Age-Dependent Association of Apolipoprotein E Genotypes With Stroke Subtypes in a Japanese Rural Population

Abstract

Background and Purpose —The association between apolipoprotein E (apoE) polymorphisms and stroke has been controversial. These controversies may be due to inaccurate classification of stroke and differences in age ranges. We investigated the association between apoE genotypes and stroke subtypes (confirmed by CT or MRI findings) by case-control study in a Japanese rural population. Methods —First-ever-stroke patients (n=322; cerebral infarction, n=201, intracerebral hemorrhage, n=84, and subarachnoid hemorrhage, n=37) aged 40 to 89 years were recruited from Hokuetsu Hospital, Japan. Healthy controls (n=1126) were selected from the general population in the same area. ApoE genotypes were determined by restriction fragment-length polymorphism analysis. Results —Compared with apoE ε3/ε3 subjects, ε2 carriers had a 2-fold risk of cerebral infarction (OR 1.9, 95% CI 1.1 to 3.2). Among cerebral infarction patients, ε2 carriers had increased risks of cortical infarction (OR 2.4, 95% CI 1.3 to 4.6) (an anatomic subtype) and atherothrombosis (OR 3.9, 95% CI 1.7 to 9.0) and cardioembolism (OR 4.9, 95% CI 1.6 to 14.4) but not lacunar infarction (clinical subtypes). ApoE ε4 carriers had a 2.5-fold risk of subarachnoid hemorrhage (OR 2.5, 95% CI 1.1 to 5.4). ApoE ε2/ε2 subjects had an increased risk of intracerebral hemorrhage (OR 4.4, 95% CI 1.0 to 19.7). ApoE ε3/ε4 subjects showed ≈2-fold increased risk of atherothrombosis (OR 2.1, 95% CI 1.0 to 4.1) and intracerebral hemorrhage (OR 1.8, 95% CI 1.0 to 3.3). The association between ε2 and stroke was accentuated in subjects aged 70 years or older but not in those aged 40 to 69 years. Conclusions —Our study suggests that apoE ε2 is a risk factor for atherothrombosis, cardioembolism, and intracerebral hemorrhage, whereas ε4 is a risk factor for atherothrombosis, intracerebral hemorrhage, and subarachnoid hemorrhage. The occurrence of stroke may be affected by interaction between age and apoE gene polymorphisms.