Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Atherosclerosis. 2011 Jan;214(1):101-6. doi: 10.1016/j.atherosclerosis.2010.10.010. Epub 2010 Oct 16.
Carotid intima-medial thickness (IMT) is a surrogate marker of subclinical atherosclerosis. This study aimed to investigate the impacts of genetic variants on IMT and future development of ischemic stroke in a cohort, followed by an independent replication study.
B-mode carotid ultrasound was performed among 3330 healthy adults in the CVDFACT cohort study, and the genetic effects of atherosclerosis-related genes including connexin37 (GJA4), C-reactive protein (CRP), paraoxonase (PON1), adiponectin (ACDC), angiotensin-converting enzyme (ACE), beta-adrenergic receptor (ADRB1, ADRB2), antithrombin III (SERPINC1), and kinesin family member 6 (KIF6) were evaluated by a multivariate regression model, adjusting for traditional vascular risk factors. Study subjects were prospectively followed for the development of ischemic stroke to assess the prognostic impacts of these genetic variants. An independent case-control study was performed to replicate the genetic association from the cohort study.
The T allele of connexin37 C1019T polymorphism significantly affected IMT (β=0.014, p=0.013) after adjusting for traditional risk factors. During an average follow-up period of 10.7 years, 80 patients with ischemic stroke (2.4%) were identified. The connexin37 1019T allele was significantly associated with an increased rate of ischemic stroke under an additive model, with hazard ratios (HR) of 2.83 (95% confidence interval, 1.2-6.66) and 1.69 (95% confidence interval, 1.06-2.71), comparing TT and CT genotype with CC, respectively. After Cox analysis, age (HR, 1.78 every 10 years), diabetes mellitus (HR, 2.63), hypertension (HR, 2.08), and the T allele of C1019T polymorphism of GJA4 (HR, 1.69) were identified as independent predictors of ischemic stroke. The relationship between T allele of C1019T polymorphism of GJA4 gene and ischemic stroke was also confirmed by an independent association study.
Connexin 37 genetic variants significantly affect carotid IMT and contribute to future development of ischemic stroke.
颈动脉内膜中层厚度（IMT）是亚临床动脉粥样硬化的替代标志物。本研究旨在通过一项队列研究，调查与动脉粥样硬化相关基因的遗传变异对 IMT 的影响及其对未来缺血性卒中的影响，并进行独立的复制研究。
在 CVDFACT 队列研究中，对 3330 名健康成年人进行了 B 型颈动脉超声检查，通过多元回归模型评估了包括缝隙连接蛋白 37（GJA4）、C 反应蛋白（CRP）、对氧磷酶（PON1）、脂联素（ACDC）、血管紧张素转换酶（ACE）、β-肾上腺素能受体（ADRB1、ADRB2）、抗凝血酶 III（SERPINC1）和驱动蛋白家族成员 6（KIF6）在内的动脉粥样硬化相关基因的遗传效应，调整了传统血管危险因素。前瞻性随访研究对象以评估这些遗传变异对缺血性卒中的预后影响。进行了一项独立的病例对照研究，以复制队列研究中的遗传关联。
在调整了传统危险因素后，缝隙连接蛋白 37 C1019T 多态性的 T 等位基因显著影响 IMT（β=0.014，p=0.013）。在平均 10.7 年的随访期间，共发现 80 例缺血性卒中患者（2.4%）。在加性模型下，缝隙连接蛋白 37 1019T 等位基因与缺血性卒中发生率增加显著相关，TT 和 CT 基因型与 CC 基因型相比，风险比（HR）分别为 2.83（95%置信区间，1.2-6.66）和 1.69（95%置信区间，1.06-2.71）。Cox 分析后，年龄（HR，每 10 年增加 1.78）、糖尿病（HR，2.63）、高血压（HR，2.08）和 GJA4 基因的 C1019T 多态性的 T 等位基因（HR，1.69）被确定为缺血性卒中的独立预测因子。GJA4 基因的 C1019T 多态性的 T 等位基因与缺血性卒中之间的关系也通过独立的关联研究得到了证实。
缝隙连接蛋白 37 基因变异显著影响颈动脉 IMT，并有助于未来缺血性卒中的发生。
