Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease

Abstract

BackgroundThe genetic architecture of coronary artery disease has not been fully elucidated, especially in Asian countries. Moyamoya disease is a progressive cerebrovascular disease that is reported to be complicated by coronary artery disease. Because most Japanese patients with moyamoya disease carry the p.R4810K variant of the ring finger 213 gene (RNF213), this may also be a risk factor for coronary artery disease; however, this possibility has never been tested.Methods and resultsWe genotyped the RNF213 p.R4810K variant in 956 coronary artery disease patients and 716 controls and tested the association between p.R4810K and coronary artery disease. We also validated the association in an independent population of 311 coronary artery disease patients and 494 controls. In the replication study, the p.R4810K genotypes were imputed from genome-wide genotyping data based on the 1000 Genomes Project. We used multivariate logistic regression analyses to adjust for well-known risk factors such as dyslipidemia and smoking habits. In the primary study population, the frequency of the minor variant allele was significantly higher in patients with coronary artery disease than in controls (2.04% vs. 0.98%), with an odds ratio of 2.11 (p = 0.017). Under a dominant model, after adjustment for risk factors, the association remained significant, with an odds ratio of 2.90 (95% confidence interval: 1.37–6.61; p = 0.005). In the replication study, the association was significant after adjustment for age and sex (odds ratio = 4.99; 95% confidence interval: 1.16–21.53; p = 0.031), although it did not reach statistical significance when further adjusted for risk factors (odds ratio = 3.82; 95% confidence interval: 0.87–16.77; p = 0.076).ConclusionsThe RNF213 p.R4810K variant appears to be significantly associated with coronary artery disease in the Japanese population.

Tyrosine kinase inhibitor toxicity manifesting as comorbid Moyamoya syndrome and obstructive coronary artery disease: A case report and review of the literature

“…The exact pathogenesis is unknown, though genetic factors and disruption in angiogenesis or vasculogenesis have been implicated as potential etiologies . Importantly, some studies have even demonstrated a significant association between Moyamoya disease/syndrome and CAD, which is of particular relevance to this case …”

“…6,7 Importantly, some studies have even demonstrated a significant association between Moyamoya disease/syndrome and CAD, which is of particular relevance to this case. 8,9 The association between Moyamoya disease/syndrome, CAD, and the TKI medication class may be reflected in the pathological lesions observed in these conditions. Imaging techniques, such as intravascular ultrasound virtual histology and coronary CTA, have shown culprit lesions demonstrating eccentric intimal thickening mainly composed of fibrous tissue, with a relatively small proportion of fatty tissue or necrotic core.…”

Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms

“…The presence of RNF213 4810G > A variant was at increased risk for ischemic stroke, which was largely attributable to large-artery atherosclerosis [36]. Recent reports have also described associations between RNF213 variants and extracranial systemic vasculopathy involving coronary, renal, and pulmonary arteries [37][38][39].…”

Identification of Susceptibility Loci for Cardiovascular Disease in Adults With Hypertension, Diabetes and Dyslipidemia 

“…[31] RNF213 has been identi ed as a susceptibility gene of Moyamoya disease, [32] intracranial arterial stenoses, [33] and systemic vasculopathy among East Asian populations [32] and CAD in the Japanese population. [33] Recently, the signi cance of RNF213 and SLC26A11 in Caucasian populations were reported as well, [28] which encourages its reevaluation within other ethnicities. RPTOR is a component of the mTOR pathway, which regulates cell growth in response to nutrient levels by associating with the mammalian target of rapamycin (mTOR).…”