Impact of the Common Genetic Associations of Age-Related Macular Degeneration upon Systemic Complement Component C3d Levels

Abstract

Age-related macular degeneration (AMD) is a common condition that leads to severe vision loss and dysregulation of the complement system is thought to be associated with the disease. To investigate associations of polymorphisms in AMD susceptibility genes with systemic complement activation, 2655 individuals were genotyped for 32 single nucleotide polymorphisms (SNPs) in or near 23 AMD associated risk genes. Component 3 (C3) and its catabolic fragment C3d were measured in serum and AMD staging was performed using multimodal imaging. The C3d/C3 ratio was calculated and associations with environmental factors, SNPs and various haplotypes of complement factor H (CFH) genes and complement factor B (CFB) genes were analyzed. Linear models were built to measure the influence of genetic variants on the C3d/C3 ratio. The study cohort included 1387 patients with AMD and 1268 controls. Higher C3d/C3 ratios were found for current smoker (p = 0.002), higher age (p = 1.56×10−7), AMD phenotype (p = 1.15×10−11) and the two SNPs in the C3 gene rs6795735 (p = 0.04) and rs2230199 (p = 0.04). Lower C3d/C3 ratios were found for diabetes (p = 2.87×10−6), higher body mass index (p = 1.00×10−13), the SNPs rs1410996 (p = 0.0001), rs800292 (p = 0.003), rs12144939 (p = 4.60×10−6) in CFH, rs4151667 (p = 1.01×10−5) in CFB and individual haplotypes in CFH and CFB. The linear model revealed a corrected R-square of 0.063 including age, smoking status, gender, and genetic polymorphisms explaining 6.3% of the C3d/C3 ratio. After adding the AMD status the corrected R-square was 0.067. In conclusion, none of the evaluated genetic polymorphisms showed an association with increased systemic complement activation apart from two SNPs in the C3 gene. Major genetic and non-genetic factors for AMD were not associated with systemic complement activation.

Local complement activation in aqueous humor in patients with age-related macular degeneration

“…13,14 The differences were statistically significant due to slightly higher median values in a large number of samples with a big overlap in the range of values between both groups. This is not relevant on the individual level because there is a large variation in systemic complement levels.…”

“…1,[5][6][7][8][9][10][11][12] Although AMD disease manifestation is localized in the eye, a slight systemic elevation of complement components and activation products in AMD patients were found for FB and factor D as well as for 3a, C5a, C3d, and Ba, respectively. 13,14 However, little is known about the extent and relationship between systemic and local complement dysregulation in AMD. In this study, we analyzed various complement proteins, their activation products and regulators in aqueous humor and in EDTAplasma of patients with and without nAMD.…”

Complement Activation Levels Are Related to Disease Stage in AMD

“…27 Disturbances of these regulating mechanisms lead to an increase in complement activation and subsequently an increased inflammatory reaction, which may ultimately result in tissue damage and AMD. 28 Systemic levels of complement components have been associated with environmental factors such as age, sex, smoking, body mass index, triglyceride levels, [29][30][31] and genetic AMD variants in complement genes (C3, CFB, and CFH), indicating that at least a part of the complement activation is influenced by genetics. 11 Modulation of the complement system by targeting the regulating components is now the focus for the development of new treatment modalities for AMD.…”

Anti-glutamine synthetase and other potential autoantibody biomarkers in the sera of patients with age-related macular degeneration

“…Sera from AMD patients showed strong reactivities to a variety of complement factors. In other studies, SNPs in the genes C3 and CFH involved in complement activation were strongly associated with AMD (Scholl et al 2008, Ristau et al 2014. C3 activates the complement pathway whereas CFH serves as a regulator of complement activation, and CFH-deficient mice tend to develop ocular features characteristic of AMD compared with wild type controls (Coffey et al 2007).…”