Genetic Basis of AMD

Genetic Basis of AMD

AMD results from a combination of environmental and genetic factors. Environmental factors associated with AMD include age, gender, smoking and diet. Evidence for genetic risk has also been supported by several family studies and twin studies. Results from these studies revealed that people with an affected parent have approximately twice the risk of getting AMD than someone whose parent does not have AMD.

DNA is the chemical in our cells that gives our bodies instructions about how to grow, develop and function. DNA is a string of coded messages organised into specific instructions called genes. Humans have 30,000 different genes, arranged on a number of thread-like structures, called chromosomes. We inherit our chromosomes from our parents, 23 from our mother and 23 from our father, so we have two sets of 23 chromosomes, or 23 ‘pairs’. A good description is If you think of genetics as the book of life, then the DNA are the letters, the genes are words, and the chromosomes are the chapters.

If you think of a mutation as a spelling mistake or a series of words changed in a sentence, then this causes a problem in the meaning and interpretation, and it is just this that happens when there is a mistake or a mutation occurs in a gene – it can cause a condition like inherited AMD.
Sometimes a mutation will have no effect at all. This depends on environmental factors, an element of chance, or mutations in other genes. Mutations can cause problems if they stop the gene or chromosome communicating the correct instructions needed for the body to function properly.

In the largest study of the complete set of human genes to date, it was reported that AMD is associated with a number of types of mutations, 45 common single nucleotide polymorphisms (SNPs) and 7 rare variants across 34 genetic loci, which explain 34% of AMD risk​³​. Many of these genetic variants reside in the complement factor H (CFH) gene on chromosome 1 and ARMS2/HTRA genes on chromosome 10. Other variants can be seen in and around genes involved in the cholesterol metabolism, collagen production and cell signalling. This suggests that AMD is a complex disease associated with multiple genetic risk factors​⁴​.

Stages of AMD

AMD pathology is characterized by degenerative changes in the outer portion of the retina, photoreceptors, retinal pigment epithelium (RPE), Bruch’s membrane, and the choriocapillaris, which ultimately lead to central vision loss in the later stages of the disease. The earliest visible sign of AMD during an eye exam is the appearance of yellowish deposits of an extracellular lipoprotein, called drusen, which accumulate underneath the retina, between the retinal pigment epithelium (RPE) and Bruch’s membrane.​⁵​

Progression and severity of AMD can be classified as ‘early’ or ‘intermediate’ or ‘late’ based on the size of drusen and the presence of pigmentary abnormalities in the retina of the affected eye.​⁶​

Early AMD is diagnosed based on the presence of medium-sized drusen (>63 and ≤125 μm) but is not usually associated with any loss of visual function or other symptoms. (Small drusen particles (≤63 μm) can appear in the retina as part of the normal aging process and are not associated with an increased risk of progression to late-stage AMD.)

Intermediate AMD is characterised by the presence of large drusen (>125 μm), abnormalities in the retinal pigment, or both. Intermediate AMD also tends to be asymptomatic. People who develop intermediate AMD are at an increased risk of developing late-stage AMD.

Late-AMD, associated with central vision loss that occurs as a result of damage to the macula, can be classified into two types: ​⁶​

Geographic atrophy (GA) (also known as “late-stage dry” or ‘non-exudative’ AMD) is characterised by the progressive, irreversible loss of the retinal pigment epithelium (RPE), photoreceptor cells, and underlying choriocapillaris layer of the macula, resulting in a decline in visual function.

Neovascular AMD (nAMD)  (also known as ‘wet’ or ‘exudative’ AMD) is defined by growth and invasion of immature blood vessels from the underlying choroid into the retina. Leakage from these fragile blood vessels can cause build-up of blood and fluid under the retina leading to detachment of the RPE or retina and scarring.

Progression from early/intermediate- to late- AMD (GA and/or neovascular AMD) is a complex process. Some people progress quickly to late-stage AMD (either GA or neovascular AMD), whereas others may progress slowly over several years.​⁷​ The underlying mechanisms that cause an eye to develop GA versus neovascular AMD are not fully understood. No reliable genetic or environmental risk factors have been identified to predict whether a patient will develop one form or the other.​⁸​  Both types can occur simultaneously in the same eye, or simultaneously in different eyes; it has in fact been suggested that GA and neovascular AMD are not mutually exclusive diseases, but that they lie on the same disease continuum.​⁹​ Eyes developing both types may in fact be at a more advanced stage than either GA or neovascular AMD alone.

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