Complement activation products, single nucleotide polymorphisms and age-related macular degeneration (AMD).

Abstract

Purpose : Histological, biochemical and genetic data have linked an overactive complement system to the incidence of both wet and dry AMD. Components of the alternative pathway of complement are elevated in plasma of AMD subjects, and haplotypes in AMD-associated complement loci are associated with these changes. Here we extend this analysis by examining novel single nucleotide polymorphisms (SNPs) predicted to be associated with AMD and examining additional complement activation products including complement factor H (CFH) activity.

Methods : 224 subjects, including 91 AMD patients and 133 control individuals were evaluated. Bb, C3a and C5a were measured by commercial ELISA, CFH activity was assessed in sheep cell lysis assays. Univariate and multivariable logistic regression models were used for analysis; with the final model based on the smallest Akaike’s Information Criterion.

Results : Subjects with AMD were found to have significantly higher levels of the complement factors C3a and Bb and significantly lower levels of C5a. Controlling for other factors, a 10% increase in the level of C3a was associated with a 10% increase, whereas a 10% increase in C5a levels is associated with a 17% decrease in the odds of being AMD positive. While CFH activity levels were not correlated with disease, there was a significant interaction between patient age and levels of activity, thus the impact of age or factor H activity on the odds of having AMD need to be considered jointly. The occurrence of AMD among whites was significantly associated with the additive effect of rs1536304 (VEGFA) and marginal associations were also noted for the additive effect of the rs3766404 SNP (CFH).

Conclusions : Our results confirm and extend reports of alternative pathway of complement components in serum as potential biomarkers for AMD, and suggest that this increase in complement activation could be attributed to a decrease in CFH activity in younger patients. We also identified a novel susceptibility and protective haplotypes in the AMD population.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.