DOI: 10.1161/STROKEAHA.118.024712
Introduction
A groundbreaking study published in the journal Stroke has shed light on the genetic underpinnings of early-onset stroke, particularly in the presence of intracranial arterial stenosis, through the analysis of the RNF213 p.R4810K gene variant among Japanese patients. The study aimed to unravel the prevalence and implications of this mutation in noncardioembolic stroke patients between the ages of 20 and 60 years, who do not have moyamoya disease – a known cerebrovascular disorder of genetic origin.
Background
Ischemic stroke is a leading cause of mortality and long-term disability globally. It most often occurs in elderly populations; however, an increasing incidence in younger demographics emphasizes the need to explore unique etiological factors, including genetic variations. The RNF213 gene, recognized as a susceptibility gene for moyamoya disease and large-artery ischemic stroke in East Asia, encodes for a protein that is part of the ubiquitin-protein ligase family involved in fundamental cellular processes.
Study Summary
Conducted at the National Cerebral and Cardiovascular Center in Osaka, Japan, the research team, led by Teppei Kamimura et al., evaluated the incidence of the RNF213 p.R4810K variant in a cohort of 70 patients who suffered an early-onset ischemic stroke associated with intracranial arterial stenosis.
Key Findings
The RNF213 p.R4810K variant was identified in 24% of the study cohort, which was a striking discovery. The variant was more prevalent among women; it was found in 38% of females compared to 16% of males in the group, resulting in a significant odds ratio of 3.3. Furthermore, the mutation occurred overwhelmingly in patients with stenosis in the anterior circulation, particularly the M1 segment of the middle cerebral artery or the A1 segment of the anterior cerebral artery, with an odds ratio of 25.0.
Interestingly, traditional atherosclerotic risk factors, such as high blood pressure, cholesterol levels, and smoking, were not markedly different between carriers of the genetic variant and noncarriers. This emphasizes the distinct pathophysiological mechanism behind the RNF213 p.R4810K variant’s association with early-onset stroke.
Clinical and Research Implications
The study’s findings underscore the need to consider genetic screening in young patients with ischemic stroke, especially when intracranial arterial stenosis is present. Understanding this genetic variant’s role could lead to more personalized treatment plans and potentially advance preventive strategies for high-risk individuals.
Outcomes also suggest that RNF213 p.R4810K could serve as a biomarker for a novel subtype of stroke, distinct from those in which traditional atherosclerotic risk factors play a pivotal role. This genetic insight opens avenues for further research into the pathogenesis of early-onset stroke, as well as the development of targeted therapies.
Limitations and Further Research
While this study offers significant insights, it is limited by its single-center design and the relatively small sample size, which may not represent the broader Asian population or other ethnicities. It also raises questions on the expression and function of the RNF213 protein and how it contributes to stroke pathogenesis, necessitating further exploration.
Future investigations should expand to multicenter, multinational cohorts to validate these findings and potentially discover additional genetic risk factors. There is also an imperative to investigate the biological consequences of the RNF213 p.R4810K variant, to understand the molecular pathways through which it influences early-onset stroke development.
Conclusion
This pivotal study has demonstrated that the RNF213 p.R4810K variant is a prevalent and significant genetic factor in early-onset ischemic stroke with anterior circulation stenosis among Japanese individuals. Its findings renew the directive for comprehensive research into the role of genetic variations in stroke pathogenesis and highlight the importance of personalized medicine in cerebrovascular diseases.
References
1. Kamimura, T., Okazaki, S., Morimoto, T., Kobayashi, H., Harada, K., Tomita, T., … Ihara, M. (2019). Prevalence of RNF213 p.R4810K Variant in Early-Onset Stroke With Intracranial Arterial Stenosis. Stroke, 50(6), 1561–1563. https://doi.org/10.1161/STROKEAHA.118.024712
2. Bang, O. Y., Fujimura, M., & Kim, S. K. (2016). The pathophysiology of moyamoya disease: an update. Journal of Stroke, 18(1), 12–20. https://doi.org/10.5853/jos.2015.01760
3. Liu, W., Morito, D., Takashima, S., Mineharu, Y., Kobayashi, H., Hitomi, T., … Koizumi, A. (2011). Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS ONE, 6(7), e22542. https://doi.org/10.1371/journal.pone.0022542
4. Miyawaki, S., Imai, H., Takayanagi, S., & Mukasa, A. (2019). Genetic landscape of RNF213: Its function and role in moyamoya disease and associated conditions. Neurologia medico-chirurgica, 59(7), 243–251. https://doi.org/10.2176/nmc.ra.2019-0067
5. Koizumi, A., Kobayashi, H., Hitomi, T., Harada, K. H., Habu, T., & Youssefian, S. (2016). A new horizon of moyamoya disease and associated health risks explored through RNF213. Environmental Health and Preventive Medicine, 21(2), 55–70. https://doi.org/10.1007/s12199-015-0498-1
Keywords
1. RNF213 gene stroke
2. Early-onset ischemic stroke
3. Intracranial arterial stenosis
4. Genetic risk factors for stroke
5. Moyamoya disease gene variant