Abstract
Purpose: :
To determine whether common variants of complement component 3 (C3) gene are associated with neovascular (NV) AMD and geographic atrophy (GA) after considering the impact of variants in other AMD-associated genes, age, and smoking.
Methods: :
We applied data from 557 participants of the Age-Related Eye Disease Study (AREDS) who were self-identified as white, not of Hispanic origin to examine the distribution of ten C3 variants as they may relate to advanced AMD; our sample contained 184 AMD-free people, 131 people with GA, 194 people with NV AMD, and 48 people with GA + NV AMD. Primary outcomes (GA, NV AMD, or NV AMD and/or GA) were ascertained prospectively with a standardized method by masked professional graders from color fundus photographs collected annually across a 12 year period. Our comparison group contained people who remained AMD-free across the course of the study.
Results: :
Arg102Gly of exon 3 was the only C3 variant associated with advanced AMD in models adjusted for age, smoking history, and other AMD-associated SNPs. The likelihood of having pure NV AMD was increased more than 2-fold among people carrying one or two risk alleles of Arg102Gly; respective odds ratios (OR) are 2.6 (95% CI, 1.6-4.2, P ≤ 0.00007) and 3.1 (95% CI, 1.3-7.6, P ≤ 0.013). The magnitude of relationship was similar for GA. For people with a single risk allele OR=2.1 (95%CI, 1.3-3.6, P ≤ 0.004); for people homozygous for the risk allele OR=2.7 (95% CI, 0.98--7.7, P ≤ 0.06). Additive models yielded the following results: (1) for NV AMD OR=2.1 (95% CI, 1.5-3.1, P ≤ 0.00004); for GA OR=1.9 (95%CI, 1.3-2.8, P ≤ 0.002).
Conclusions: :
A common functional variant in the complement component 3 gene (Arg102Gly, rs2230199) is associated both with NV AMD and GA after considering the impact of age, smoking, and known genetic risk factors. Our results support the idea that there is an inflammatory and immune-related basis of AMD pathogenesis. We are currently examining these relationships in independent populations.
Clinical Trial: :
www.clinicaltrials.gov NCT00000145
Keywords: age-related macular degeneration • clinical (human) or epidemiologic studies: risk factor assessment • genetics