Should Genetic Risk for ARMD Play a Role in Intra-Ocular Lens

Selection?

Steve A. Arshinoff MD FRCSCHumber River Regional Hospital

Departments of Ophthalmology and Vision Sciences,University of Toronto & McMaster University

Financial Disclosures - SAA:

Carl Zeiss Inc - Consultant

Alcon Laboratories Inc. - Consultant

Arctic Dx. Inc - Consultant

Financial Disclosures - BZ:

Arctic Dx. Inc – Shareholder

Brent Zanke, MD PhD FRCPCDivision of Hematology

University of Ottawa

UV 400 filtering ? Blue Light Filtering ? Multifocal ?

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) HaplotypesThe 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. ARMS2The 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

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 mt factor 1 for GG diplotype 1 for A 2.7 for TG diplotype 2.16 for G

C3 factor Smoking factor 1 for CC diplotype 1 for never 1.7 for GC diplotype 1.46 for ex smoker 2.6 for GG diplotype 3.14 for current smoker

Risk Score X = (CFH factor)(ARMS2 factor)(C3 factor)(mt factor)(smoking factor)

Risk Score (X) Risk Category1-7.9 1

8.0-28.9 229.0-101 3101.1-185 4

185.1-2600 5

AMD-Associated Blindness Lifetime Risk Prevalence by Risk Category

Note: Level 3 + 4 + 5 = 20% of population A=Average

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

21

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.

• MaculaRisk testing demonstrated his risk of ARMD by age 80 to be only 5-15% (Category 2 – average) !

OD OS

AMD-risk sensitive IOL choice Algorithm

Low Risk

• Clear or

• MIOL

AMD Genetic Testing

High Risk

• 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 “macula-protective”, it seems reasonable to consider ARMD risk when choosing an IOL. We have presented the first algorithm developed for this purpose.