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

描述(申请人提供)：众所周知，帕金森氏病(PD)患者的脑铁含量高于健康受试者，有证据表明，过量的脑铁沉积会导致神经退化。然而，一些证据表明，与对照组相比，帕金森病患者的血清铁水平可能更低：为了支持这一点，我们先前已经发现，Hp 2-1表型的结合珠蛋白(Hp)与特发性帕金森病(PD)的风险增加相关(Costa-Mallen等，2008)，并且Hp 2-1表型已被证明使其携带者的血清铁水平较低(Langlois等人，2000)。我们还从我们的初步结果中观察到，与年龄和性别匹配的健康对照组相比，PD患者的血清铁水平较低。我们推测，PD患者铁水平降低不是由于慢性疾病的贫血，而是一种特殊的铁平衡失调模式，其特征是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水平，高于正常血清铁蛋白水平。我们还提出了一个假设，即血清铁和脑铁呈负相关，低血清铁与较高的脑铁积累量相对应。我们将通过测量442名研究参与者、100名PD患者和342名按年龄、性别和种族与PD患者匹配的健康正常对照的血清总铁、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、结合珠蛋白表型来验证这些假设。我们将测试PD患者和对照组之间铁结合蛋白水平的差异是如何被结合珠蛋白表型改变的。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，磁化率加权成像法(SWI)以及R2素数方法。我们预计受试者的脑铁与血清总铁呈负相关，而与血清铁蛋白和血清可溶性转铁蛋白受体呈正相关。这项拟议研究的另一个方面与吸烟有关。吸烟一直被证明对帕金森病的风险具有保护作用，其机制仍需阐明。在这项拨款中，我们建议测试这一新的假设，即吸烟可以预防帕金森氏症，因为它会导致循环中总铁的增加和脑铁的减少，特别是对于携带Hp 2-2表型的受试者，我们以前发现这种表型可以防止帕金森氏症的风险(Costa-Mallen等人，2008年)。我们将通过比较经常吸烟和从不吸烟的人的血清铁和铁结合蛋白，并通过核磁共振测量50名参与者的脑铁来检验这一假设，其中25人将经常吸烟，25人从不吸烟。

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.