Personalised management of Age Related Macular Degeneration by identification of high risk genetic variants in complement factor I.
Lead Research Organisation:
Newcastle University
Department Name: Institute of Human Genetics
Abstract
Keywords: Tissue disease & degeneration
Abstract: Age related macular degeneration (AMD) is the most common cause of blindness in the developed world, affecting one in three people by age 75.
A genetic role in the pathogenesis of AMD had been suggested by familial aggregation, segregation, linkage, and twin studies. In 2005 several land mark Genome Wide Association studies identified a genetic loci linked to AMD, including a major loci in the complement factor H (CFH) gene on 1q32. Factor H (FH), in concert with Factor I (FI) are the principle regulators of the "always switched on" alternative pathway of complement. Further evidence for the central role of the complement system in AMD has come to light via many additional studies of genes in the complement pathway and through animal modelling, such as the aged cfh+/- mice.
Most known genetic AMD variants are common single nucleotide polymorphisms, without established disease mechanisms. Recently, with our collaborators (Seddon, Atkinson) we sequenced the exons of 681 genes within AMD-associated loci and pathways in ~2500 AMD cases and controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (OR=3.6, p=2x10-8) (Nat Genet 45:1366).
To evaluate the functional impact we measured circulating serum factor I (FI) protein levels in individuals with and without rare CFI variants. In individuals with CFI variants which resulted in decreased FI levels, there was an increased risk of AMD (OR13.6) (Hum Mol Genet, 24:386).
Enhancing FI activity may be therapeutic and measuring FI provides a screening tool for identifying patients who are most likely to benefit from complement inhibitory therapy.
However, 58% of the rare genetic variants we identified in the AMD population were not associated with low FI levels and their functional significance is as yet unclear. It is critical to establish whether these rare genetic variants are functionally significant and therefore whether these individuals would benefit from FI supplementation. This project will examine the functional significance of these rare variants.
Abstract: Age related macular degeneration (AMD) is the most common cause of blindness in the developed world, affecting one in three people by age 75.
A genetic role in the pathogenesis of AMD had been suggested by familial aggregation, segregation, linkage, and twin studies. In 2005 several land mark Genome Wide Association studies identified a genetic loci linked to AMD, including a major loci in the complement factor H (CFH) gene on 1q32. Factor H (FH), in concert with Factor I (FI) are the principle regulators of the "always switched on" alternative pathway of complement. Further evidence for the central role of the complement system in AMD has come to light via many additional studies of genes in the complement pathway and through animal modelling, such as the aged cfh+/- mice.
Most known genetic AMD variants are common single nucleotide polymorphisms, without established disease mechanisms. Recently, with our collaborators (Seddon, Atkinson) we sequenced the exons of 681 genes within AMD-associated loci and pathways in ~2500 AMD cases and controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (OR=3.6, p=2x10-8) (Nat Genet 45:1366).
To evaluate the functional impact we measured circulating serum factor I (FI) protein levels in individuals with and without rare CFI variants. In individuals with CFI variants which resulted in decreased FI levels, there was an increased risk of AMD (OR13.6) (Hum Mol Genet, 24:386).
Enhancing FI activity may be therapeutic and measuring FI provides a screening tool for identifying patients who are most likely to benefit from complement inhibitory therapy.
However, 58% of the rare genetic variants we identified in the AMD population were not associated with low FI levels and their functional significance is as yet unclear. It is critical to establish whether these rare genetic variants are functionally significant and therefore whether these individuals would benefit from FI supplementation. This project will examine the functional significance of these rare variants.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013840/1 | 01/10/2016 | 30/09/2025 | |||
| 1786288 | Studentship | MR/N013840/1 | 01/10/2016 | 02/08/2021 | Thomas Cox |
| Description | Invited to speak at the Newcastle University Academic Medicine Society Conference 2017 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Undergraduate students |
| Results and Impact | 20 medical students attended a lecture conducted by myself and another PhD student on "The complement system and Age-related macular degeneration" as part of the Newcastle University Academic Medicine Society Conference 2017. The presentation was inform the students about the research being conducted in this area and was followed by a question and answer session where we discussed life in the lab and other aspects of the PhD student experience. |
| Year(s) Of Engagement Activity | 2017 |