C9: A new genetic risk factor for AMD

Research details

  • Type of funding: PhD Studentship
  • Grant Holder: Dr David Kavanagh
  • Institute: Newcastle University
  • Region: North East
  • Start date: December 2015
  • End Date: November 2018
  • Priority: Causes
  • Eye Category: AMD


Age-related macular degeneration (AMD) causes people to lose their central vision. Several studies have linked the risk of getting AMD to certain genetic changes that affect what’s known as the ‘complement system’. This is part of the body’s defence against bacteria and viruses, but if it goes wrong it can turn on the body’s own cells.

The research team has recently found a new genetic link to a protein called C9, which is part of the complement system. In this project they will study blood and cell samples from patients with AMD to find out whether C9 is overactive. They will also try to develop an antibody test that would identify which patients could benefit from new drugs that stop the complement system from becoming overactive.

At the end of the project the team aim to have a test that can identify people at risk of AMD due to C9 and the data needed to develop targeted drug treatments.

  • Scientific summary

    Genetic variants of complement terminal pathway components in age-related macular degeneration

    Age-related macular degeneration (AMD) is a common disease with multifactorial aetiology. In addition to behavioural and environmental factors, more than 20 common genetic loci have been confirmed to be associated with AMD. Genome wide association studies in 2005 linked a common polymorphism in complement factor H to AMD with subsequent studies identifying associations in other complement alternative pathway genes.

    The team has identified a genetic variant in the terminal pathway of complement associated with AMD (C9; p.Pro167Ser; OR=2.2). This project probes the functional consequences of this variant in order to understand how it influences risk of AMD.

    The student is first assessing the effect of the C9Pro167Ser variant on plasma haemolytic activity; native and variant C9 is then being purified from plasma and, in parallel, recombinant C9wt/Pro167Ser is being generated. Surface plasmon resonance will assess binding to complement regulatory proteins, components of the membrane attack complex and the C5b-8 complex. Reconstitution haemolytic assays and cell activation assays on retinal pigment epithelia will further assess functional consequences of the variant. C9Pro167Ser variant specific monoclonal antibodies are being generated to produce an ELISA that quantifies variants in plasma. The student is exploring the available large cohorts to identify private C9 genetic variants that segregate in AMD pedigrees. By demonstrating a causative role for the final effector molecule, C9, in AMD pathogenesis, this project will provide a rationale for late complement inhibition in disease. In addition, a risk variant specific ELISA identifies those patients most likely to benefit from complement inhibitory therapy.