RNF213 p.R4810K Variant a Key Marker for Intracranial Artery Stenosis Progression

Individuals with the RNF219 p.R4810L variant have a greater risk for intracranial artery stenosis progression.

The variant RNF213 p.R4810K is a strong predictor of progression of intracranial artery stenosis, according to study findings published in the journal Neurology Genetics.

The most common cause of ischemic stroke worldwide is intracranial artery stenosis. The higher prevalence of ischemic stroke amongst people of East Asian descent suggests that environmental and genetic factors may play a role. Recent research has found the p.R4810K variant of the RNF213 gene present in 20%-50% of the East Asian population with intracranial artery stenosis, which is only present in 1%-2% of the general population.

For the study, researchers assessed this genetic variant and its role in the progression and prognosis of intracranial artery stenosis in patients in a 15-year follow up survey.

The researchers collected data on patients with intracranial artery stenosis who were >1 month after stroke onset. Patients were enrolled in 1 of 2 collected registries (NCVC Genome Registry and Osaka Clinical Research Network for Stroke) between September 1, 2006 and October 31, 2021. Inclusion criteria consisted of patients aged >20 years who consented to genetic testing and who have had periodic magnetic resonance imaging (MRI) follow up >5 years. Those who had intellectual disability or who participated in other clinical trials were excluded from the study.

Targeted prevention and management strategies, including aggressive lipid lowering therapy, are warranted for RNF213 p.R4810K variant carriers with intracranial artery stenosis.

A validated grading scale of 1-4 was used to classify the degree of stenosis. Inclusion of stenosis was defined as a diameter of 30%-99% (grades 2-3). Progression was defined as an increase of stenosis by at least 1 grade. Blood samples were obtained from all patients for RNF213 p.R4810K genotyping to define patients as homozygous, heterozygous, or noncarriers.

A total of 52 eligible patients were enrolled in the study, of which 22 (42%) were carriers of the RNF213 p.R4810K variant. No patients were homozygous for the genotype. Patients were followed up for a median of 10.3 years and an average of 10 MRI scans were performed per patient.

Intracranial artery stenosis progression was evidenced in 14 (64%) of variant carriers and 8 (27%) of noncarriers (OR, 4.81; 95% CI, 1.47–15.77; P = 0.011). Progression of stenosis was found in 8 (36%) carriers and 3 (10%) noncarriers (OR, 5.14; 95% CI, 1.18–22.49; P = 0.037).

A significant association was found with time to progression of intracranial artery stenosis and time to marked progression in those with the RNF213 p.R4810K variant (Log-rank P = 0.004 and log-rank P = 0.0025, respectively).

Cox regression analysis found carriers of the RNF213 p.R4810K variant were significantly associated with intracranial artery stenosis (HR, 3.31; 95% CI, 1.38–7.90; P = 0.007).

Compared with patients who did not use statins, those who did experienced a reduced progression of intracranial stenosis. Carriers of the RNF213 p.R4810K variant who had statin treatment were found to have a significant risk reduction (HR, 0.20; 95% CI 0.06–0.63; P = 0.006) but not in noncarriers (HR, 0.65; 95% CI, 0.16–2.63; P = 0.55).

The researchers found 45% of carriers had a symptomatic stroke and/or transient ischemic attack (TIA), compared with 13% of noncarriers (OR, 5.52; 95% CI, 1.41–20.82; P = 0.013).

Study limitations included the exclusion of those with moyamoya disease, in which 80%-90% of patients have the genetic variant. This could underestimate the risk of the RNF213 p.R4810K variant.

The researchers concluded, “Our results indicate the importance of genetic testing for RNF213 in patients with intracranial stenosis for predicting prognosis. Targeted prevention and management strategies, including aggressive lipid lowering therapy, are warranted for RNF213 p.R4810K variant carriers with intracranial artery stenosis.”


Okazaki S, Yoshimoto T, Ohara M, et al. Effect of the RNF213 p.R4810K variant on the progression of intracranial artery stenosis: a 15-year follow-up studyNeurol Genet. 2022;8(5):e200029. doi:10.1212/NXG.0000000000200029