1. Background of Programme Area and Objectives

1.1 'Glaucoma' is a term that covers a heterogeneous group of conditions that have in common an irreversible, and usually progressive, optic neuropathy, characterised by distinctive patterns of structural change at the optic nerve head (ONH) and by distinctive patterns of loss of visual function (visual field loss). The glaucomas include primary open-angle glaucoma (POAG, high- and normal-pressure types), acute and chronic angle-closure glaucoma, and secondary glaucomas. Most glaucoma is associated with raised intraocular pressure.

1.2 The human genome has now been published and, with the advent of techniques such as microarray technology, there is now the opportunity to link genotyping with phenotyping and relate these to the natural history of glaucoma and its response to therapy. There is a unique opportunity in the UK to do this in the context of The UK Population Biomedical Collection (Wellcome).

1.3 Epidemiological and Service Issues

· Natural history of glaucoma and risk factors for progression

1.4 Clinical and Laboratory Issues

· Genotype/phenotype correlation

  2. Programme plan

2.1 Research into the causes, distribution and control of disease in populations will focus on:

2.1.1 A definition of the size of the problem and its relation to determinants of disease at a population level is of fundamental importance. Some risk factors for disease are only measurable at the population level, and some interventions are only possible at the population level. Large-scale population studies will be undertaken to establish significant risk-factors for disease.

2.1.2 Prevalence and incidence estimates for the different types of glaucoma in different populations will be established. More accurate estimates are becoming possible with the advent of more refined diagnostic techniques (visual field testing and optic nerve head imaging). The UK is becoming increasingly multicultural and the prevalence and behaviour of glaucoma needs to be defined for each population.

2.1.3 The proportions of diagnosed and undiagnosed glaucoma sufferers, and the relationship of diagnostic status to health care usage and risk factors for disease, is of great importance for the planning and design of health care resources. The introduction of new diagnostic technologies into the primary care setting may improve the rate of early diagnosis and reduce the burden of visual disability. The impact of new technologies should be investigated, and should include cost/benefit analyses.

2.1.4 The impact of health interventions on the population needs to be evaluated. Whether there are variations in the quality of care across the country and whether best practice guidelines are adhered to need to be established. The delivery of health care, including the development of diagnostic and management strategies with paramedical ophthalmic practitioners, is an area for continuing research.

2.1.5 The economic and social burden of glaucoma needs to be quantified, particularly in the light of an ageing population, so that health resources can be better planned.

2.2 Genetic epidemiology and research

2.2.1 Almost all diseases have a major genetic component, with a gene responsible alone, or in combination with other genes, for disease or disease susceptibility. Open angle glaucoma is likely to be a complex disorder in which environmental factors and age interact with several genes to generate glaucomatous optic neuropathy. Our understanding of the genetic basis of glaucoma is at an early stage. There is a need for high quality genetic epidemiology to determine the heritability (the variation in any given phenotype that has a genetic basis) of aspects of the ocular phenotype that are relevant to glaucoma.

2.2.3 It is likely that subtle variation in coding regions, the control of gene or post-translational modification will generate subtle cellular defects that will in time result in glaucomatous damage. The identification of these changes will require the application of complex mathematical techniques that have been developed to analyse other complex genetic traits (eg psychological disease). Linkage studies will remain an important aspect of this work but will be complemented by data from other methods of analysis - for example those relying on association models and sibling-pair models of analysis.

2.2.4 The most powerful genetic epidemiological studies are based on twin data. These are a scarce resource, collaboration between interested groups is essential for this to succeed. Furthermore, collaboration should also be encouraged to recruit families for the identification of candidate genes. It is important that we collaborate with others as twin registers are established in the UK and overseas.

2.2.5 The understanding of the cellular mechanisms that result in raised intraocular pressure and tissue damage will allow the development of gene therapies to alter aqueous secretion and outflow, and modulate tissue responses to physical and molecular damage.

  3. Future development work in the programme during 2002/3

3.1 Further development of our programme focused on phenotype and genotype which has had some notable successes this year. We have identified a number of genetic changes specific for subsets of the glaucoma population. Progress in this area will allow us, in collaboration with molecular genetics laboratories in the UK and the USA, to develop specific kits for genetic diagnosis of glaucoma types. We look towards the time when this knowledge will help us tailor treatment to the individual patient. We have made progress in the detection of change in chronic glaucoma by quantifying the inherent variability of measurement methods. These investigations are moving the goal of assessing rate of change closer to clinical practice. This will improve measurement of the outcomes of treatment, and will allow the risk benefit ratio to be ascertained for the individual patient.