Glaucoma screening strategies and improvements in diagnostic tests help identify symptomatic patients as early as possible.Credit: Arztsamui/Shutterstock
Accelerating basic and clinical research is crucial for genetic eye diseases, such as age-related macular degeneration (AMD), the third biggest cause of vision loss worldwide. AMD is expected to affect more than 55 million people in China by 2050. Zhenglin Yang, the president of Sichuan Provincial People’s Hospital, explains his research into genetic eye diseases to enable targeted therapies and early intervention.
Zhenglin Yang, Sichuan Provincial People’s Hospital presidentCredit: Sichuan Provincial People’s Hospital
What inspired your research into eye diseases?
From growing up in a remote village in China to working in hospitals, I have witnessed how blind people and their families are subjected to physical and psychological distress. That led me to take part in different stages of research into eye diseases from pathogenic mechanism, genetic identification to molecular diagnostics. My studies in the last 20 years have broadened my horizons of how new technologies can accelerate improvements, and I have been looking to apply these innovations for wider clinical adoption in China.
What difficulties have you overcome?
Confirming pathogenic genes and their mutation sites is resource intensive. The human genome contains thousands of mutation sites, and most of these mutations do not affect genetic functions. It is necessary to screen massive data samples to pin down the effect of specific genetic variants on gene functions for a particular disease stage. We have successfully identified more than a dozen genes for monogenetic diseases and several important susceptibility genes for complex diseases, exploring potential intervention strategies via modelling.
How do these strategies work in AMD studies?
We have developed a comprehensive model of how environmental and genetic factors influence the pathogenic mechanism of AMD, which usually first affects the middle part of the vision of patients entering their 50s, leading to progressive vision loss.
We studied mouse models and patients, alongside control subjects, to show the roles and mechanisms of two most important genes linked to AMD in the Han Chinese population, HTRA1 and CFH. Zooming into polypoidal choroidal vasculopathy (PCV), a subtype of AMD, we looked into how the mutation of another specific gene, FGD6, which plays an important role in maintaining the normal functions of retinal vascular endothelial cells, is associated with PCV.
Results of these analyses inspired our effort in establishing a three-tier AMD risk prediction and prevention system for China to reduce incidence and progression. We also encourage high-risk groups to avoid smoking and adopt a diet including more antioxidant foods.
Outline your recent focus on familial exudative vitreoretinopathy (FEVR)?
As part of our long-term project on blindness-inducing retinal vascular diseases, for which FEVR is a typical example which has no effective treatment so far. We believe that elucidating its genetic and molecular mechanisms can inform its early diagnosis.Our paper in The Journal of Clinical Investigation this year demonstrates, via mouse models, that the regulated activation of the protein β-catenin by the Catenin Alpha 1 (CTNNA1) gene is critical for retinal vascular development. We identified three mutations in the CTNNA1, which cause FEVR by over-activating the β-catenin signalling pathway. We hope to provide more new insights for pathogenesis of FEVR.
Top-tier infrastructure accelerates research.Credit: Sichuan Provincial People’s Hospital
What are the main thrusts from your glaucoma research?
Glaucoma is the second leading cause of blindness worldwide. We aim at developing early-screening strategies based on genetic data from glaucoma patients.For example, our collected data led us to the discovery of a genetic variant near the ABCA1 gene, which is associated with glaucoma. Given that ABCA1 participates in generating high-density lipoprotein (HDL), we found the average level of HDL in the plasma of glaucoma patients was lower, suggesting that glaucoma may be related to the lower HDL level. We would advise people with a lower HDL level to pay more attention for possible development of glaucoma.
How are you planning to use technologies for interdisciplinary research?
Together with third-generation sequencing technology, we want to strengthen our application of artificial intelligence and big data in researching the mechanisms of retinal diseases, and effectively locating structural variations of the genome which were otherwise too difficult to identify.
Modifier genes, or genes that affect the phenotypic or molecular expressions of other genes, constitute another study focus. For example, we may need to explain the varying severity of FEVR patients from a same family by the modifier genes at different sites of the genome. We also want to study the pathological changes of the visual cortex of the brain in association with retinal diseases.
We want to explore the potential of biomedical engineering such as photosensitive materials and artificial vision. Research into environmental factors also helps us advise carriers of high-risk variants with suggestions on lifestyle changes. These will inform our development of effective and affordable treatment and prevention strategies.