The Eyes Have It Studying Age-Related Macular Degeneration …. The GenEpi Way

1. The Eyes Have ItStudying Age-Related Macular Degeneration….The GenEpi Way Brooke Longville PhD Candidate Supervisors: Prof. Lyle Palmer (Western Australian Institute for Medical Research) Prof. Piroska Rakoczy (Lions Eye Institute) Dr Wayne Greene (Murdoch University) Western Australian Institute for Medical Research

2. So… what is a macula?

3. Your Eye: The macula contains a high concentration of rod and cone photoreceptors… This enables high quality, detailed vision- very useful!

4. What is Age-Related Macular Degeneration (AMD)? • AMD is the leading cause of blindness in the elderly • Causes 60% of all severe vision loss • Characterized by changes in the macula: (a region of the retina responsible for our central and most important field of vision) • Deposition of waste debris (drusen) • New formation of unwanted blood vessels • Atrophy = very irregular and distressed retina surface!

5. What causes AMD? • Complex array of risk factors suspected: • Genetic • Inherited risk (20% of sufferers have a first relative family history) • Possible correlation with other diseases/disorders such as cardiovascular, inflammatory etc.. • Environmental • SMOKING – associated with 2 - 4x increased risk • Diet • UV exposure • And many more suspects • No cure yet (hence the research…)

6. Taking a closer look…

7. … at a chunk of your retina.

8. Dry AMD Wet AMD Choroidal Neovascularisation Geographic Atrophy Drusen (hard type) Drusen (Exudative/wet/soft type)

9. This is an example of what a person with severe AMD would see

10. Now, for a wee bit more detail…

11. AMD- Two Forms: Dry and Wet • Dry Form • Most common form of AMD • Accounts for 90% of AMD cases • Less impact on vision than wet form • Clinical Signs: • Geographic Atrophy (GA) • shrinkage/degeneration of retinal cells, resulting in thinning of retina • Drusen • yellow deposits of debris on the retina • No known effective treatment

12. AMD- Two Forms: Dry and Wet • Wet Form(aka Exudative/Neovascular) • Less common than dry form • Accounts of 10% of AMD cases • But more serious… • Accounts for 85% of AMD-related legal blindness • Clinical Signs: • Drusen • Choroidal Neovascularisation (CNV) • Formation of new, undesired blood vessels behind the retina • Can result in leakage or bleeding • Vision loss may be sudden and severe • Has been linked to smoking… nicotine is an angiogenic agent • Existing treatments for management of wet AMD • Laser treatment may help destroy the new blood vessels • Surgery to remove haemorrhage

13. Impact of AMD • 800,000 Australians currently have some signs of AMD, and 2/3rds of us will experience AMD symptoms at some stage of our lives • AMD significantly impairs quality of life • Reduced ability to work, socialize, perform daily tasks independently • Economic importance • Reduced productivity • Increased medical and caring expenditure

14. Getting down to business.(Here’s where I come in)The WA Macular Degeneration StudyAKA Brooke’s PhD research

15. Study Hypothesis • We hypothesize that genetic factors contribute significantly to the risk of AMD development, and that these factors may be found by studying whole genome scans of AMD affected patients. • This technique has been used successfully by Haines, Klein and Edwards(2005) to discover one such genetic risk factor, a complement factor H gene variant.

16. The AMD Study… • Prospective study: 5 years, 5000 participants • all participants are AMD patients at Lions Eye Institute • Collect blood – extract DNA • Whole Genome Scan (100,000 SNPs) • Questionnaire • Environmental factors • Clinical data • Ophthalmologists’ diagnoses and observations • Retina Photographs • Objectivity and disease progression

17. Questionnaire content • Patient questionnaire: • Smoking -Diet • UV exposure -Education • Medications • Medical history (i.e. cancer, high blood pressure) • Ethnic background • Family history -Alcohol consumption • Clinical questionnaire: Patient’s visual acuity Observations from fluorescien angiography Observations from colour photography Diagnosis Treatments administered

18. The big picture… AMD database DNA and Serum Specimen Data Clinical Data Genome scan – SNP analysis Environmental Data Planned future data linkage Reference location only Retina photos (LEI database) Other relevant databases Eg. Health department: -morbidity, mortality Family connections Etc..

19. Disease Linkage • AMD study cases • linked to health dept. data • de-identified • Correlation/Linkage • Search for correlation between AMD and other diseases i.e. atherosclerosis • Search for linkage with gene variants that are known/suspected to cause disease • Heritability • Investigate AMD occurrence in related individuals

20. Recent Research Discoveries • Complement Factor H (CFH) variant • Reported May 2005 (Haines; Klein; Edwards) • Thought to contribute significantly to risk of AMD development • Normally, CFH… • Regulates rate of complement deposition • Prevents complement buildup on host tissues • Is thought to be positively affected by 2mM [Zn] • Plasma CFH levels increase with age (of patient) • Plasma CFH levels decrease in smokers

21. But when CFH VARIANT is present… • CFH variant is thought to be inactive or less active than normal CFH • Single amino acid differs at substrate binding site • Thus: • Complement deposition is not regulated properly • Complement buildup in host tissues more likely • As the population ages (and plasma CFH levels increase), those with defective CFH will become more apparent

22. Aims of Study • Find genetic factors contributing to risk of AMD development • Search for the CFH variant (as described by Haines; Klein; Edwards) • Are their findings supported? • Investigate linkage/correlation between AMD and other diseases • Consider influence of other factors, such as smoking

23. Contributors • My Supervisors (all legends): • Prof. Lyle Palmer (WAIMR) • Prof. Piroska Rakoczy (LEI) • Dr Wayne Greene (Murdoch) • Other important sources of wisdom: • Prof. Ian Constable (LEI) • LEI Clinic Staff • PathCentre Staff • The WAIMR GenEpi Group (office budskis) • Everyone else in my email inbox • Big thanks to the study patients!