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Editorial IGR 9-4

Moving Forward with Glaucoma Science
R.N. Weinreb, MD
La Jolla

Human genetic variation

I look forward to receiving my copy each December of an issue of the journal Science, in which the editors announce the breakthroughs of the year. In the December 21 issue from several weeks ago, the faster, cheaper technologies for sequencing DNA and assessing variation in genomes was selected as the leading breakthrough in 2007. With these technologies, we are finding out how really different we are from one another. And these technologies already are having an impact on glaucoma genetics.

Although I am by no means a genetics expert, I am beginning to understand enough of this once arcane science to know that the genetics of what makes each of us unique, and different from each other, will have an important impact on medicine, science and society. However, it was little more than six years ago that I stood at the podium during a meeting of the European Glaucoma Society in London and wondered out loud what, if anything, the recent announcement of the deciphering of the human genome held in store for glaucoma. The lay press triumphed this signal achievement in banner headlines and predicted an era of personalized medicine based on individual genetic testing. The view of the scientific community, in contrast, was more sober and downplayed the achievement as another step, albeit an important one, in what would be a long process of discovery. With little published information about the genetic basis of glaucoma, my view was that one only could be hopeful that this event would accelerate the discovery of one glaucoma gene after another. But, alas, this was not to be. For progress has been slow with one or another mutation being reported again and again, but still a major glaucoma gene remained to be discovered. But, perhaps, this has now changed.

A paper, published in Science, by a group based in Iceland, that was discussed (click here to see the first comment and on) is a large step forward in unraveling the genetic code of glaucoma. Perhaps even more important than the discovery itself are the methods that were employed, viz whole-genome association, perhaps the most powerful new tool in modern genetics. Whole genome association studies scan patients’ DNA for single nucleotide polymorphism (SNP) variants and then compare the results to an unaffected control group. Those SNPs appearing more frequently in patients will often point to a nearby gene that confers risk. The same methods have been employed recently with great fanfare to identify genes associated with a variety of diseases including diabetes type 2 and multiple sclerosis. Exfoliation was an attractive target because it offered the possibility of a homogeneous genetic basis. Diseases that are a spectrum of conditions, as for example may be the case for primary open angle glaucoma, will provide a more daunting task because there could be a multiplicity of mutations, including many rare ones, that could predispose to many POAG subtypes. By lumping all patients with POAG together, it will likely be more difficult to find specific genes. Nevertheless, the rapid improvements and reductions in cost for DNA sequencing and understanding the variation in the genome make it likely that this will soon be sorted out.

World Glaucoma Association Consensus V

Perhaps no subject in glaucoma has ignited a plethora of passionate debates and arguments as much as Glaucoma Screening. With a high rate of undiagnosed disease and the presence of severe glaucomatous optic neuropathy in most symptomatic patients, pundits have opined for decades that screening for open angle glaucoma was desirable and would improve the health of communities in diverse communities throughout the world. Others, primarily governmental agencies, have questioned whether screening for open angle glaucoma was a good investment with respect to resource allocation, especially when compared with general medical diseases associated with increased mortality. Although it has not been as widely discussed as open-angle glaucoma, at least until recently, the subject of screening for angle closure and angle-closure glaucoma has been problematic, as well. It has been increasingly evident that closed-angle glaucoma is highly prevalent in certain regions of the world, and that there are large numbers of individuals who are blind from it. Moreover, the number of undiagnosed angle-closure patients may be even higher than observed with open-angle glaucoma.

While there are many important considerations in determining whether some form of screening for a disease is worthwhile, it has been proposed that several essential questions be addressed at the outset before deciding on the feasibility of screening.

1. Is the disease an important health problem?
2. Is there an accepted and effective treatment for affected patients?
3. And is it more effective when initiated in the early, asymptomatic stage than when begun in the later, symptomatic stages?
4. Are facilities for diagnosis and treatment available? Is there an appropriate, acceptable, and reasonably accurate screening test?
5. Is the natural history of the condition, including development from latent to manifest disease, adequately understood?
6. Is the cost of case – finding (including diagnosis and treatment of patients diagnosed) economically balanced in relation to possible expenditure on medical care as a whole?

It is these questions that will be considered during the fifth Consensus of the World Glaucoma Association. The subject will be Glaucoma Screening for both open-angle and angle-closure glaucoma. As with prior consensuses, consensus participants will ponder these questions through e-room discussion, and the documents that formalize these discussions then will be vetted for comments through each of the member societies of the WGA. The resulting document then will be discussed at the Screening Consensus meeting in Fort Lauderdale on April 26, 2008, immediately preceding the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO). An important goal will be to formulate consensus points for promulgation. As has been done with each of the consensuses, presentations of these consensus points will be distributed to member societies and also placed in a downloadable format on the website of the WGA.

Previous publications in the Consensus Series can be obtained through Kugler Publications, click here for more information