Genetics in Glaucoma- The Importance and The Interpretation

1. Geneticsin Glaucoma-The Importance and The Interpretation Hani Levkovitch-Verbin, MD Goldschleger Eye Institute, Sheba Medical Center

2. Genetics in glaucoma- why?? Family history- important risk factor for developing glaucoma and progression (Baltimore Eye Survey, Barbados Eye Study, Notingham Family Glaucoma Screening Study)

3. Genetics in glaucoma • In most studies the prevalence of glaucoma in first degree relatives is higher than 10%. • First degree relatives- eightfold increased risk of developing POAG

4. Heredity of POAG • The lifetime risk of a sibling to develop glaucoma by the age of 70 is almost 20%. For glaucoma suspect the risk is higher. • Prevalence varies between ethnic groups • 5 times higher in African American than in Caucasians • In Barbados 12.8% • In St. Lucia 8.8%

5. Up to date in genetics of glaucoma • Rationale • Novel findings • limitations of genetic information • The future- diagnostic and predictive tests?? gene therapy? • Genetic study- in Sheba Medical Center

6. Progression in the field • The Human Genome Project- completed in 2001 • Identified 20000-25000 genes in human nuclear DNA • Identify the sequence of 3 billion base pairs • The HapMap project- describes the common patterns of human DNA- genetic variation in different populations worldwide

7. Progression in the field • Unraveling causes of ocular diseases • Identifying high-risk groups for interventions • Screening • early intervention with available treatment • New ethical, legal and moral concerns • privacy and discrimination • Psychological responses • Nonpaternity and adoption

8. AMD • Mutations in complement factor H were identified as major risk factor for AMD • Confirmed by several independent research groups Klein et al, Science 2005, Haines et al, Science 2005, Edwards et al, Science 2005, Hageman et al , PNAS 2005

9. Glaucoma • A single gene carried the bulk of the disease burden is unlikely • Complex multi-factorial trait • Autosomal dominant • Autosomal recessive Congenital Developmental

10. POAG Genes that contribute to • IOP elevation (Aqueous outflow regulation) • Optic nerve susceptibility (death and survival of RGC) • Independent actions and interaction of multiple genes +

11. POAG- Mendelian trait • Glaucoma predisposing genes have been identified in 7 genetic loci among them are: • GLC1A-myocilin(TIGR) • GLC1E- optineurin • GLC1G- WDR36 Responsible for small percentage of POAG that is inherited as mendelian trait

12. POAG • Defects in MYOC gene coding for the myocilin protein associated with • 3-5% of adult onset POAG • 20% of early onset POAG • Some mutations are more common with early onset POAG and others with adult onset

13. Myocilin • Glycoprotein that function in the extracellular environment • The role of the normal myocilin protein in aqueous outflow is unknown and it is not required for normal outflow • The mutant form is aggregated inside the cells. May be toxic to trabecular cells or disturb their normal function

14. POAG- complex traitthe majority • Studies on large numbers of sibling pairs and large affected families • 7 additional genetic loci were found in different populations. • Glaucoma susceptibility genes are significant risk factors • chromosomes 5q and 14q are suspicious although a disease locus has not yet been identified

15. POAG- environmental factors • Little is know • Steroid responsiveness for endogenous steroids (stress) or pharmacologic is possible

16. NTG • Strong family history is a risk factor • A single gene susceptibility gene is unlikely • Multiple genes and environmental factors are involved • Associated with mutations in a novel gene OPTN. • Optineurin is expressed in many ocular tissues as well as nonocular

17. NTG • Optineurin may protect the optic nerve from apoptosis caused by TNFα signaling pathway • Functional loss of Optineurin decrease the threshold for RGC death in patients with glaucoma • Altered expression of p53, a known regulatory gene of apoptosis

18. Pseudoexfoliation • A recent breakthrough(Thorleifsson et al Science 2007) • A gene variant confers an extremely high risk of development PXF • Icelandic study that was confirmed in in a Swedish population • The particular SNP is located in a gene that responsible for LOXL1 protein (lysyl oxidase –like protein 1)

19. Pseudoexfoliation • The enzyme helps form elastin fibrils and its malfunction might lead to PXF • A person carrying both high risk variants is 700 times more likely to develop PXF than low risk variants • How exactly it cause PXF- studies in animal models that are genetically engineered • Genetic way to diagnose and prevent blindness • Genetic correction by ocular treatment

20. Future directions • Discover new glaucoma genes and their phenotypes • Developing mutation database for • early diagnosis • prognostic testing

21. Genotype-phenotype correlations Clinical features should be correlated with specific mutations • Onset of disease • course of disease • Response to therapy • In order to know: • Prognosis • Association with particular aspects of the disease • Require additional environmental factors or gene- gene interactions

22. Genetic studyP.I.- Hani Levkovitch-Verbin • 1000 patients • 200 POAG • 200 OHT • 200 PXF • 200 PXFG • 200 Controls

23. Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning Winston Churchill, 1942