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

1
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
• Humber River Regional Hospital
• Departments of Ophthalmology and Vision
  Sciences,University of Toronto McMaster
  University

Brent Zanke, MD PhD FRCPC Division of
Hematology University of Ottawa

• Financial Disclosures - SAA
• Carl Zeiss Inc - Consultant
• Alcon Laboratories Inc. - Consultant
• Arctic Dx. Inc - Consultant

• Financial Disclosures - BZ
• Arctic Dx. Inc Shareholder

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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.

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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.

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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?

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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
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Algorithm Development Method

• Disease prevalence
• Odds ratio of risk alleles
• Odds ratio of smoking
• Prevalence of risk factors

Logisticregression-generated model of absolute
risk.
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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.

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Markers and Risk Algorithm
Risk Score X (CFH factor)(ARMS2 factor)(C3
factor)(mt factor)(smoking factor)

CFH factor CFH factor
1 for favorable diplotype (H1, H3 and H5-8 combinations) 1 for favorable diplotype (H1, H3 and H5-8 combinations) 1 for favorable diplotype (H1, H3 and H5-8 combinations)
4.33 for intermediate diplotype (mixture of 1 favorable and 1 unfavorable diplotype) 4.33 for intermediate diplotype (mixture of 1 favorable and 1 unfavorable diplotype) 4.33 for intermediate diplotype (mixture of 1 favorable and 1 unfavorable diplotype)
17.97 for unfavorable diplotype (H2 and H4 combinations) 17.97 for unfavorable diplotype (H2 and H4 combinations) 17.97 for unfavorable diplotype (H2 and H4 combinations)

ARMS2 factor mt factor mt factor
1 for GG diplotype 1 for A 1 for A
2.7 for TG diplotype 2.16 for G 2.16 for G
C3 factor Smoking factor Smoking factor
1 for CC diplotype 1 for never 1 for never
1.7 for GC diplotype 1.46 for ex smoker 1.46 for ex smoker
2.6 for GG diplotype 3.14 for current smoker 3.14 for current smoker

Risk Score (X) Risk Category
1-7.9 1
8.0-28.9 2
29.0-101 3
101.1-185 4
185.1-2600 5
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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
AAverage
Note Level 3 4 5 20 of population
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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)
  !

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AMD-risk sensitive IOL choice Algorithm
High Risk
AMD Genetic Testing

• Retinal assessment
• Retinal micronutrients
• Amsler Grid
• Regular followup
• Blue filter IOL
• Avoid MIOL

Low Risk

• Clear or
• 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.

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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.

Thank you Steve Arshinoff Brent Zanke
ifix2is_at_sympatico.ca bzanke_at_me.com