Haptoglobin Phenotype and Smoking: Effects on Iron Levels in Parkinson's Disease

描述（由申请人提供）：已知帕金森病（PD）患者的脑铁水平高于健康受试者，并且有证据表明过量的脑铁沉积可导致神经变性。然而，一些证据表明，与对照相比，PD患者的血清铁水平可能较低：为了支持这一点，我们先前发现血红蛋白结合蛋白触珠蛋白（Hp）的Hp 2 - 1表型与特发性帕金森病（PD）的风险增加相关（Costa-Mallen et al.，2008），并且先前已显示Hp 2 - 1表型赋予其携带者较低的血清铁水平（Langlois et al.，2000年）。我们还从我们的初步结果中观察到，PD患者的血清铁低于年龄和性别匹配的健康对照组。我们推测，PD患者的低铁水平不是由于慢性疾病的贫血，而是代表了PD中存在的铁稳态失调的特定模式，其特征在于低于正常血清铁和血红蛋白水平，高于正常可溶性转铁蛋白受体，高于正常血清铁蛋白。我们还提出了血清铁和脑铁呈负相关的假设，并且较低的血清铁将对应于较高的脑铁积累。我们将通过测量442名研究参与者、100名PD患者和342名年龄、性别和种族与PD患者匹配的健康正常对照者的血清总铁、血红蛋白、红细胞计数、转铁蛋白、转铁蛋白饱和度%、可溶性转铁蛋白受体、触珠蛋白表型来检验这些假设。我们将测试PD病例和对照之间的铁结合蛋白水平的差异是如何被结合珠蛋白表型修饰的。我们还将通过磁共振成像（MRI）直接测量50名参与者的脑铁水平。我们将使用两种方法通过MRI测量脑铁，磁敏感加权成像方法（SWI）以及R2 prime方法。我们预期受试者的脑铁与血清总铁呈负相关，并与血清铁蛋白和血清可溶性转铁蛋白受体直接相关。拟议研究的另一个方面与吸烟有关。吸烟一直被证明对PD风险具有保护作用，其机制仍有待阐明。在这项研究中，我们提出了一个新的假设，即吸烟可以预防PD，因为它会导致总循环铁增加和脑铁减少，特别是对于携带Hp 2 - 2表型的受试者，我们以前发现它可以预防PD风险（Costa-Mallen et al，2008）。我们将通过比较曾经吸烟者和从不吸烟者之间的血清铁和铁结合蛋白以及通过MRI测量50名参与者的脑铁来验证这一假设，其中25名参与者将是曾经吸烟者和25名从不吸烟者。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) patients are known to have higher levels of brain iron than healthy subjects, and there is evidence that excessive brain iron deposition can result in neurodegeneration. However, some evidence suggests that serum iron levels may be lower in PD patients as compared to controls: in support of this, we have previously found that the Hp 2-1 phenotype of the hemoglobin-binding protein haptoglobin (Hp) was associated with increased risk of idiopathic Parkinson's disease (PD) (Costa-Mallen et al., 2008), and the Hp 2-1 phenotype has been previously shown to confer lower serum iron levels to its carriers (Langlois et al., 2000). We also observed from our preliminary results that PD patients have lower serum iron than age- and gender- matched healthy controls. We hypothesize that the low iron levels present in PD patients are not due to anemia of chronic disease but represent a specific pattern of iron homeostasis dysregulation present in PD characterized by lower than normal serum iron and hemoglobin levels, higher than normal soluble transferrin receptor, and higher than normal serum ferritin. We also make the hypothesis that serum and brain iron are inversely correlated, and that lower serum iron will corresponds to higher brain iron accumulation. We will test these hypotheses by measuring total serum iron, hemoglobin, red blood cells count, transferrin, transferrin % saturation, soluble transferrin receptor, haptoglobin phenotype, in 442 study participants, 100 PD patients and 342 healthy normal controls who are matched by age, gender, and ethnicity to the PD patients. We will test how differences in iron-binding protein levels between PD cases and controls are modified by the haptoglobin phenotype. We will also measure directly brain iron levels in a subset of 50 participants, by Magnetic Resonance Imaging (MRI). We will use two methods for brain iron measurements by MRI, the susceptibility weighted imaging method (SWI) as well as the R2 prime method. We expect brain iron in a subject to be inversely correlated with total serum iron, and to be directly correlated to serum ferritin and serum soluble transferrin receptor. Another aspect of the proposed research is related to tobacco smoking. Tobacco smoking has been consistently shown to be protective for PD risk, with mechanisms that still have to be elucidated. In this grant we propose to test the novel hypothesis that smoking protects from PD because it causes an increase in total circulatory iron and a decrease in brain iron, especially for subjects carrying the Hp 2-2 phenotype, which we previously found protects from PD risk (Costa-Mallen et al, 2008). We will test this hypothesis by comparing serum iron and iron-binding proteins between ever-smokers and never-smokers and by measuring brain iron by MRI in the 50 participants, of whom 25 will be ever-smokers and 25 never-smokers.