What Does the Competent
Ophthalmologist Need to Know About Glaucoma
Genetics?
Wallace L.M. Alward, M.D.
University of Iowa College of Medicine
Four Points
1. Competent ophthalmologists already use genetics in managing
glaucoma.
2. We know a lot about rare glaucomas.
3. We know a little about common glaucomas.
4. Competent ophthalmologists hold the keys to finding the
next gene.
1) Competent ophthalmologists already use genetics in
managing glaucoma.
We evaluate patients with an eye to their family history.
This is done in an intuitive way.
Is there early onset glaucoma in the family?
Is there a history of extremely fragile optic nerves in the
family?
2) We know a lot about rare glaucomas.
These diseases are easier to study because they frequently
are:
Early onset.
Easy to diagnose.
Autosomal dominant with high penetrance.
These features yield large pedigrees that permit linkage analysis.
What
we know:
| Inheritance |
Disease |
Gene |
| |
|
|
| Autosomal Dominant |
|
|
| |
Juvenile Open Angle |
Myocilin |
| |
Axenfeld-Rieger |
PITX2 |
| |
Axenfeld-Rieger |
FOXC1 |
| |
Aniridia |
PAX6 |
| Autosomal Recessive |
|
|
| |
Primary Congenital |
CYP1B1 |
| “Sporadic” |
|
|
| |
Peters Anomaly |
PAX6 |
| |
Peters Anomaly |
PITX2 |
| |
Peters Anomaly |
FOXC1 |
| |
Peters Anomaly |
CYP1B1 |
3) We know a little about common glaucomas.
These are difficult disease to study because they are:
Late onset.
Often difficult to diagnose.
Apparently complex in their inheritance.
These features yield tiny pedigrees that make linkage analysis
difficult.
What we know:
Disease |
Gene |
Prevalence |
|
|
|
Primary open angle |
Myocilin |
3-5% |
Normal tension glaucoma
|
Myocilin |
1% |
|
Optineurin |
<1% |
Pigmentary |
Myocilin |
1.5% |
Exfoliative |
Myocilin |
1.7% |
Myocilin
Linkage to chromosome 1q discovered in a large family with juvenile
open angle glaucoma (GLC1A).
Sheffield VC, Stone EM, Alward WLM, et al. Genetic linkage
of familial open angle glaucoma to chromosome 1q21-q31. Nature
Genetics 1993;4:47-50.
The gene at this site was subsequently found to be myocilin.
Stone EM, Fingert JH, Alward WLM, et al. Identification of
a gene that causes primary open angle glaucoma. Science 1997;275:668-670.
~100% of AD JOAG.
6.4% of sporadic JOAG.
3 - 5% of POAG.
Rarely pigmentary, exfoliative, NTG.
Alward WL, Fingert JH, Coote MA, et al. Clinical features
associated with mutations in the chromosome 1 open- angle
glaucoma gene (GLC1A). N Engl J Med 1998;338:1022-7.
Alward WL, Kwon YH, Khanna CL, et al. Variations in the
myocilin gene in patients with open-angle glaucoma. Arch
Ophthalmol 2002;120:1189-97.
MYOC.mt1 Promoter Polymorphism
A site in the promoter region, 1000 base pairs upstream from
the myocilin gene, was found to have polymorphisms. Colomb and
colleagues studied a selected set of patients. They discovered
that the patients with the rarer polymorphism had somewhat worse
visual field scores and had worse response to a non-standardized
medical regimen.
Colomb E, Nguyen TD, Bechetoille A, et al. Association of
a single nucleotide polymorphism in the TIGR/MYOCILIN gene
promoter with the severity of primary open-angle glaucoma.
Clin Genet 2001;60:220-5.
This became the basis of the OcuGene test.
We attempted to confirm their findings:
University of Iowa Series Studied
All qualifying patients presenting to four clinics at the University
of Iowa over 9 months.
Full time phlebotomist in clinic.
814 met the entry criteria (OAG or suspect).
782 (96%) participated.
393 Adult-onset, high IOP, POAG patients.
Mean age at diagnosis 61.4 years.
From the same population as the patients.
POAG with and without MYOC.mt1 (p value)
No difference in:
Age at diagnosis (0.572)
Age at first treatment (0.602)
Highest IOP (0.772)
Visual field loss (0.388 - 0.680)
C/D ratio (0.955)
Number of medications (0.208)
Trabeculoplasty (0.264)
Number of surgeries (0.612)
Alward WL, Kwon YH, Khanna CL, et al. Variations in the myocilin
gene in patients with open-angle glaucoma. Arch Ophthalmol
2002;120:1189-97.
Bottom line on the mt1 polymorphism.
Our laboratory can genotype 2500 patients per day.
I have the ability to screen for the MYOC.mt1 promoter polymorphism
at no cost to my patients.
I do not test for this polymorphism.
Optineurin
GLC1E
Gene was found to be mutated in 16.7% of 52 British families
with dominant glaucoma with at least one family member having
NTG.
Rezaie T, Child A, Hitchings R, et al. Adult-onset primary
open-angle glaucoma caused by mutations in optineurin. Science
2002;295:1077-9.
In a study of 1048 glaucoma patients a OPTN mutation was found
in one (<0.1%) - a patient with AD NTG. It was not mutated
in POAG or in non-familial NTG.
Alward WLM, Kwon YH, Kawase K, et.al. Evaluation of optineurin
sequence variations in 1,048 patients with open angle glaucoma.
Am J Ophthalmolol, in press 2003.
The role of optineurin has yet to be determined. Because it
is an optic nerve gene it holds great interest in understanding
optic nerve function. It is a rare cause of glaucoma.
4) Competent ophthalmologists hold the keys to finding
the next gene.
The only way molecular geneticists will get their hands on
the next family with inherited glaucoma is if there is an alert
ophthalmologist asking the right questions.
• How will genetic knowledge impact ophthalmologists?
Better understand the pathophysiology of glaucoma.
Develop better diagnoses.
Develop better treatments.
Targeted
More effective
Safer
• References
“Scorecard” in handout Online Mendelian Inheritance
in Man (OMIM) http://www.ncbi.nlm.nih.gov/omim/
• Special Thanks To:
Edwin M. Stone, M.D., Ph.D.
Val C. Sheffield, M.D., Ph.D.
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