify the impact of reduced CFI levels on the odds of developing AAMD.

Main Methods:

• Two-sample Mendelian Randomisation (MR) analysis was employed to assess the relationship between CFI levels and AAMD risk.
• Genetic instruments for systemic CFI levels were derived from the INTERVAL study.
• Genome-wide association study data from AAMD cases and controls (IAMDGC) and proteomic data were utilized.

Main Results:

• A common CFI variant (rs7439493) strongly associated with low CFI levels showed that each standard deviation (SD) decrease in CFI increased AAMD odds by 1.47 (95% CI 1.30-1.65).
• A rare CFI variant (rs141853578) also significantly lowered CFI levels, with each SD decrease increasing AAMD odds by 1.79 (95% CI 1.46-2.19).
• Proteomic assay results corroborated these findings, associating a 1 SD reduction in CFI with a 1.67-fold increased odds of AAMD.

Conclusions:

• Genetic evidence strongly supports a potentially causal role for lower CFI levels in increasing AAMD risk.
• The concordance between rare and common variant analyses provides robust support for this conclusion.
• These findings highlight CFI levels as a significant factor in AAMD pathogenesis.