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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    ABSTRACT: Age-related macular degeneration (AMD) is a complex disease caused by a combination of genetic and environmental factors. Genome-wide association studies have identified several common genetic variants associated with AMD, which together account for 15%-65% of the heritability of AMD. Multiple hypotheses to clarify the unexplained portion of genetic variance have been proposed, such as gene-gene interactions, gene-environment interactions, structural variations, epigenetics, and rare variants. Several studies support a role for rare variants with large effect sizes in the pathogenesis of AMD. In this work, we review the methods that can be used to detect rare variants in common diseases, as well as the recent progress that has been made in the identification of rare variants in AMD. In addition, the relevance of these rare variants for diagnosis, prognosis, and treatment of AMD is highlighted.
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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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    ABSTRACT: Complement activation is thought to contribute to the pathogenesis of age-related macular degeneration (AMD), which may be mediated in part by para-inflammatory processes. We aimed to investigate the expression and localization of C3, a crucial component of the complement system, in the retina during the course of aging. SD rats were born and reared in low-light conditions, and euthanized at post-natal (P) days 100, 450, or 750. Expression of C3, IBA1, and Ccl- and Cxcl- chemokines was assessed by qPCR, and in situ hybridization. Thickness of the ONL was assessed in retinal sections as a measure of photoreceptor loss, and counts were made of C3-expressing monocytes. C3 expression increased significantly at P750, and correlated with thinning of the ONL, at P750, and up-regulation of GFAP. In situ hybridization showed that C3 was expressed by microglia/monocytes, mainly from within the retinal vasculature, and occasionally the ONL. The number of C3-expressing microglia increased significantly by P750, and coincided spatiotemporally with thinning of the ONL, and up-regulation of Ccl- and Cxcl- chemokines. Our data suggest that recruited microglia/monocytes contribute to activation of complement in the aging retina, through local expression of C3 mRNA. C3 expression coincides with age-related thinning of the ONL at P750, although it is unclear whether the C3-expressing monocytes are a cause or consequence. These findings provide evidence of activation of complement during natural aging, and may have relevance to cellular events underling the pathogenesis of age-related retinal diseases.
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