Association study of the G258S transferrin gene polymorphism and Parkinson's disease in the Spanish population

Ezquerra, Mario; Campdelacreu, Jaume; Muñoz, Esteban; Tolosa, Eduard

doi:10.1007/s00415-005-0695-1

Cited by 11 publications

(9 citation statements)

References 9 publications

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“…Previous case-control studies have tried to assess causality and direction of the association by investigating the effect on PD risk of genes involved in iron metabolism and homeostasis, although their findings are somewhat inconsistent with only some supporting the hypothesis of a causal association. Among the many genes evaluated, which include FTL , FTH1 , TF , TFRC , IREB2 , LTF , CP , FXN , HFE [52], HPX , HAMP , HFE2 [53], and FTMT [54], only the G258S polymorphism in the TF gene showed a statistically significant association with PD [17], although the finding was not replicated in a subsequent study [55], and a haplotype in the SLC11A2 gene was found to occur more frequently in PD [56]. However, all these previous studies were relatively small and therefore underpowered to detect modest genetic effects on PD risk.…”

Section: Discussionmentioning

confidence: 84%

Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study

et al. 2013

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In this study, Mendelian randomization was used to study genes known to modify iron levels, and the effect of iron on Parkinson's disease (PD) risk was estimated. Based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date, the findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson's disease for every 10 µg/dL increase in iron. The results of this analysis have potentially important implications for future research into the prevention of Parkinson's disease. Please see later in the article for the Editors' Summary

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Section: Discussionmentioning

confidence: 84%

Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study

et al. 2013

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“…Specifically, alterations in Prdx6 levels are associated with Pick disease, dementia with Lewy body disease, and sporadic Creutzfeldt-Jacob disease (17,33,34). Most interesting in connection with brain function is the finding that Prdx6 is elevated in Pick disease, a type of neurodegeneration related to progressive supranuclear palsy and frontotemporal dementia, both of which correlate with the STH Q allele (4,12,13). Quite intriguingly, all these types of dementia are tangle-only tauopathies.…”

Section: Discussionmentioning

confidence: 90%

“…Recent work may have resolved the conflicting results by indicating that the R allele is associated with Alzheimer disease specifically resulting from the ApoE4 susceptibility factor (11). Furthermore, the Q allele has been shown to be over-represented in several neurodegenerative diseases: progressive supranuclear palsy (12,13), frontotemporal dementia (4), and Parkinson disease (14). Taken together, these results suggest that identifying a function of STH could implicate several proteins and/or pathway(s) as potential contributors in these neurodegenerative diseases as well.…”

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confidence: 99%

Saitohin, Which Is Nested in the tau Locus and Confers Allele-specific Susceptibility to Several Neurodegenerative Diseases, Interacts with Peroxiredoxin 6

Gao

Tse

Conrad

et al. 2005

Journal of Biological Chemistry

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Saitohin is a gene unique to humans and their closest relatives, the function of which is not yet known. Saitohin contains a single polymorphism (Q7R), and its Q and R alleles belong to the H1 and H2 tau haplotype, respectively. The Saitohin Q allele confers susceptibility to several neurodegenerative diseases. To get a handle on Saitohin function, we used it as a bait in a yeast two-hybrid screen. By this assay and subsequent co-immunoprecipitation and glutathione S-transferase pull-down assays, we discovered and confirmed that Saitohin interacts with peroxiredoxin 6, a unique member of that family that is bifunctional and the levels of which increase in Pick disease. The strength of the interaction appeared to be allelespecific, giving the first distinction between the two forms of Saitohin. Saitohin (STH),2 an intronless gene encoding an open reading frame of 128 amino acids, is located in the intron between exons 9 and 10 of the human tau gene (1). It bears no obvious homology to any known protein or motif, and its expression pattern is very similar to that of tau in human tissues. The DNA sequences homologous to the human STH gene reveal an intact, highly conserved open reading frame in the primates most closely related to humans (chimpanzee, bonobo, and gorilla) but not in other primates or in rodents (2, 3). STH provides an evolutionary locus that separates humans and their closest relatives from other mammals.A single nucleotide polymorphism of human STH has been identified that changes glutamine residue 7 to arginine (Q7R (1)). This polymorphism is associated with the two tau gene haplotypes: the Q allele with H1, the R allele with H2 (2, 4). The Q allele is the most common haplotype in humans, but all nonhuman primates are homozygous for the R allele, which makes the Q allele a human-specific marker (2, 3). Hence, the R allele is the ancestral haplotype, whereas the Q allele evolved after the human lineages separated from the other primates.In addition to evolution studies, the R allele of STH was initially found to be associated with Alzheimer disease (1), although subsequent data showing association of the R allele with Alzheimer disease have been inconsistent (2, 4 -10). Recent work may have resolved the conflicting results by indicating that the R allele is associated with Alzheimer disease specifically resulting from the ApoE4 susceptibility factor (11). Furthermore, the Q allele has been shown to be over-represented in several neurodegenerative diseases: progressive supranuclear palsy (12, 13), frontotemporal dementia (4), and Parkinson disease (14). Taken together, these results suggest that identifying a function of STH could implicate several proteins and/or pathway(s) as potential contributors in these neurodegenerative diseases as well.To discover putative functions of STH, we used it as a bait in a yeast two-hybrid screening. We discovered that it interacts with a unique member of the peroxiredoxin family, peroxiredoxin 6 (Prdx6), which has both an antioxidant function and phospholipase act...

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“…The H63D (rs1799945) variant, which we were unable to assess in our study populations and is not investigated in most of the GWAS, may (Blanco-Rojo et al, 2011) or may not (Whitfield et al, 2000) be associated with serum transferrin levels, but is associated with serum iron and transferrin saturation in the one study reporting on that variant (Whitfield et al, 2000). Our lack of observed associations between PD and genetic variation in hemochromatosis ( HFE ) or hepcidin ( HAMP ), both proteins with recognized roles in systemic iron regulation (Ezquerra et al, 2005, Benyamin et al, 2009a, Drakesmith and Prentice, 2012), support a hypothesis that the pathologic role of iron in PD could be unrelated to systemic iron homeostasis.…”

Section: Discussionmentioning

confidence: 58%

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

Rhodes¹,

Buchanan

Ahmed

et al. 2014

Neurobiology of Disease

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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 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.

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Association study of the G258S transferrin gene polymorphism and Parkinson's disease in the Spanish population

Cited by 11 publications

References 9 publications

Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study

Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study

Saitohin, Which Is Nested in the tau Locus and Confers Allele-specific Susceptibility to Several Neurodegenerative Diseases, Interacts with Peroxiredoxin 6

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

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