Genetics in GlaucomaThe Importance and The
Interpretation
Hani Levkovitch-Verbin, MD
Goldschleger Eye Institute,
Sheba Medical Center
Genetics in glaucomawhy??
Family historyimportant risk factor for
developing glaucoma and
progression (Baltimore Eye Survey, Barbados
Eye Study, Notingham Family Glaucoma Screening
Study )
Genetics in glaucoma
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In most studies the prevalence of
glaucoma in first degree relatives
is higher than 10%.
First degree relatives- eightfold
increased risk of developing POAG
Heredity of POAG
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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%
Up to date in genetics of
glaucoma
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Rationale
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Novel findings
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limitations of genetic information
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The future- diagnostic and
predictive tests?? gene therapy?
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Genetic study- in Sheba Medical
Center
Progression in the field
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The Human Genome Projectcompleted in 2001
– Identified 20000-25000 genes in human
nuclear DNA
– Identify the sequence of 3 billion base pairs
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The HapMap project- describes the
common patterns of human DNAgenetic variation in different
populations worldwide
Progression in the field
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Unraveling causes of ocular diseases
Identifying high-risk groups for
interventions
– Screening
– early intervention with available treatment
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New ethical, legal and moral concerns
– privacy and discrimination
– Psychological responses
– Nonpaternity and adoption
AMD
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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
Glaucoma

A single gene carried the bulk of the disease
burden is unlikely
 Complex
multi-factorial trait
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Autosomal dominant
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Autosomal recessive
Congenital
Developmental
POAG
Genes that contribute to
 IOP elevation
(Aqueous outflow regulation)

Optic nerve susceptibility
(death and survival of RGC)
+
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Independent actions and interaction of
multiple genes
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
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
Myocilin
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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
POAG- complex trait
the majority
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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
POAG- environmental
factors
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Little is know
Steroid responsiveness for
endogenous steroids (stress) or
pharmacologic is possible
NTG
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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
NTG
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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
Pseudoexfoliation
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A recent breakthrough
Science 2007)
(Thorleifsson et al
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)
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 PXFstudies in animal models
that are genetically engineered
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Genetic way to diagnose and prevent blindness
Genetic correction by ocular treatment
Future directions
Discover new
glaucoma genes
and their phenotypes
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Developing mutation database for
– early diagnosis
– prognostic testing
Genotype-phenotype
correlations
Clinical features should be correlated with
specific mutations
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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 genegene interactions
Genetic study
P.I.- Hani Levkovitch-Verbin

1000 patients
– 200 POAG
– 200 OHT
– 200 PXF
– 200 PXFG
– 200 Controls
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