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In an exciting new publication, a collaborative international team - led in part by UCL’s Professor Alison Hardcastle - reports on the world’s first keratoconus study with enough patient data to be able to detect novel genetic risk factors.

Keratoconus is a condition that can perturb vision and usually first presents in young adults. This condition causes the cornea – the clear front of the eye – to get thinner and distorted over time. This results in blurred vision and sometimes even sight loss.

What is Keratoconus?

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Keratoconus is a non-inflammatory eye condition. It causes the cornea, a round dome-shaped clear window of the eye, to progressively thin and distort, causing a cone-like bulge to develop. This eventually impairs the ability of the eye to focus properly, causing poor vision.

  • It is usually diagnosed in young people in their late teens or early twenties
  • The exact cause(s) remain unknown but genetics and environment factors have both been implicated
  • It is more common in non-Caucasian populations and people whose family have the condition, hinting at the importance of genetics
  • At early stages of the condition, glasses or contact lenses may be used to correct vision
  • The only available treatment that has been shown to slow the progression of the keratoconus is cornea cross-linking’, a procedure where targeted UV light is used to strengthen the corneal tissue
  • In very advanced cases a corneal transplant may be needed

Unfortunately, very little is known about the causes of keratoconus. Although it is believed that there must be a genetic component, the details have remained elusive.

With funding support from Moorfields Eye Charity, researchers from UCL, Moorfields, Kings College London and other national and international collaborators aimed to investigate this key unsolved question in keratoconus.

Results from their research have now been published in Communications Biology, a new open access journal from Nature Research. 

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1 in 375

people are affected by keratoconus - depending on ethnicity

Their findings suggest that small variations in the sequence of keratoconus patients’ DNA might offer clues about how keratoconus develops.

These promising insights weren’t possible in previous studies due to insufficient sample sizes. However, thanks to the thousands of keratoconus patients who donated a DNA sample to research, this current study could address this. 

Lead co-author on this study, Professor Alison Hardcastle

We do know that genetic risk factors are likely to play a major role in the development of keratoconus. The challenge was to identify these variants in the human genome. This study represents a substantial advance of our understanding of keratoconus. We can now use this new knowledge as the basis for developing a genetic test to identify individuals at risk of keratoconus, at a stage when vision can be preserved, and in the future develop more effective treatments.

Professor Alison Hardcastle, UCL Institute of Ophthalmology

What did they find?

In this genome-wide association study the researchers compared the full genetic code of 4,669 people with keratoconus to that of 116,547 people without the condition. Using robust computational and statistical analyses, they were able to pinpoint short sequences of DNA that were significantly altered in genomes of people with keratoconus.

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genomes from people with keratoconus were sequenced

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new genetic variations implicated in increased keratoconus risk for the first time

This study used genome-wide analysis to demonstrate a novel link between defects in the eye’s supporting collagen with the risk of keratoconus. This means that people with keratoconus might have faulty collagen structures in their corneas. This might explain why their cornea becomes thin and distorted over time.

The research team were also able to detect changes in DNA located close to key genes that regulate relevant stem cells. These changes suggest that keratoconus could, at least in part, be attributable to an inability to produce essential corneal cells from stem-like parent cells.

By performing comprehensive genome-wide research in this way, it was possible for the team to find clues about the biology of keratoconus that have been missed previously. 

This important genetic study has shown that 1 in 8 cases of keratoconus can be traced back to a distinct set of the most common DNA risk factors.

The results of this work will enable us to diagnose keratoconus even before it manifests; this is great news because early intervention can avoid blinding consequences.

Dr Pirro Hysi, King’s College London, co-author on the study

Hear from Professor Alison Hardcastle

Professor Alison Hardcastle discusses the exciting potential of using a combination of genetics and cell biology to help diagnose patients and test therapies at the UCL Institute of Ophthalmology.

What’s next for keratoconus research?

Future work will now aim to understand the precise effects of these DNA variations on corneal biology and pinpoint the mechanism by which keratoconus then develops. It will also be crucial to identify the remaining genetic variations which some keratoconus patients might have that were not picked up in this study. 

Importantly, this work has brought us a step closer to earlier diagnosis and potentially even new therapeutic targets, offering hope to current and future keratoconus patients. 

As a first step, the team hope that patients’ DNA might be included in clinical risk calculations, such as individuals who seek refractive error surgery.

If we can find ways to identify keratoconus early, corneal collagen cross linking can prevent progression of the disease in the great majority of cases. We would like to thank the thousands of individuals who attend our Moorfields Eye Hospital cornea clinic and donated a DNA sample, without whom this important study would not have been possible.

Professor Stephen Tuft, Moorfields Eye Hospital, co-author on the study

This research was supported by a Moorfields Eye Charity project grant (GR000076) and the publication costs were funded by a research enhancement award (GR001317).