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

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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.