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Glaucoma Glaucoma Pharmacogenetics Georg Mossböck and Christoph Faschinger Department of Ophthalmology, Medical University Graz, Graz, Austria Abstract An individuals’ reaction to a specific drug is influenced by various factors including environmental, systemic and genetic factors. In most cases the reactions of a group of individuals are of the Gaussian type with non- to low responders at the lower end of the curve and high- to ultra-high responders at the upper end of the curve. As these extraordinary reactions to a drug are at least partly genetically determined pharmacogenetics is set to decipher the underlying genetic constitution and to establish an individualised genotype-based drug therapy. Candidate genes in pharmacogenetics include genes of receptors as well as their downstream pathway and genes of drug metabolising or activating enzymes. Most prominent examples from the medical literature are warfarin, clopidogrel and various psychotropic and oncological drugs. Regarding glaucoma therapy studies investigating the role of polymorphisms in the genes of β-adrenergic receptors, the important metabolising enzyme CYP2D6 and the prostaglandin F2α receptor have been performed. Results of these studies are presented and an outlook on the role of pharmocogenetics in glaucoma therapy will be provided. Keywords Glaucoma, pharmacogenetics, betablocker, prostaglandin analogues Disclosure: The authors have no conflict of interest to declare. Received: 11 November 2011 Accepted: 23 January 2012 Citation: European Ophthalmic Review, 2012;6(3):146–8 Correspondence: Georg Mossböck, Department of Ophthalmology, Medical University of Graz, Auenbruggerplatz 4, 8036 Graz, Austria. E: g.mossboeck@medunigraz.at The effect of a drug in terms of desired effects and undesired side-effects on an individual basis is still not 100 % predictable. 1 Undoubtedly, this prediction would be a great advantage for patients’ safety and societies’ economies and therefore, it has been subject to research ever since drugs have been used in a scientific manner. 2 It is well known that an individuals’ response to a certain drug is influenced by extrinsic as well as intrinsic factors. 3 Among the extrinsic factors there are lifestyle issues like diet, alcohol consumption or nicotine abuse and geographical factors. Intrinsic factors comprise constant factors like age, sex, ethnic group and, more specifically, the colour of the iris, but also modifiable ones like the body mass index or concomitant systemic or ocular disease. Furthermore, the personal genetic constitution determines at least partially the pharmacokinetics and pharmacodynamics of a drug. Polymorphic receptors or their downstream pathway targets may aggravate or attenuate the effects of a drug, whereas variants of metabolising or activating enzymes can lead to increased or decreased levels of a drug. The aim of pharmacogenetics is to describe these polymorphisms and their impact on an individuals’ reaction to a specific drug. As pharmacogenetic research started about 30 years ago, pharmacogenetic data on a range of drugs have now been reported. 4 Today, the Food and Drug Administration (FDA) lists pharmocogenetic biomarkers in drug labels for more than 100 drugs, most of them anticancer or psychiatric drugs. 5 For example, warfarin dose is greatly influenced by the genotype of the metabolising enzyme CYP2C9 and the genotype of the target enzyme vitamin K epoxide reductase (VKORC1), which together account for roughly 40  % of the © TOUCH BRIEFINGS 2012 interindividual variance of warfarin dose. 6 CYP2D6 is necessary for about 25  % of all drugs metabolised in the human liver, including various psychiatric drugs and beta-blockers. 7 Furthermore CYP2D6 is also mandatory for the activation of codeine to morphine and of tamoxifen to its most therapeutically active metabolite endoxifen. Depending on the existence of active, inactive or alleles, with decreased activity, individuals can be grouped in poor, intermediate, extensive or ultrarapid metabolisers. 4 In case of ultrarapid metabolisers (1–2 % of Caucasians) levels of a metabolised drug might be too low for the intended effect, whereas morphine levels after codeine medication might be dangerously high. 8 Clopidogrel is a antiplatelet agent prodrug activated by CYP2C19, which activity – as is the case for CYP2D6 – depends on the genotype. Poor or intermediate metabolisers (2 % and 26 % in Caucasians, respectively) are therefore at increased risk for cardiovascular events or stent thrombosis compared to extensive metabolisers. 9 Interestingly, recent studies provided evidence that the CFH Y402H genotype has significant impact on anti-vascular endothelial growth factor (VEGF) therapy. Patients with the T/T or T/C genotype showed improved visual acuity in 53  % versus 10  % of the patients with the C/C genotype, moreover these patients required more intravitreal injections. 10,11 Pharmcogenetics in Glaucoma Lowering the intraocular pressure (IOP) is still the only effective therapy for glaucoma patients. However, responsiveness in terms of IOP lowering and toxicity varies greatly among patients. For ocular hypotensive drugs the term non- or low responsiveness is not universally defined and percentages of non- or low responders are infrequently provided. For example, low responsiveness for timolol and prostaglandin analogues has been commonly defined as IOP 146