Glaucoma: How much do genetics matter?

Pubblicato il

Tuesday, 10 January 2023

Argomento

Glaucoma

The glaucoma is one of the leading causes of irreversible vision loss globally and affects more than 70 million people worldwide.

Although the underlying causes of the pathogenesis of glaucoma are still not entirely clear, understanding the role played by genetics makes it possible to take fundamental steps:

for the development of diagnostic and screening tests, which could identify individuals at risk of the disease before irreversible optic nerve damage occurs;

to discover new disease-related genes and gain new insights into the molecular mechanisms underlying glaucoma, which could enable the development of specific new therapies;

to understand as yet unknown molecular mechanisms responsible for the disease.

Glaucoma can affect individuals of all ages. Early-onset forms of glaucoma, which affect children and young adults, are rarer and are typically associated with genetics and are therefore inherited. In contrast, glaucoma affecting the elderly, the most common form, has a more complex inheritance and is often the result of both environmental and genetic causes.

Glaucoma genetics: how it is studied

The genes responsible of early onset glaucoma and those associated with later onset in adults have been identified using various genetic and genomic technologies and approaches. For example, many studies on entire families, to analyse the familiarity of certain genetic variants and how these are passed on to offspring. In addition, studies are conducted to analyse and sequence the entire genome and thus identify regions of our DNA that may contribute to the onset of glaucoma.

Future directions for the discovery of new genes implicated in this eye disease include the use of next-generation sequencing techniques, the study of ever-larger patient populations and the evaluation of interactions between genes and the environment.

Genetics of early-onset glaucoma

Compared to glaucoma that begins in adulthood, early-onset forms of glaucoma have a lower incidence, ranging from 1/2500 to 1/20,000. Several genes, including those coding for myocilin (MYOC, GLC1A) and optineurin (OPTN, GLC1E), are associated with hereditary-type glaucoma in at least 10% of glaucoma cases.

Myocilin-associated mutations generally occur in the juvenile or early adult form of primary open-angle glaucoma, which is characterised by very high levels of intraocular pressure. This mutation is less prevalent in adult forms, but carriers of myocilin mutations are 90% more likely to develop glaucoma. Although the mechanism by which myocilin underlies glaucoma has not yet been fully elucidated, it appears that mutations in the gene coding for this protein lead to altered regulation of intraocular pressure.

Unlike individuals with mutations in the gene MYOCthose carrying alterations in the gene OPTN have normal levels of ocular pressure. Data reported in the literature suggest that optineurin may have a neuroprotective role, which is lost when this protein is mutated.

Role of genetics in adult and elderly forms

The role of genetics in late-onset forms of glaucoma, which affect adults and the elderly, is less pronounced than in early-onset forms. In fact, in this case, other risk factors, as well as environmental factors, are largely contributing to the development of the disease. However, robust genetic associations have been found with some genes and even some variants that increase the risk of developing glaucoma. Because of this increased complexity, many studies are underway to better understand the biological pathways involved in the development of glaucoma and the complex interactions between different genes and between genes and the environment, which may contribute to the onset of this ocular disease.

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