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Should Genetic Risk for ARMD Play a
Role in Intra-Ocular Lens Selection?
UV 400 filtering ?
Blue Light Filtering ?
Multifocal ?
Steve A. Arshinoff MD FRCSC
Brent Zanke, MD PhD FRCPC
Humber River Regional Hospital
Departments of Ophthalmology and Vision Sciences,
University of Toronto & McMaster University
Division of Hematology
University of Ottawa
Financial Disclosures - SAA:
Carl Zeiss Inc - Consultant
Financial Disclosures - BZ:
Alcon Laboratories Inc. - Consultant
Arctic Dx. Inc – Shareholder
Arctic Dx. Inc - Consultant
Age Related Macular Degeneration (ARMD)
Future Risk Considerations in IOL Selection.
• ARMD causes reduction in image resolution resulting in
severely decreased performance of mulltifocal IOLs
(MIOLs) and patient dissatisfaction.
• Blue light filtering IOLs may reduce subsequent risk of
ARMD after cataract extraction in those at heightened
genetic risk.
• Those at low genetic risk for ARMD may get optimal
short and long term visual benefit from a clear, rather
than a yellow lens.
Can ARMD be predicted on
genetic grounds?
• ARMD is slowly being shown to be a disease of impaired
repair mechanisms. This should not surprise us, as the
retinal pigment epithelium (RPE) is the most
metabolically active tissue in our bodies, and that diurnal
photic damage is repaired by nocturnal RPE activity. Age
and Genetics are therefore, not surprisingly, the single
largest determinants of ARMD risk.
• Like another previously phenotypically recognized retinal
disease group, retinitis pigmentosa, it is becoming ever
more likely that ARMD will be subdivided genotypically,
not phenotypically.
Other ARMD Risk Factors
• Environment risk factors include smoking and
perhaps life-time UV exposure, but these are
minor when compared to the influence of
genetics.
• Can genetics accurately predict ARMD?
• Can we create an algorithm to calculate combined
genetic and smoking behavioral risk?
Genetic Risk Prediction : The Technology
Genotype “Single Nucleotide Polymorphisms” (SNPs) that
predict for ARMD risk have been discovered, can be
tabulated for any individual, and interpreted in a validated
mathematical algorithm assessing individual ARMD risk.*
*Zanke et al. Canadian Journal of Ophthalmology VOL. 45, NO. 1, 2010
Algorithm Development Method
 Disease prevalence
 Odds ratio of risk alleles
 Odds ratio of smoking
 Prevalence of risk factors
Logistic
regression-generated
model of absolute
risk.
Genetic Markers to Assess MaculaRisk
1.
Complement Factor H (CFH) Haplotypes
The CFH region of chromosome 1 is a major risk gene associated with
ARMD. Several sequence variations consistently inherited together
(haplotypes) may occur, each carrying its own risk. We can distinguish 8
different haplotypes; some highly protective, some neutral, and some
associated with increased risk. Caucasians are at higher risk of ARMD,
and much of this risk is associated with C3H haplotype.
2.
Complement component 3 (C3)
The C3 gene variant is associated with double the risk of advanced dry
and wet ARMD, compared to the consensus sequence variant.
3.
ARMS2
The ARMS gene, located on chromosome 10, codes for a protein
important in the response to oxidative stress. One sequence variant is
associated with up to 7 time risk for ARMD.
4.
Mitochondrial DNA Mutation 4917G (mt factor)
This gene is important in response to oxidative stress, and one
variant is associated with over 2 times the risk of ARMD.
Markers and Risk Algorithm
Risk Score X = (CFH factor)(ARMS2 factor)(C3 factor)(mt factor)(smoking factor)
CFH factor
1 for favorable diplotype (H1, H3 and H5-8 combinations)
4.33 for intermediate diplotype (mixture of 1 favorable and 1 unfavorable diplotype)
17.97 for unfavorable diplotype (H2 and H4 combinations)
ARMS2 factor
1 for GG diplotype
2.7 for TG diplotype
C3 factor
1 for CC diplotype
1.7 for GC diplotype
2.6 for GG diplotype
mt factor
1 for A
2.16 for G
Smoking factor
1 for never
1.46 for ex smoker
3.14 for current smoker
Risk Score (X) Risk Category
1-7.9
8.0-28.9
29.0-101
101.1-185
185.1-2600
1
2
3
4
5
AMD-Associated Blindness Lifetime Risk
Prevalence by Risk Category
Category
Risk Level
Risk Range: age 80
Prevalence
1
Reduced
0-5%
49.6%
2
Average
6-15%
30.6%
3
Increased
16-40%
16.6%
4
High
40-55%
2.2%
5
Very High
55-94%
1.0%
5
4
3
A
2
1
Note: Level 3 + 4 + 5 = 20% of population
A=Average
Case Example
• 55 y.o. myopic (-5D ou) white male PhD pharmaceutical
company researcher has been followed for 20 years for
unchanging “early ARMD”. He seeks advice for his
cataract surgery.
OD
OS
• MaculaRisk testing demonstrated his risk of ARMD by
age 80 to be only 5-15% (Category 2 – average) !
AMD-risk sensitive IOL choice
Algorithm
High Risk
AMD Genetic
Testing
Low Risk
• Clear or
• MIOL
• Retinal assessment
− Retinal micronutrients
− Amsler Grid
− Regular followup
• Blue filter IOL
• Avoid MIOL
• The patient described on the preceding slide elected not to have a
multifocal IOL, but is shown for educational value. Sometimes genotype
will not match expectations from phenotype, suggesting that disease
progression rate may primarily be genetically based.
Summary
• Age Related Macular Degeneration is progressively recognized as
a genetic disorder of repair, with some environmental contribution.
• ARMD will be increasingly classified genotypically rather than
phenotypically.
• Genetic assessment can determine individual risk of ARMD.
• As some IOLs may perform worse under conditions of reduced
contrast sensitivity, while others may be somewhat “maculaprotective”, it seems reasonable to consider ARMD risk when
choosing an IOL. We have presented the first algorithm developed
for this purpose.
[email protected] & [email protected]