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Pooled analysis of iron-related genes in Parkinson's disease: association with transferrin.

ABSTRACT: Pathologic features of Parkinson's disease (PD) include death of dopaminergic neurons in the substantia nigra, presence of ?-synuclein containing Lewy bodies, and iron accumulation in PD-related brain regions. The observed iron accumulation may be contributing to PD etiology but it also may be a byproduct of cell death or cellular dysfunction. To elucidate the possible role of iron accumulation in PD, we investigated genetic variation in 16 genes related to iron homeostasis in three case-control studies from the United States, Australia, and France. After screening 90 haplotype tagging single nucleotide polymorphisms (SNPs) within the genes of interest in the US study population, we investigated the five most promising gene regions in two additional independent case-control studies. For the pooled data set (1289 cases, 1391 controls) we observed a protective association (OR=0.83, 95% CI: 0.71-0.96) between PD and a haplotype composed of the A allele at rs1880669 and the T allele at rs1049296 in transferrin (TF; GeneID: 7018). Additionally, we observed a suggestive protective association (OR=0.87, 95% CI: 0.74-1.02) between PD and a haplotype composed of the G allele at rs10247962 and the A allele at rs4434553 in transferrin receptor 2 (TFR2; GeneID: 7036). We observed no associations in our pooled sample for haplotypes in SLC40A1, CYB561, or HFE. Taken together with previous findings in model systems, our results suggest that TF or a TF-TFR2 complex may have a role in the etiology of PD, possibly through iron misregulation or mitochondrial dysfunction within dopaminergic neurons.

SUBMITTER: Rhodes SL

PROVIDER: S-EPMC3968945 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Pooled analysis of iron-related genes in Parkinson's disease: association with transferrin.

Rhodes Shannon L SL Buchanan Daniel D DD Ahmed Ismaïl I Taylor Kent D KD Loriot Marie-Anne MA Sinsheimer Janet S JS Bronstein Jeff M JM Elbaz Alexis A Mellick George D GD Rotter Jerome I JI Ritz Beate B

Neurobiology of disease 20131008

Pathologic features of Parkinson's disease (PD) include death of dopaminergic neurons in the substantia nigra, presence of α-synuclein containing Lewy bodies, and iron accumulation in PD-related brain regions. The observed iron accumulation may be contributing to PD etiology but it also may be a byproduct of cell death or cellular dysfunction. To elucidate the possible role of iron accumulation in PD, we investigated genetic variation in 16 genes related to iron homeostasis in three case-control ...[more]

PMID: 24121126

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Project description:Substantia nigra (SN) hyperechogenicity is present in most Parkinson's disease (PD) cases but is occasionally absent in some. To date, age, gender, disease severity, and other factors have been reported to be associated with SN hyperechogenicity in PD. Previous studies have discovered that excess iron deposition in the SN underlies its hyperechogenicity in PD, which may also indicate the involvement of genes associated with iron metabolism in hyperechogenicity. The objective of our study is to explore the potential associations between variants in iron metabolism-associated genes and SN echogenicity in Han Chinese PD. Demographic profiles, clinical data, SN echogenicity and genotypes were obtained from 221 Han Chinese PD individuals with a sufficient bone window. Serum ferritin levels were quantified in 92 of these individuals by immunochemical assay. We then compared factors between PD individuals with SN hyperechogenicity and those with SN hypoechogenicity to identify factors that predispose to SN hyperechogenicity. Of our 221 participants, 122 (55.2%) displayed SN hyperechogenicity, and 99 (44.8%) displayed SN hypoechogenicity. Gender and serum ferritin levels were found to be associated with SN hyperechogenicity. In total, 14 genes were included in the sequencing part. After data processing, 34 common single nucleotide polymorphisms were included in our further analyses. In our data, we also found a significantly higher frequency of PANK2 rs3737084 (genotype: OR = 2.07, P = 0.013; allele: OR = 2.51, P = 0.002) in the SN hyperechogenic group and a higher frequency of PLA2G6 rs731821 (genotype: OR = 0.45, P = 0.016; allele: OR = 0.44, P = 0.011) in the SN hypoechogenic group. However, neither of the two variants was found to be correlated with serum ferritin. This study demonstrated that genetic factors, serum ferritin level, and gender may explain the interindividual variability in SN echogenicity in PD. This is an explorative study, and further replication is warranted in larger samples and different populations.

Project description:It was well documented that macro/trace elements were associated with the neurodevelopment. We aimed to investigate the relationship between copper (Cu)/zinc (Zn)/iron/calcium (Ca)/magnesium (Mg) levels and cerebral palsy (CP) by performing a meta-analysis. We searched the PubMed, Embase, Cochrane and Chinese WanFang databases from January 1985 to June 2022 to yield studies that met our predefined criteria. Standard mean differences (SMDs) of Cu/Zn/Iron/Ca/Mg levels between CP cases and healthy controls were calculated using the fixed-effects model or the random-effects model, in the presence of heterogeneity. 95% confidence intervals (CI) were also computed. Sensitivity analysis was performed by omitting each study in turn. A total of 19 studies were involved in our investigation. CP cases showed markedly lower Cu, Zn, iron and Ca levels than those in controls among overall populations (SMD = - 2.156, 95% CI - 3.013 to - 1.299, P < 10-4; SMD = - 2.223, 95% CI - 2.966 to - 1.480, P < 10-4; SMD = - 1.092, 95% CI - 1.513 to - 0.672, P < 10-4; SMD = - 0.757, 95% CI - 1.475 to - 0.040, P = 0.038) and Asians (SMD = - 2.893, 95% CI - 3.977 to - 1.809, P < 10-4; SMD = - 2.559, 95% CI - 3.436 to - 1.683, P < 10-4; SMD = - 1.336, 95% CI - 1.807 to - 0.865, P < 10-4; SMD = - 1.000, 95% CI - 1.950 to - 0.051, P = 0.039). CP cases showed markedly lower Zn level than that in controls among Caucasians (SMD = - 0.462, 95% CI - 0.650 to - 0.274, P < 10-4). No significant differences of Cu, iron and Ca levels between CP cases and controls among Caucasians (SMD = - 0.188, 95% CI - 0.412 to 0.037, P = 0.101; SMD = - 0.004, 95% CI - 0.190 to 0.182, P = 0.968; SMD = 0.070, 95% CI - 0.116 to 0.257, P = 0.459) were observed. No marked difference of Mg level between CP cases and controls was noted among overall populations (SMD = - 0.139, 95% CI - 0.504 to 0.226, P = 0.455), Asians (SMD = - 0.131, 95% CI - 0.663 to 0.401, P = 0.629), and Caucasians (SMD = - 0.074, 95% CI - 0.361 to 0.213, P = 0.614). Sensitivity analysis did not change the overall results significantly for Cu, Zn, iron and Mg. CP cases demonstrated significantly lower levels of Cu/Zn/iron/Ca than those in healthy controls, particularly in Asians. Decreasing trend of Cu/Zn/iron/Ca levels merit attention, particularly in the population with high susceptibility to CP. Frequent monitoring and early intervention may be needed.

Dataset Information

Pooled analysis of iron-related genes in Parkinson's disease: association with transferrin.

Publications

Pooled analysis of iron-related genes in Parkinson's disease: association with transferrin.

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