PURPOSE: Systemic complement activation is associated with age-related macular degeneration (AMD) and has mainly been attributed to a risk allele in the complement factor H (CFH) gene. Whether other important AMD genes also influence complement activation is unclear. In the present case-control study, complement activity and concentrations of complement components and their activation products are measured in AMD patients and in unaffected controls and correlated with genetic variants in the CFH, ARMS2, C3, CFI, and CFB genes. DESIGN: Case-control study. PARTICIPANTS: A cohort of 197 confirmed AMD patients and 150 unaffected age-matched controls were recruited prospectively for the study. METHODS: Hemolytic complement assays (AP50, CP50, and LP50), complement components (C3, CFB, CFI, and CFH), and the activation products (C3d, C5a, and SC5b-9) were analyzed in serum or plasma. The DNA samples were genotyped for 5 single nucleotide polymorphisms (SNPs) previously associated with AMD in the CFH, ARMS2, C3, CFB, and CFI genes. MAIN OUTCOME MEASURES: Complement concentrations and their associations with SNPs in the CFH, ARMS2, C3, CFB, and CFI genes. RESULTS: The AMD patients had increased activation of the alternative complement pathway (P = 0.003) and elevated levels of complement activation components C3d (P<0.0001) and C5a (P<0.0001), CFB (P<0.0001), and an increased C3d/C3 ratio (P<0.0001) calculated as a measure of C3 activation. While the CFH risk genotype was significantly associated with the elevated C3d/C3 ratios obtained, in the absence of CFH risk alleles the ARMS2 risk genotype also showed significantly increased levels of complement activation (P = 0.013). Furthermore, the carriers of the CFB protective allele had lower CFB concentrations. CONCLUSIONS: The current study found evidence showing that in AMD risk alleles in CFH and ARMS2 are independently associated with complement activation. Especially the C3d/C3 ratio seems to be a strong marker for AMD. The findings suggest that CFH and ARMS2 share a common pathway in the pathogenesis of AMD.
PURPOSE: Systemic complement activation is associated with age-related macular degeneration (AMD) and has mainly been attributed to a risk allele in the complement factor H (CFH) gene. Whether other important AMD genes also influence complement activation is unclear. In the present case-control study, complement activity and concentrations of complement components and their activation products are measured in AMDpatients and in unaffected controls and correlated with genetic variants in the CFH, ARMS2, C3, CFI, and CFB genes. DESIGN: Case-control study. PARTICIPANTS: A cohort of 197 confirmed AMDpatients and 150 unaffected age-matched controls were recruited prospectively for the study. METHODS: Hemolytic complement assays (AP50, CP50, and LP50), complement components (C3, CFB, CFI, and CFH), and the activation products (C3d, C5a, and SC5b-9) were analyzed in serum or plasma. The DNA samples were genotyped for 5 single nucleotide polymorphisms (SNPs) previously associated with AMD in the CFH, ARMS2, C3, CFB, and CFI genes. MAIN OUTCOME MEASURES: Complement concentrations and their associations with SNPs in the CFH, ARMS2, C3, CFB, and CFI genes. RESULTS: The AMDpatients had increased activation of the alternative complement pathway (P = 0.003) and elevated levels of complement activation components C3d (P<0.0001) and C5a (P<0.0001), CFB (P<0.0001), and an increased C3d/C3 ratio (P<0.0001) calculated as a measure of C3 activation. While the CFH risk genotype was significantly associated with the elevated C3d/C3 ratios obtained, in the absence of CFH risk alleles the ARMS2 risk genotype also showed significantly increased levels of complement activation (P = 0.013). Furthermore, the carriers of the CFB protective allele had lower CFB concentrations. CONCLUSIONS: The current study found evidence showing that in AMD risk alleles in CFH and ARMS2 are independently associated with complement activation. Especially the C3d/C3 ratio seems to be a strong marker for AMD. The findings suggest that CFH and ARMS2 share a common pathway in the pathogenesis of AMD.
Authors: Gabriëlle H S Buitendijk; Elena Rochtchina; Chelsea Myers; Cornelia M van Duijn; Kristine E Lee; Barbara E K Klein; Stacy M Meuer; Paulus T V M de Jong; Elizabeth G Holliday; Ava G Tan; André G Uitterlinden; Theru S Sivakumaran; John Attia; Albert Hofman; Paul Mitchell; Johannes R Vingerling; Sudha K Iyengar; A Cecile J W Janssens; Jie Jin Wang; Ronald Klein; Caroline C W Klaver Journal: Ophthalmology Date: 2013-10-10 Impact factor: 12.079
Authors: Nathan G Lambert; Hanan ElShelmani; Malkit K Singh; Fiona C Mansergh; Michael A Wride; Maximilian Padilla; David Keegan; Ruth E Hogg; Balamurali K Ambati Journal: Prog Retin Eye Res Date: 2016-05-06 Impact factor: 21.198
Authors: S Scott Whitmore; Elliott H Sohn; Kathleen R Chirco; Arlene V Drack; Edwin M Stone; Budd A Tucker; Robert F Mullins Journal: Prog Retin Eye Res Date: 2014-12-05 Impact factor: 21.198
Authors: Ronald Klein; Chelsea E Myers; Stacy M Meuer; Ronald E Gangnon; Theru A Sivakumaran; Sudha K Iyengar; Kristine E Lee; Barbara E K Klein Journal: JAMA Ophthalmol Date: 2013-03 Impact factor: 7.389
Authors: Johannes P H van de Ven; Sara C Nilsson; Perciliz L Tan; Gabriëlle H S Buitendijk; Tina Ristau; Frida C Mohlin; Sander B Nabuurs; Frederieke E Schoenmaker-Koller; Dzenita Smailhodzic; Peter A Campochiaro; Donald J Zack; Maheswara R Duvvari; Bjorn Bakker; Codrut C Paun; Camiel J F Boon; Andre G Uitterlinden; Sandra Liakopoulos; B Jeroen Klevering; Sascha Fauser; Mohamed R Daha; Nicholas Katsanis; Caroline C W Klaver; Anna M Blom; Carel B Hoyng; Anneke I den Hollander Journal: Nat Genet Date: 2013-05-19 Impact factor: 38.330