Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study
Publication Date
June 04, 2013
Journal
PLOS Medicine
Authors
Irene Pichler, Fabiola Del Greco M., Martin Gögele, Christina M. Lill, et al
Volume
10
Issue
6
Pages
e1001462
DOI
https://dx.plos.org/10.1371/journal.pmed.1001462
Publisher URL
http://journals.plos.org/plosmedicine/article?id=10.1371%2Fjournal.pmed.1001462
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/23750121
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672214
Europe PMC
http://europepmc.org/abstract/MED/23750121
Web of Science
000321034800006
Scopus
84879529900
Mendeley
http://www.mendeley.com/research/serum-iron-levels-risk-parkinson-disease-mendelian-randomization-study-8
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{"title"=>"Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study", "type"=>"journal", "authors"=>[{"first_name"=>"Irene", "last_name"=>"Pichler", "scopus_author_id"=>"12782295300"}, {"first_name"=>"M. Fabiola", "last_name"=>"Del Greco", "scopus_author_id"=>"6701869066"}, {"first_name"=>"Martin", "last_name"=>"Gögele", "scopus_author_id"=>"18233616400"}, {"first_name"=>"Christina M.", "last_name"=>"Lill", "scopus_author_id"=>"25923452200"}, {"first_name"=>"Lars", "last_name"=>"Bertram", "scopus_author_id"=>"7003737404"}, {"first_name"=>"Chuong B.", "last_name"=>"Do", "scopus_author_id"=>"42061293600"}, {"first_name"=>"Nicholas", "last_name"=>"Eriksson", "scopus_author_id"=>"24343781500"}, {"first_name"=>"Tatiana", "last_name"=>"Foroud", "scopus_author_id"=>"7006590374"}, {"first_name"=>"Richard H.", "last_name"=>"Myers", "scopus_author_id"=>"35380404100"}, {"first_name"=>"Michael", "last_name"=>"Nalls", "scopus_author_id"=>"55630773200"}, {"first_name"=>"Margaux F.", "last_name"=>"Keller", "scopus_author_id"=>"55251777900"}, {"first_name"=>"Beben", "last_name"=>"Benyamin", "scopus_author_id"=>"16314927500"}, {"first_name"=>"John B.", "last_name"=>"Whitfield", "scopus_author_id"=>"16187873900"}, {"first_name"=>"Peter P.", "last_name"=>"Pramstaller", "scopus_author_id"=>"7003683728"}, {"first_name"=>"Andrew A.", "last_name"=>"Hicks", "scopus_author_id"=>"7006388546"}, {"first_name"=>"John R.", "last_name"=>"Thompson", "scopus_author_id"=>"55546704200"}, {"first_name"=>"Cosetta", "last_name"=>"Minelli", "scopus_author_id"=>"55161773700"}], "year"=>2013, "source"=>"PLoS Medicine", "identifiers"=>{"pui"=>"369203080", "issn"=>"15491277", "isbn"=>"1549-1676 (Electronic)\\r1549-1277 (Linking)", "doi"=>"10.1371/journal.pmed.1001462", "scopus"=>"2-s2.0-84879529900", "pmid"=>"23750121", "sgr"=>"84879529900"}, "id"=>"7ebdfd7c-b4a1-3614-bcdc-bffdd6a7b030", "abstract"=>"BACKGROUND: Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. METHODS AND FINDINGS: We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p = 0.001) per 10 microg/dl increase in serum iron. CONCLUSIONS: Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made. Please see later in the article for the Editors' Summary.", "link"=>"http://www.mendeley.com/research/serum-iron-levels-risk-parkinson-disease-mendelian-randomization-study-8", "reader_count"=>14, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Ph. D. Student"=>4, "Other"=>1, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Ph. D. Student"=>4, "Other"=>1, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>6, "Medicine and Dentistry"=>2, "Neuroscience"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>0}

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Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1074463", "https://ndownloader.figshare.com/files/1074465", "https://ndownloader.figshare.com/files/1074466", "https://ndownloader.figshare.com/files/1074468", "https://ndownloader.figshare.com/files/1074469", "https://ndownloader.figshare.com/files/1074471", "https://ndownloader.figshare.com/files/1074474", "https://ndownloader.figshare.com/files/1074476", "https://ndownloader.figshare.com/files/1074477"], "description"=>"<div><p>Background</p><p>Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date.</p><p>Methods and Findings</p><p>We used as instrumental variables three genetic variants influencing iron levels, <i>HFE</i> rs1800562, <i>HFE</i> rs1799945, and <i>TMPRSS6</i> rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%–6%; <i>p = </i>0.001) per 10 µg/dl increase in serum iron.</p><p>Conclusions</p><p>Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made.</p><p><i>Please see later in the article for the Editors' Summary</i></p></div>", "links"=>[], "tags"=>["parkinson", "mendelian", "randomization"], "article_id"=>711693, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Irene Pichler", "Fabiola Del Greco M.", "Martin Gögele", "Christina M. Lill", "Lars Bertram", "Chuong B. Do", "Nicholas Eriksson", "Tatiana Foroud", "Richard H. Myers", "Michael Nalls", "Margaux F. Keller", "Beben Benyamin", "John B. Whitfield", "Peter P. Pramstaller", "Andrew A. Hicks", "John R. Thompson", "Cosetta Minelli"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001462.s001", "https://dx.doi.org/10.1371/journal.pmed.1001462.s002", "https://dx.doi.org/10.1371/journal.pmed.1001462.s003", "https://dx.doi.org/10.1371/journal.pmed.1001462.s004", "https://dx.doi.org/10.1371/journal.pmed.1001462.s005", "https://dx.doi.org/10.1371/journal.pmed.1001462.s006", "https://dx.doi.org/10.1371/journal.pmed.1001462.s007", "https://dx.doi.org/10.1371/journal.pmed.1001462.s008", "https://dx.doi.org/10.1371/journal.pmed.1001462.s009"], "stats"=>{"downloads"=>15, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Serum_Iron_Levels_and_the_Risk_of_Parkinson_Disease_A_Mendelian_Randomization_Study_/711693", "title"=>"Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-06-04 00:28:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/1074462"], "description"=>"<p>Details on individual datasets are reported in <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001462#pmed.1001462.s009\" target=\"_blank\">Text S1</a> and in <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001462#pmed.1001462.s005\" target=\"_blank\">Tables S1</a> and <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001462#pmed.1001462.s006\" target=\"_blank\">S2</a>.</p>a<p>Unpublished data. The original sample size was 22,444, but genotype and phenotype data were available only for 21,567.</p>b<p>23andMe: slightly expanded version of the cohort used in <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001462#pmed.1001462-Do1\" target=\"_blank\">[23]</a>.</p>c<p>IPDGC: USA-NIA and USA-dbGAP studies were not included in our analysis due to overlap with PD GWAS Consortium; the Icelandic dataset was not available for analysis.</p>", "links"=>[], "tags"=>["studies", "included"], "article_id"=>711692, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Irene Pichler", "Fabiola Del Greco M.", "Martin Gögele", "Christina M. Lill", "Lars Bertram", "Chuong B. Do", "Nicholas Eriksson", "Tatiana Foroud", "Richard H. Myers", "Michael Nalls", "Margaux F. Keller", "Beben Benyamin", "John B. Whitfield", "Peter P. Pramstaller", "Andrew A. Hicks", "John R. Thompson", "Cosetta Minelli"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001462.t001", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characteristics_of_the_studies_included_for_the_gene_8211_iron_and_gene_8211_PD_associations_/711692", "title"=>"Characteristics of the studies included for the gene–iron and gene–PD associations.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-06-04 00:28:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1074459"], "description"=>"<p>The size of the squares is proportional to the precision of the MR estimates for each polymorphism, with the horizontal lines indicating their 95% confidence intervals. The combined MR estimate is represented by the centre of the diamond, with the lateral tips indicating its 95% confidence interval. The solid vertical line is the line of no effect.</p>", "links"=>[], "tags"=>["mr", "estimates"], "article_id"=>711689, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Irene Pichler", "Fabiola Del Greco M.", "Martin Gögele", "Christina M. Lill", "Lars Bertram", "Chuong B. Do", "Nicholas Eriksson", "Tatiana Foroud", "Richard H. Myers", "Michael Nalls", "Margaux F. Keller", "Beben Benyamin", "John B. Whitfield", "Peter P. Pramstaller", "Andrew A. Hicks", "John R. Thompson", "Cosetta Minelli"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001462.g002", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Forest_plot_of_the_MR_estimates_from_the_three_instruments_/711689", "title"=>"Forest plot of the MR estimates from the three instruments.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-04 00:28:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1074457"], "description"=>"<p>*Reported is the allele that increases iron levels, together with its frequency (AF). **This corresponds approximately to an OR per unit µg/dl increase in iron of 0.997 (95%CI 0.994–0.999), that is 0.3% (0.1%–0.6%) relative reduction in PD risk per 1 µg/dl increase in iron.</p>", "links"=>[], "tags"=>["mr", "estimates"], "article_id"=>711687, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Irene Pichler", "Fabiola Del Greco M.", "Martin Gögele", "Christina M. Lill", "Lars Bertram", "Chuong B. Do", "Nicholas Eriksson", "Tatiana Foroud", "Richard H. Myers", "Michael Nalls", "Margaux F. Keller", "Beben Benyamin", "John B. Whitfield", "Peter P. Pramstaller", "Andrew A. Hicks", "John R. Thompson", "Cosetta Minelli"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001462.g001", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Graphical_representation_of_the_MR_approach_with_all_estimates_used_to_derive_the_final_MR_estimate_/711687", "title"=>"Graphical representation of the MR approach, with all estimates used to derive the final MR estimate.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-06-04 00:28:07"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2013-01-01T00:00:00Z", "end_date"=>"2013-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences", "average_usage"=>[269, 466, 588, 697, 800, 896, 988, 1076, 1165, 1254, 1340, 1417]}, {"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[284, 491, 620, 738, 843, 945, 1043, 1137, 1225, 1315, 1400, 1479, 1555]}, {"subject_area"=>"/Physical sciences/Mathematics", "average_usage"=>[259, 431, 541, 639, 727, 816, 898, 980, 1061, 1136, 1214, 1294, 1356]}, {"subject_area"=>"/Social sciences", "average_usage"=>[289, 475, 593, 703, 805, 902, 990, 1078, 1158, 1250, 1336, 1417, 1482]}]}
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