Effect of Myocilin Genetic Variants on Intraocular Pressure and Pressure Variation in Sitting and Supine Positions

Glaucoma is an important public health issue, and identifying new markers to improve
treatment outcomes is a high priority. Progress in Mendelian genetic approaches has led to
identifying 15 genes and 31 loci (http://www.ncbi.nlm.nih.gov/); however, since these
monogenic forms of glaucoma are uncommon, other approaches are needed to identify genetic
markers that contribute to common risk factors, such as elevated IOP, IOP fluctuation, and
drug response variation.

It is well known that IOP varies over a 24-hour period,1-6 but the mechanisms that regulate
this IOP rhythm are not yet fully known. Drance reported that 84% of normal eyes (N=320
eyes) had IOP fluctuations of less than 5 mmHg in contrast to only 6% of untreated
glaucomatous eyes (N=138).7 Drance clearly recognized that IOP factors were more variable in
eyes with glaucoma. Attention to this IOP fluctuation during glaucoma treatment is important
because fluctuation leads to progression. The variation in IOP drug response profiles
measured at selected times over a 24-hour period is related to the mechanism of action of
these drugs, endogenous circadian rhythms, and glaucoma. We now have the molecular and
genomic tools to identify potential genetic markers for these variable traits.

Advancing clinical research to the "translational" level is an important step to integrate
our ever increasing knowledge base in genomics and proteinomics with clinical trials and
clinical studies. Given the infrastructure at the University of Michigan with the strength
in both glaucoma genetics and our resources in the clinic, we are well-positioned to conduct
such translational research in glaucoma. Although it is known that myocilin (MYOC) mutations
cause the phenotype of high pressure open-angle glaucoma (OAG), the effect of these MYOC
mutations in "pre-symptomatic" subjects and patients with early OAG on IOP variation is not
known.

Inclusion Criteria:

- Early OAG, as determined by a comprehensive ophthalmic examination

- Greater than or equal to 18 years of age

- Either gender

- Any race

- Both eyes meet eligibility criteria

- Cup to disc ratio less than 0.8 determined by fundoscopy and confirmed by disc photos

- Visual field parameters in the study eye: Pattern Standard Deviation (PSD) greater
than 1.0 dB but less than 6.0 dB

- Ability to cooperate for an outpatient study involving at least five visits over a
four month study period

- Ability to comply with Cosopt treatment regimen

Exclusion Criteria:

- Less than or equal to 18 years old

- Refusal to be genotyped or sign Informed Consent for Protocol 1991-144

- Pregnant or lactating women

- Medical conditions of severe pulmonary compromise with asthma or emphysema or cardiac
contraindications to beta-blockers

- Ocular disease of chronic angle-closure glaucoma, iridocorneal endothelial disease,
posterior polymorphous corneal dystrophy, epithelial downgrowth, uveitic glaucoma, or
neovascular glaucoma

- Ocular surgery for glaucoma, including trabeculectomy, other glaucoma filtration
surgery, glaucoma drainage implant, or laser cyclophotocoagulation

- Current use of systemic steroids or chemotherapeutic agents that non-selectively
inhibit dividing cells

- Proliferative diabetic retinopathy, history of panretinal photocoagulation treatment,
diabetic macular edema, or history of macular grid laser treatment

- History of changing treatment involving the use oral beta-blockers, angiotensin
converting enzyme inhibitors, calcium channel blockers, or oral alpha 2-agonists in
the prior two months or in the next month (i.e., must be on stable treatment with any
of these drugs for at least two months)

- Patients taking erectile dysfunction drugs (i.e., Viagra, Cialis, Levitra)

- Contradictions:

- bronchial asthma or a history of bronchial asthma

- severe chronic obstructive pulmonary disease

- sinus bradycardia

- second or third degree atrioventricular block

- overt cardiac failure

- cardiogenic shock

- hypersensitivity to any component of Cosopt