At his clinic, Ian MacDonald, MD, has seen firsthand how the power of personalized medicine can influence patient treatment. He relates the story of a patient about to undergo a recess and resect operation on the horizontal recti for strabismus. Genetic testing before the operation detected Thomsen’s disease, or myotonia congenital, an inherited myopathy that inhibits muscle relaxation.

Because myopathy is a chloride-channel disorder, giving this patient anesthetic with intubation and induction with succinyl choline would have triggered immediate muscle rigidity, mimicking malignant hyperthermia. “So identifying the patient prior to the surgery as having this genetic disorder enabled us to use a different kind of anesthetic, propofol, so we could go ahead with surgery without complications,” says Dr. MacDonald, chair of the ophthalmology department at the University of Alberta in Edmonton. This helped his team avoid a “calamitous” event and cancellation of surgery.

Therein lies one potential of personalized medicine in routine ophthalmological practice: to avoid potential surgical complications. But within the next decade, clinical investigators say, personalized medicine has the potential to give ophthalmologists widely accessible tools to target therapies, eliminate trial-and-error treatments and better differentiate high- and low-risk patients.

Personalized Medicine Defined

Personalized medicine refers to tailoring medical treatment to the unique characteristics of each patient. The promise is that drug therapy targets an individual’s genetic makeup. Environment, diet, age, lifestyle and health status can influence a person’s risk for disease and response to therapy.

“If we found a strong genetic risk and if we knew that genetic factors were significant modifiers to make the disease worse, we might even titrate the care in a far more aggressive fashion,” Dr. MacDonald says. For example, genetic profiling could define a select group of glaucoma patients that may be better suited for surgery early on rather than medicotherapy.

“By personalizing a person’s care, by identifying the high-risk individual and giving him or her the most appropriate care, that’s going to prevent disease; and for siblings in a family, maybe potentially remove the risk for them and then reduce health care costs by simply not following those patients as assiduously as others,” Dr. MacDonald says.

Two recent events may help fast- track personalized medicine into clinical practice: creation of the Patient-Centered Outcomes Research Insti-tute that will conduct comparative effectiveness research, which many investigators say is key for evaluating genetic therapies; and government subsidies for electronic medical record systems that can enable the capture and analysis of more data to aid in comparative effectiveness research.1

Dan Roden, MD, assistant vice-chancellor for personalized medicine at Vanderbilt University in Nashville, recently co-authored a paper that outlines the possibilities of EMR in personalized medicine. “I see no reasonable alternative to the vision that we and others espouse: The genetic information will be generated prior to its being needed and accessed and acted upon by sophisticated information technology systems to improve the choice of drugs, the drug doses and things like preventive screening and therapies,” he says. Dr. Roden and his team used Vanderbilt’s DNA data bank to extract genetic data from EMR systems.

The State of Genetic Science

Thanks to the Human Genome Project, scientists have determined the human genome comprises approximately 20,500 genes.2 The genome is a complete set of DNA in an organism. Human and mouse genomes, for example, have some 3 billion DNA base pairs. DNA in the human genome is arranged into 24 distinct chromosomes.

Genetic research has been done in all forms of ocular disease, including glaucoma, macular degeneration and retinal degenerations. “Macular degeneration and glaucoma are common, complex ocular disorders, both with respect to genotype and phenotype,” says Janey Wiggs, MD, PhD, a clinical investigator at Massachusetts Eye and Ear Infirmary in Boston. Genotype is the internal code of a genetic organism; phenotype is the observable properties and physical structures of an organism.

In ocular disease, investigators have linked approximately 70 genes or loci to glaucoma, mostly monogenic forms that account for 10 percent of glaucoma cases.3 In macular degeneration, investigators have identified about nine causative genes, says Johanna M. Seddon, MD, ScM, director of the Ophthalmic Epidemiology and genetics Service at Tufts Medical Center in Boston.

“We should think of these causative genes for disease and predictive genes for treatment outcomes as biomarkers,” says Sayoko Moroi, MD, PhD, a researcher at the University of Michigan. “So like the cardiovascular markers of cholesterol and lipids, future biomarkers for ocular diseases and treatment outcomes may also include different chemical markers in the blood.” Thus, blood levels of protein or other inflammatory markers could provide another tool for monitoring progression of glaucoma or macular degeneration in a patient, she says.

Personalized medicine could turn trial-and-error medicine on its head. “This whole idea of starting a medication and then following the patients to see if the medicine works is a fundamental problem in all areas of medicine, and pharmacogenomics is one possible solution,” says Stephen G. Schwartz, MD, MBA, associate professor and medical director at Bascom Palmer Eye Institute at Naples, Fla.

The State of the Science: Glaucoma

Personalized medicine still has a way to go before it’s applied in everyday glaucoma practice, but investigators point to significant strides in this area. Already a test exists that can identify the myocilin (MYOC) gene, which has been linked to glaucoma, Dr. MacDonald says. “You might be able to identify an individual who has carried the mutation, follow that individual more closely at an earlier age, and then intervene when appropriate,” he says. “If that individual’s sibling doesn’t carry the mutation, you would not have to see that person on an ongoing basis. You would unburden that individual from the genetic risk.”

Researchers at the University of California, San Diego, School of Medicine and the National Eye Institute have localized gene variants for glaucoma in a black population.4
“We have now identified very common gene variants that have a dramatic impact on an individual’s risk for developing glaucoma,” says Kang Zhang, MD, PhD, director of the Institute for Genomic Medicine at the Shiley Eye Center at UC, San Diego. The variants were identified in 40 percent of individuals in the Barbados Family Study Group and explain nearly one-third of their genetic risk for the disease. “Once we understand the specific gene or protein structure that is altered in the disease, we are one step closer to developing gene or stem cell-based therapies to treat glaucoma,” Dr. Zhang says.

Now that investigators have identified the suspect genes in glaucoma, the next step is to understand how environmental and behavioral factors interact in the disease process. Louis Pasquale, MD, director of the glaucoma service at Harvard University, oversees the only group investigating ocular disease as part of the Gene Environment Association Studies, or GENEVA.5

“It may take several years to perform all the secondary analyses, but the data will be out there for those analyses to take place,” Dr. Pasquale says. “We hope this may mean ultimately that we discover new drug-able targets for primary open angle glaucoma. Our current strategies for treating this disease are really not rooted in the fundamental understanding of the molecular biology.”

Research at the University of Mich-igan has focused on separating out poor responders to glaucoma drug therapy, Dr. Moroi says. “In addition to those genes that give risk for glaucoma disease, we also want to look for genes that determine high pressure as well as low pressure, and also those genes that predict “non-responders” to glaucoma medications,” she says. “After we complete the ‘discovery phase’ of genes that place an individual at risk for the common diseases and that are predictive of treatment outcomes, we need to apply these genetic biomarkers to find new treatments and to inform patients on potential behaviors that prove to lower disease risk.”

Identifying genetic variants that contribute to primary open-angle glaucoma is the goal of the National Eye Institute Glaucoma Human Genetics Collaboration, or NEIGHBOR,6 led by Drs. Pasquale and Wiggs. “We’re very excited about this collaborative opportunity with NEIGHBOR to find these ‘under the radar’ genes for the common forms of glaucoma,” says Dr. Moroi, a NEIGHBOR collaborator. “You need a very large number of patients to do this kind of study.” NEIGHBOR involves more than 5,000 patients split between POAG cases and controls.

Gene-Environment Interactions

Investigators consider an understanding of gene-environment interactions crucial in disease treatment. “For macular degeneration, multiple genes have been associated with the disease, and having more than one risk genotype increases the overall risk of the disease,” Dr. Wiggs says. “The additional environmental risks of obesity and smoking increase the overall risk. Combinations of genes and environmental risks in any given patient can give some indication of the chance of developing disease.” However, the existing knowledge on gene-environment interactions in eye disease does not yet add up to the overall sensitivity and specificity needed for a quality screening test, she adds.

Dr. Pasquale has found himself defending the search for gene-environment interactions. “People have said that the discovery of gene-environment interactions for a complex disease is a cliché. I couldn’t disagree more,” he says. “If you have some good hypotheses on where you might find gene-environment interactions, then you can find them and we have.” His team has already published a report showing interactions in four of five NOS3 synthase gene variants and postmenopausal hormone use among women with high-tension POAG.7

Meanwhile, GENEVA investigators are still working out the methodology to identify gene-environment interactions using a database of genes associated with type 2 diabetes, Dr. Pasquale says.

Macular Degeneration

Glaucoma genetics may be lagging behind macular degeneration by five to 10 years, according to Dr. Wiggs, but she expects researchers to close that gap quickly. “In five years the macular degeneration field has gone from not having a gene to having a pretty robust panel of genetic variants that contribute to the disease,” she says.

Dr. Schwartz at Bascom Palmer says genetics are useful in treating and understanding macular degeneration in two ways. “One, it does seem that various genetic markers may be predictive of who’s going to get the disease and how severe the disease is going to be; and other researchers are doing work on pharmacogenomics of medications used to treat macular degeneration, specifically the anti-VEGF [vascular endothelial growth factor] agents.”

Genetics may help explain why about 30 percent of patients with macular degeneration do not respond to anti-VEGF therapies, Dr. Wiggs says. “That would suggest that these patients have the disease due to other underlying biological problems,” she explains.
“To target disease in those people you would need to use a different therapeutic approach.”

Dr. Seddon, at Tufts Medical Center, co-authored one of the first studies linking genetics and patient response to dietary supplements commonly used for age-related macular degeneration.8 “We showed that there might be a reduced effect of the antioxidant supplement with the two risk alleles for the CFH gene,” she says. “So if you have a stronger genetic predisposition but still there was some effect, it was still worth taking the vitamins, but there did seem to be some relationship to the genotype.” Alleles in a given gene differ in DNA sequence, and an allelic variant can change a gene’s phenotype.

A Canadian company, Arctic DX, markets a molecular test for age-related macular degeneration, but Dr. Schwartz questions its clinical practicality. “The biggest barrier with the macular degeneration testing is that the clinician doesn’t necessarily know what to do with that information,” he says. “If you tell patient that he might have macular degeneration in the future, I’m not sure if you’ve done that patient a service.” However, that knowledge would become more valuable if an intervention were developed to delay the onset of macular disease in asymptomatic high-risk carriers, he says.

Testing: The Present and Future

More clinicians will embrace personalized medicine as the price of genetic testing drops, investigators say. Dr. MacDonald envisions what that day will be like. “We’re not quite there yet where we can take a panel of patients and apply a test and then say we should be moving to this drug because it’s probably going to be more effective, but I think that’s coming,” he says.

Pricing of genetic tests will reach a point where health insurance will pay for them, Dr. MacDonald says. “Say we have two drugs, one more expensive than other,” he says.
“An HMO would be willing to pay for the more expensive drug because it’s going to be more effective in a group of patients and we’ll have the genetic evidence for that.”

Other barriers beside price must come down before personalized medicine is adopted in everyday medical practice. Clinician knowledge is another, Dr. Schwartz says. “A practicing ophthalmologist on the front lines would mostly have to be aware the test even exists,” he says. Eventually, he anticipates clinicians ordering genetic tests like any other laboratory testing.

Funding for clinical trials to verify genetic testing may be another barrier, Dr. Moroi explains. “For any new test, whether it’s using an instrument or blood test device, we have to first make sure that it is sensitive to detect disease, and that it is accurate,” she says. “So once you identify certain genes in a population you have to study whether it’s reproducible in a second population and if it is applicable across different ethnoracial groups.” The burden of proof would then come in clinical trials—if funding is available.

For genetic testing to be cost-effective, Dr. Moroi envisions a panel of tests for genes that confer risk for common diseases, such as diabetes, hypertension, certain cancers, specific autoimmune disorders along with glaucoma and macular degeneration—“the big public health problems,” in her words. “It would be too expensive to have individual tests for glaucoma, macular degeneration and these major systemic diseases,” she says.

Where We Go from Here

Another challenge facing clinical investigators in advancing personalized medicine is a lack of phenotype data, Dr. Wiggs says. “We have cataloged genes, sequences, etc., but the pace of data collection on the phenotype side has not been as quick, so there’s a gap between genotype and phenotype information,” she says.

“Even for the Mendelian (genetic) diseases, diagnosis can be confirmed and established and occasionally prognostic information can be added, but that’s kind of the end of the line,” she says. “There isn’t anything yet that helps with therapy for those diseases.”

Patients may have a role in driving personalized medicine, Dr. MacDonald says. “The genetic tools are becoming more robust, availability is improving, and it will be part of the future care of patients in the next five years,” he says. “The patients in fact will be asking, ‘Should I have genetic testing done?’ It’s not just an academic exercise any longer.”

1. Ritchie MD, Denny JC, Crawford DC, et al. Robust replication of genotype-phenotype associations across multiple diseases in an electronic medical record. Am J Hum Genet. 2010; DOI: 10.1016/j.ajhg.2010.03.003

2. Clamp M, Fry B, Kamal M, et al. Distinguishing protein-coding and noncoding genes in the human genome. Proc Natl Acad Sci USA. 2007;104:19428-19433.

3. Moroi SE, Raoof DA, Reed DM, et al. Progress toward personalized medicine for glaucoma. Expert Rev. Ophthalmol. 2009;4:146-161.

4. Jiao X, Yang Z, Yang X, et al. Common variants on chromosome 2 and risk of primary open-angle glaucoma in the Afro-Caribbean population of Barbados. Proc Natl Acad Sci. 2009;106:17105-17110

5. Cornelis MC, Agrawal A, Cole JW, et al. The gene, environment association studies consortium (GENEVA): maximizing the knowledge obtained from GWAS by collaboration across studies of multiple conditions. Genet Epidemiol. 2010 Jan 20. [Epub ahead of print]

6. National Eye Institute/National Institutes of Health. NEI Initiiatives on Glaucoma. Available at: http://www.nei.nih.gov/news/statements/glaucoma_initiatives.asp. Accessed April 8, 2010

7. Kang JH, Wiggs JL, Rosner BA, et al. Endothelial nitric oxide synthase gene variants and primary open-angle glaucoma: interactions with sex and postmenopausal hormone use. Invest Ophthalmol Vis Sci. 2010;51:971-979.

8. Klein ML, Francis PJ, Rosner BA, et al. CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology. 2008;115:1019-1025.