두개강내 동맥경화증, 두개강외 동맥경화증 및 소혈관 폐색 간의 유전자 변이에 관한 비교 연구

Abstract

Although the distribution of cervicocephalic arterial atherosclerosis varies with race, the reason behind this difference remains unclear. As conventional vascular risk factors alone cannot explain this variability in the location of cerebral atherosclerosis, genetic differences involving vascular tortuosity and ICAS have been suggested to play a role. We aimed to investigate the association between polymorphisms of genes related to vascular tortuosity, RNF213, and MMP2, and the location of cervicocephalic arterial stenosis. A prospective case-control study was conducted on patients with cerebral infarction or transient ischemic attack and age- and sex-matched stroke-free controls. The stroke patients were categorized into those with intracranial artery atherosclerosis (ICAS), extracranial artery atherosclerosis (ECAS), and small vessel occlusion (SVO) according to the presence and location of vascular stenosis. The location, number, and degree of steno-occlusive lesions were assessed by magnetic resonance angiography. Six single nucleotide polymorphisms (SNPs) including rs2118181 (FBN1), rs2179357 (SLC2A10), rs1036095 (TGFBR2), rs243865 (MMP2), rs1800470 (TGFB1), and rs112735431 (RNF213) were analyzed with the TaqMan Genotyping Assay, and the distribution of genotype was compared. None of the six SNPs was associated with stroke in our initial analysis comparing the 449 stroke patients (71 with ECAS, 169 with ICAS, and 209 with SVO) with the 447 controls. In the analysis looking at stroke subgroups, the adjusted odds ratios (aORs) for age and sex indicated a significant association between rs112735431 and ICAS in the allele comparison (aOR=2.79, 95% CI: 1.17-6.66, p=0.0206) and in the additive and dominant models (aOR=2.86, 95% CI: 1.19-6.90, p=0.0192). rs2179357 was significantly associated with ICAS in the recessive model (aOR=1.65, 95% CI: 1.03-2.64, p =0.0383), and rs1800470 was significantly associated with ECAS in the recessive model (aOR=0.47, 95% CI: 0.22-0.99, p=0.0467) when compared to the controls. The analysis of the location of vascular stenosis showed that rs112735431 was associated with anterior circulation (aOR=4.94, 95% CI: 1.33-18.41, p=0.0172) and both anterior and posterior circulation (aOR=7.01, 95% CI: 1.29-38.16, p=0243), especially in the middle cerebral artery, but not with posterior circulation alone. Finally, the analysis of the burden of vascular stenosis revealed that the number (aOR=3.09, 95% CI: 1.23-7.76, p=0.0161) and degree (aOR=3.77, 95% CI: 1.48-9.58, p=0.0053) of the stenotic vessel were increased in patients with rs112735431 polymorphism. rs112735431 was associated with ICAS in the Korean population. The variant allele of rs112735431 was shown to be associated with anterior circulation vascular stenosis and an increased burden of vascular stenosis in ICAS. rs2179357 and rs1800470 was associated with ICAS and ECAS, respectively. Further large-scale studies are needed to confirm the effect of rs2179357 and rs1800470.