Subtitle: A New Study Sheds Light on a Genetic Susceptibility Behind Non-Arteritic Retinal Artery Occlusion in East Asian Populations
Retinal artery occlusion (RAO) is a sudden, severe eye condition that can cause significant and sometimes irreversible vision loss. It occurs when the blood supply to the retina—the light-sensitive layer at the back of the eye—is blocked, leading to tissue damage from lack of oxygen.
While RAO can act as a warning sign for broader problems within the circulatory system, such as a heightened risk of stroke or carotid artery disease, the underlying reasons why some people develop RAO and others do not remain poorly understood. However, a recent study has identified a compelling genetic factor: a variant in the RNF213 gene (specifically, p.Arg4810Lys) appears to markedly increase the risk for non-arteritic RAO—at least in East Asian populations.
Understanding RAO and Its Broader Implications
Non-arteritic retinal artery occlusion (NA-RAO) is the most common form and is not caused by inflammation. Instead, it often results from a small blood clot or cholesterol plaque becoming lodged in the retinal artery.
Japan, in particular, sees a relatively high incidence of RAO compared to other countries, reporting 5.84 cases per 100,000 person-years—much higher than the United States or Croatia. Earlier research has linked RAO with issues such as extracranial carotid artery stenosis and has shown that experiencing RAO correlates with a higher risk of stroke or heart attack, both in the short and long term.
Despite these connections, scientists have only recently begun to investigate genetic susceptibility to RAO. Previous attention to the gene RNF213 arose from its association with moyamoya disease—a rare condition characterized by chronic narrowing of the arteries at the base of the brain. Given the gene’s role in other forms of vascular disease, researchers launched an in-depth search for its involvement in NA-RAO.
The Study: Linking RNF213 p.Arg4810Lys to NA-RAO
In a year-long investigation at Kyorin University’s Department of Ophthalmology, researchers examined all patients diagnosed with acute painless vision loss consistent with NA-RAO between May 2020 and April 2021. Each patient underwent thorough neurological and cardiovascular testing, including magnetic resonance imaging, blood tests, and genetic analysis. The centerpiece of the genetic testing was looking for the p.Arg4810Lys variant in the RNF213 gene.
The study eventually included 28 patients with confirmed NA-RAO and compared them to a control group of 1,202 healthy individuals without a history of stroke, recruited from the University of Tokyo Medical Genome Center.
The results were striking: the RNF213 p.Arg4810Lys variant was present in 10.7% of the NA-RAO group but only in 1.1% of the healthy controls. Adjusting for age and sex using logistic regression, the analysis found that individuals carrying the variant had an estimated 13.5 times greater risk of developing NA-RAO than those without it.
Notably, all three NA-RAO patients with the RNF213 variant exhibited branch retinal artery occlusion (BRAO) specifically, a subset of NA-RAO. Among all NA-RAO cases, more than three-quarters had hypertension, and about half had simultaneous strokes, emphasizing the intersection of vascular disease across the body.
Clinical Context: What Makes This Gene Special?
RNF213 p.Arg4810Lys first drew attention as a key susceptibility gene for moyamoya disease, prevalent among Japanese and other East Asian populations. Beyond moyamoya, the variant has been implicated in several other vascular diseases—including cerebral stenoses and narrowing of renal, pulmonary, and coronary arteries.
However, this is the first study to associate the RNF213 p.Arg4810Lys variant with non-arteritic retinal artery occlusion. Its low prevalence outside of East Asia means the findings may not be immediately applicable to other ethnicities, but they do help narrow down a biological pathway that appears to make certain individuals much more susceptible.
Previous studies have also documented an association between moyamoya disease and retinal vascular occlusion, but retinal artery involvement is not common in moyamoya. Quantitative imaging has hinted at microvascular changes in the eyes of patients with this genetic background, though how these changes link to eye or brain disease remains to be clarified.
What Does This Mean for Patients?
For clinicians, the findings add genetic testing for RNF213 p.Arg4810Lys as a potential new tool for assessing risk—particularly in East Asian populations presenting with NA-RAO or a strong family or personal history of vascular diseases. The identification of this genetic connection could aid in earlier detection of at-risk individuals and influence preventative treatment strategies.
Importantly, while a strong association was found, the study notes no significant differences between carriers and non-carriers in terms of medical history (like diabetes, heart disease), biomarkers, or major vascular imaging findings. This suggests that carrying the RNF213 variant might predispose someone to NA-RAO independently of other classic risk factors.
Limitations and Future Directions
While compelling, the study’s results are based on a relatively small number of patients (28 with NA-RAO, three of whom had the variant). RAO itself is rare, and the frequency of the RNF213 p.Arg4810Lys variant outside East Asian populations is extremely low.
Further work will need to include larger, multi-center cohorts and more comprehensive data both in patients and controls—particularly regarding other potential risk factors and more detailed vascular imaging. Such studies would help clarify whether the RNF213 variant by itself causes RAO, or if it acts alongside other genetic or environmental triggers.
Conclusion: Toward Personalized Vascular Medicine
The discovery of RNF213 p.Arg4810Lys as a probable genetic risk factor for non-arteritic retinal artery occlusion moves the field toward more personalized approaches to vascular and eye diseases. While much work remains, it provides fresh hope for targeted prevention and a deeper understanding of why some individuals—and especially those of East Asian heritage—are more vulnerable to this rare but dramatic cause of vision loss.
Reference:
Shimada, D., Miyawaki, S., Nakanishi, K., et al. (2025). RNF213 c.14429G > A (p.Arg4810Lys) is associated with non-arteritic retinal artery occlusion. Scientific Reports, 15, 35513. https://doi.org/10.1038/s41598-025-19517-2
