MAJOR EVOLUTION

Marked progress over the past few decades in understanding the environmental and genetic underpinnings of age-related macular degeneration (AMD) has formed the scientific basis for the preventive management of the disease, according to Johanna M Seddon MD, ScM, who delivered the annual Kreissig Lecture at the 14th EURETINA Congress in London.

“We have seen a major evolution in thinking from the time when everyone used to say that there is no evidence that AMD is a genetic disease, to the recognition today that we are dealing with a disease with genetic, nutritional and other environmental components. We now know that there are susceptible genotypes for AMD and the manifestation of disease may be modified by our behaviours and our lifestyle,” she said.

AMD is a common cause of irreversible visual loss and the disease burden is rising worldwide as the population ages, said Dr Seddon, Professor of Ophthalmology at Tufts University School of Medicine, and Founding Director of the Ophthalmic Epidemiology and Genetics Service of Tufts Medical Centre, New England Eye Centre, Boston, US.

While genetic factors lead to various levels of susceptibility for the development of AMD, the environment modifies the effects of this predisposition to varying degrees depending on the level of genetic risk, she explained.

With this in mind, she noted that genotyping may become a useful tool for identifying individuals who are at high risk for disease and who may therefore benefit from increased surveillance and personalised treatment strategies.

Reviewing the sea change in thinking that has taken place over the past decade or so, Dr Seddon said that numerous scientific publications now attest to the fact that both environmental and genetic factors contribute to the development of AMD.

Environmental factors

Among environmental factors, Dr Seddon identified smoking, obesity and dietary factors, including antioxidants and dietary fat intake that have been shown to influence the onset and progression of AMD.

Dr Seddon was one of the first researchers to pinpoint smoking as a clear risk factor for AMD. Her 1996 publication showed in a prospective analysis that smoking 25 cigarettes per day or more led to a 2.4 times greater risk of developing AMD over time compared to those who never smoked. Past smokers also had twice the risk of AMD.

There are several possible mechanisms by which smoking may affect the healthy functioning of the eye, said Dr Seddon. First, smoking may adversely affect blood flow in the eye, decreasing high-density lipoprotein (HDL) cholesterol that may actually prevent atheroma formation, and increasing platelet aggregation and fibrinogen.

Smoking also increases oxidative stress and lipid peroxidation, reduces plasma levels of antioxidants and increases inflammation.

Dr Seddon and co-workers were the first to carry out a systematic study of diet and AMD, and discovered the beneficial impact of dietary lutein and zeaxanthin, contained in foods such as spinach, collard greens and kale.

Studies published from 1994 to 2014 show the protective effect of a healthy diet with plenty of green leafy vegetables, fruit, fish and nuts with a high lutein/zeaxanthin content, and sufficient intake of zinc and vitamins C and E, resulting in a reduced risk of AMD of between 25-50 per cent, she said.

The correlation between AMD and cardiovascular disease, in terms of risk factors and biomarkers, has been another key finding, contributing to the discovery of inflammation’s central role in both diseases, according to Dr Seddon.

The importance of maintaining a healthy lifestyle is the key to reducing the risk of AMD and its progression in many cases, she said.

“Do not smoke. Eat a healthy diet rich in dark green leafy vegetables and low in fat, eat fish twice a week, maintain a normal weight and waist size, exercise regularly, and control blood pressure and cholesterol,” she said.

There are also several lines of evidence linking cardiovascular, immune and inflammatory biomarkers to AMD. Genome-wide association studies have revealed numerous common variants associated with AMD and sequencing is increasing knowledge of how rare genetic variants strongly impact disease.

“While the evidence for interactions between environmental, therapeutic and genetic factors is emerging, elucidating the actual mechanisms of this interplay remains a major challenge in the field,” said Dr Seddon.

About 30 common and rare AMD genetic loci have now been confirmed, gene-environment and gene treatment interactions are emerging, and both the genetic and lifestyle risk factors point to a central role for the inflammatory, immune, lipid, collagen extracellular matrix degradation, and angiogenic pathways in AMD.

Dr Seddon said that the knowledge of non-genetic, modifiable risk factors along with information about heritability and genetic risk variants for this disease acquired over the past 25 years have greatly improved patient management and the ability of clinicians to predict which patients will develop or progress to advanced forms of AMD.

Personalised medicine and individualised prevention and treatment strategies may become a reality in the near future, she said.

Dr Seddon finished her lecture by paying tribute to the work of Professor Ingrid Kreissig for her immense contribution to ophthalmic training and research, particularly in the field of retina.

Johanna M Seddon: jseddon@tuftsmedicalcenter.org