Complement C3 Variant and the Risk of Age-Related Macular Degeneration

Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
New England Journal of Medicine (Impact Factor: 55.87). 09/2007; 357(6):553-61. DOI: 10.1056/NEJMoa072618
Source: PubMed


Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.
We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.
The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish group (244 cases and 351 controls, P=5.0x10(-5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.
Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease.

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    • "Because these activation fragments are nondiscriminatory, the complement system is tightly regulated by several inhibitory proteins, including CFH and complement factor I (CFI), which protect the host cells from complement attack. A common variant (Arg102Gly; rs2230199) in the C3 gene has been significantly associated with AMD (Yates et al. 2007). To search for rare and low-frequency variants in the previously identified AMD loci, whole-genome sequencing of 2230 Icelanders was performed and identified sequence variants were predicted (imputed ) for a larger cohort of Icelanders genotyped with SNP microarrays. "
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    • "The loci with the most robust replication across multiple populations and identified as having the strongest effect on AMD risk (odds ratio, for a single risk allele >3) are CFH and ARMS2/ HTRA1 (Edwards et al., 2005; Haines et al., 2005; Jakobsdottir et al., 2005; Klein et al., 2005; Rivera et al., 2005). Candidate gene association studies identified other AMD risk genes in the complement pathway including C2/CFB (Gold et al., 2006), C3 (Maller et al., 2007; Yates et al., 2007), and CFI (Fagerness et al., 2009). "

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    • "Despite this beneficial function, a pathogenic role of the complement system in AMD has been revealed through a string of seminal gene association studies. These identified a significant association between the Y402H sequence variant in the regulatory gene complement factor H (CFH) with the incidence of AMD [16], [17], [18], [19], along with other susceptibility variants in complement pathway genes C2 [12], [20], CFB [12], [20], and the central component C3 [21], [22], [23], [24], [25] in later studies. However, a number of key aspects of the disease process remain unclear, including the cellular events that synthesise and promote complement activity in the retina (reviewed in [12]). "
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