Abbreviations
- ARMD = Age Related Macular Degeneration
- wet ARMD = neovascular ARMD with CNV
- CNV = choroidal neovascularisation
- GA = geographic atrophy
Genes in wet ARMD (Age Related Macular Degeneration)
David Kinshuck
Wet ARMD genes 2011
Wet ARMD has a substantial genetic component (Nottingham 2011) see
- chromosome 10
- compliment genes
- a combination
The chromosome 10 route (Nottingham 2011), Hageman
This pathway accounts for 92% of the genetic component of wet ARMD. This is much more common in women, as the men die early. The CNV develop average age 78, the GA about 5 years later.
| ARMS2 / HtrA / (PLEKHA1) |
 |
| vascular changes in the choroid due to lack of perfusion |
|
| reticular drusen/ pseudodrusen (these are vascular changes in the choroid, which appear as RPE changes on the OCT (but this is an artefact...the changes are in the choroid) risk |
|
| Geographic atrophy, lobulated type |
|
| CNV / wet ARMD |
The compliment route
In the last 5 years we have learnt the most important genes that affect ARMD. Many influence the complement pathway. For many years drusen have been shown to contain a lot of complement-like material, and now we know the main genes are involved in complement.
Complement is a protein in blood, used as part of the clotting mechanism. In this respect ARMD should be considered as a systemic disease. diagram diagram Patel's paper is very detailed and has many references. Here are some of the compliment genes
- complement
factor H (CFH)...at a DNA position 402 TYR protects at
location 1q32 , 10q26:
LOC 38715 (ARM 52), and HIS contributes to ARMD (a
simple one molecule change in our DNA) CFH
Y402H 2008 Farwick09.
This Y402 gene seems to be related to the difference in AMD in Chinese.
The genes affect receptor binding. - A similar gene also influences CFH.
' SNP rs3753394 in the CFH promoter carries a significantly increased risk for exudative AMD' and this can be a very important effect in smokers, greatly magnifying the harmful effect of smoking. - Pharmacogenetics of complement factor H (Y402H) influences treatment outcome, Lee Br J Ophthalmol 2009
- Complement is discussed in detail Eye
2011
- 'The
genes involved in inherited macular dystrophies such as ATP-binding
cassette, subfamily A (ABC1), member 4 (ABCA4), vitelliform macular
dystrophy (VMD2), tissue inhibitor of matrix metalloproteinase-3 (TIMP3),
and EFEMP1have yielded some important information but further confirmatory
work has yet to establish a clear association with AMD' .
- A Complement C3 Variant also increases the risk 2.6 times C3 R102G polymorphism
- there are systemic risks....CNV are often associated with a raised CRP...a 2.6x risk. This probably causes a low grade inflammation that activates complement.
- A Factor H blood test can detect risk.
- CFH LOC 387 715 determines PDT response Brantley 2009
- Eye reviews complement 2011
- NEJM Genomics 2011
- Reticular macular disease and Archives 2011 & Complement Factor H 402H Variant
- Arch 2012 'Y402H risk variant is associated with lifetime incidence of early AMD and progression of early to late AMD and that late AMD is associated with mortality risk'
- FPR Eye 14
- Autosomal dominant radial drusen (ADRD), also termed Malattia Leventinese and Doyne honeycomb retinal dystrophy, causes early-onset vision loss because of mutation in EFEMP1 Retina 15
The complement pathway is key in such functions as fighting infection. But it is also involved in ARMD. In dry ARMD it is found in drusen, and various studies of wet show a relationship.
- ARMD is not related to vitamin D deficiency Eye 2011
- Antioxidants...a different response
- Toll3 in geographic atrophy
- A summary
- Fibulin 3, 5, 6
- HTRA1 gene is linked to ARMD, particularly geographic atrophy. In Chinese
- the gete profile influences the anti-vegf response BJO 12
- ARMS2 A69S variant confers a significantly higher risk of neovascular AMD than PCV
- Geographic and CNV together HTRA1 gene Eye 2012
- Arms2 A69s Variant and Bilateral Advanced Age-Related Macular Degeneration Retina 2012
- the genes infuencing the dry and wet components may be different, and interact with smoking (Retina 2012)
- HG 2012
Smoking
Risks are 250 times higher with some gene
combinations, especially in smokers.
HIS402 and HTRA1 rs 11200638...this
combination has a very high risk. A much lower risk with TYR 402.
Seddon
09 11 has
worked out the relevant risks of each gene, and these will soon be
used to calculate each person's risk. Seddon 11
" In multivariate models, age, smoking, body mass index, single nucleotide polymorphisms in the CFH, ARMS2/HTRA1, C3, C2, and CFB genes, as well as presence of advanced AMD in 1 eye and drusen size in both eyes were all independently associated with progression."
| Risk factors used in Seddons 09 model |
|
Klein's model
"The final model included the following independent variables: age, smoking history, family history of AMD (first-degree member), phenotype based on a modified Age-Related Eye Disease Study simple scale score, and genetic variants CFH Y402H and ARMS2 A69S. "