Gebril Ola H, Kirby Janine, Savva George, Brayne Carol, Ince Paul G
Medical Research Division, National Research Centre, Cairo, Egypt.
J Neurogenet. 2011 Mar;25(1-2):7-14. doi: 10.3109/01677063.2011.556206. Epub 2011 Feb 21.
Incidental white matter lesions (WML) are a common neuroradiological finding in elderly people and have been linked to dementia and depression. Various mechanisms including hypoxia and increased production of reactive oxygen species (ROS) are implicated in the etiology of WML. The hemochromatosis (HFE) gene p.H63D and p.C282Y polymorphisms have been linked to dysregulation of iron metabolism and increased levels of ROS, whereas Angiotensin II receptor 1 (AGTR1) c.1166A → C polymorphism is known as a vascular risk factor. These genetic polymorphisms were characterized in brains donated to the UK MRC Cognitive Function and Ageing Study (CFAS) to assess their potential role in the risk for development of age-related WML. The study cohort comprised 258 brain donated to CFAS. WML severity was assessed in the postmortem brain donations using magnetic resonance imaging (MRI) scans and scored using the Scheltens' scale. Polymerase chain reaction (PCR) amplification of extracted DNA followed by restriction enzyme digestion was used to genotype the samples. Genotypes were validated using direct sequencing in a smaller sample. The results show that HFE p.H63D polymorphism is not associated with WML severity in the whole cohort. However, there is a significant association of the D allele with severity of WML in noncarriers of the APOE ε4 allele. No association is demonstrated between the HFE p.C282Y nor the AGTR1 c.1166A → C polymorphisms and WML severity. The HFE gene appears to be a genetic risk factor for severe aging WML independently of the APOE ε4 genotype. This would support the role of iron-related oxidative stress, in addition to previously studied factors, e.g., hypoxia as potential risk factors for developing prominent aging WML.
偶发性白质病变（WML）是老年人常见的神经放射学表现，与痴呆和抑郁有关。包括缺氧和活性氧（ROS）生成增加在内的多种机制与WML的病因有关。血色素沉着症（HFE）基因p.H63D和p.C282Y多态性与铁代谢失调和ROS水平升高有关，而血管紧张素II受体1（AGTR1）c.1166A→C多态性是一种血管危险因素。对捐赠给英国医学研究理事会认知功能与衰老研究（CFAS）的大脑进行这些基因多态性分析，以评估它们在与年龄相关的WML发生风险中的潜在作用。研究队列包括258个捐赠给CFAS的大脑。使用磁共振成像（MRI）扫描对死后大脑捐赠样本评估WML严重程度，并使用Scheltens量表进行评分。对提取的DNA进行聚合酶链反应（PCR）扩增，然后进行限制性酶切消化，用于对样本进行基因分型。在较小样本中使用直接测序对基因型进行验证。结果表明，在整个队列中，HFE p.H63D多态性与WML严重程度无关。然而，在APOEε4等位基因非携带者中，D等位基因与WML严重程度之间存在显著关联。未发现HFE p.C282Y或AGTR1 c.1166A→C多态性与WML严重程度之间存在关联。HFE基因似乎是严重衰老性WML的遗传危险因素，独立于APOEε4基因型。这将支持铁相关氧化应激的作用，除了先前研究的因素，如缺氧，作为发生明显衰老性WML的潜在危险因素。
