Human Molecular Genetics Advance Access [Accepted Manuscript] published online on October 13, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp472
Genetic control of the alternative pathway of complement in humans and age-related macular degeneration
1 Department of Ophthalmology, Mayo Clinic, Rochester, MN, 55905, USA 2 Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA 3 Department of Ophthalmology, University of Bonn, Bonn D-53127, Germany 4 Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen 37073, Germany
* Corresponding author: Albert O. Edwards, Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA, Phone: 507-284-2787, Fax: 507-284-4612, Email: aoe102{at}gmail.com
Received July 17, 2009; Revised October 9, 2009; Accepted October 9, 2009
Activation of the alternative pathway of complement is implicated in common neurodegenerative diseases including age-related macular degeneration (AMD). We explored the impact of common variation in genes encoding proteins of the alternative pathway on complement activation in human blood and in AMD. Genetic variation across the genes encoding complement factor H (CFH), factor B (CFB), and component 3 (C3) was determined. The influence of common haplotypes defining transcriptional and translational units on complement activation in blood was determined in a quantitative genomic association study. Individual haplotypes in CFH and CFB were associated with distinct and novel effects on plasma levels of precursors, regulators, and activation products of the alternative pathway of complement in human blood. Further, genetic variation in CFH thought to influence cell surface regulation of complement did not alter plasma complement levels in human blood. Plasma markers of chronic activation (split-products Ba and C3d) and an activating enzyme (factor D) were elevated in AMD subjects. Most of the elevation in AMD was accounted for by the genetic variation controlling complement activation in human blood. Activation of the alternative pathway of complement in blood is under genetic control and increases with age. The genetic variation associated with increased activation of complement in human blood also increased the risk of AMD. Our data are consistent with a disease model in which genetic variation in the complement system increases AMD risk by a combination of systemic complement activation and abnormal regulation of complement activation in local tissues.
Presented at the Annual Association for Research in Vision and Ophthalmology (ARVO) meeting, May 5, 2009.