1. Should Genetic Risk for ARMD Play a Role in Intra-Ocular Lens Selection? Steve A. Arshinoff MD FRCSC Humber 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 FRCPC Division of Hematology University of Ottawa UV 400 filtering ?Blue Light Filtering ?Multifocal ?

2. 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.

3. 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.

4. 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?

5. 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

6. 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.

7. 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.

8. 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 factorSmoking 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 Category 1-7.91 8.0-28.92 29.0-1013 101.1-1854 185.1-26005

9. AMD-Associated Blindness Lifetime Risk Prevalence by Risk Category Note: Level 3 + 4 + 5 = 20% of population A=Average CategoryRisk LevelRisk Range: age 80Prevalence 1Reduced0-5%49.6% 2Average6-15%30.6% 3Increased16-40%16.6% 4High40-55%2.2% 5Very High55-94%1.0% 5 4 3 A 2 1

10. 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) ! ODOS

11. 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.

12. 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.