Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study

Irene Pichler, Fabiola Del Greco M, Martin Gögele, Christina M Lill, Lars Bertram, Chuong B Do, Nicholas Eriksson, Tatiana Foroud, Richard H Myers, PD GWAS Consortium, Michael Nalls, Margaux F Keller, International Parkinson's Disease Genomics Consortium, Wellcome Trust Case Control Consortium 2, Beben Benyamin, John B Whitfield, Genetics of Iron Status Consortium, Peter P Pramstaller, Andrew A Hicks, John R Thompson, Cosetta Minelli, Vincent Plagnol, Dena G Hernandez, Manu Sharma, Una-Marie Sheerin, Mohamad Saad, Javier Simón-Sánchez, Claudia Schulte, Suzanne Lesage, Sampath Arepalli, Roger Barker, Yoav Ben-Shlomo, Henk W Berendse, Daniela Berg, Kailash Bhatia, Rob M A de Bie, Alessandro Biffi, Bas Bloem, Zoltan Bochdanovits, Michael Bonin, Jose M Bras, Kathrin Brockmann, Janet Brooks, David J Burn, Gavin Charlesworth, Honglei Chen, Patrick F Chinnery, Sean Chong, Carl E Clarke, Mark R Cookson, J Mark Cooper, Jean Christophe Corvol, Carl Counsell, Philippe Damier, Jean-François Dartigues, Panos Deloukas, Günther Deuschl, David T Dexter, Karin D van Dijk, Allissa Dillman, Frank Durif, Alexandra Dürr, Sarah Edkins, Jonathan R Evans, Thomas Foltynie, Jianjun Gao, Michelle Gardner, J Raphael Gibbs, Alison Goate, Emma Gray, Rita Guerreiro, Clare Harris, Jacobus J van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Heiko Huber, Gavin Hudson, Sarah E Hunt, Thomas Illig, Jean-Charles Lambert, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Delia Lorenz, Alisdair McNeill, Catriona Moorby, Matthew Moore, Huw R Morris, Karen E Morrison, Ese Mudanohwo, Sean S O'Sullivan, Justin Pearson, Joel S Perlmutter, Pierre Pollak, Bart Post, Simon Potter, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Stephen Sawcer, Anthony Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Ellen Sidransky, Colin Smith, Chris C A Spencer, Joanna D Stockton, Amy Strange, Kevin Talbot, Carlie M Tanner, Avazeh Tashakkori-Ghanbaria, Daniah Trabzuni, Bryan J Traynor, André G Uitterlinden, Daan Velseboer, Marie Vidailhet, Robert Walker, Bart van de Warrenburg, Mirdhu Wickremaratchi, Nigel Williams, Caroline H Williams-Gray, Sophie Winder-Rhodes, Maria Martinez, John Hardy, Peter Heutink, Alexis Brice, Thomas Gasser, Andrew B Singleton, Nicholas W Wood, Peter Donnelly, Ines Barroso, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Peter Donnelly, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Ines Barroso, Panos Deloukas, Mark I McCarthy, Willem H Ouwehand, Aparna Radhakrishnan, Jennifer Sambrook, Daniela Toniolo, Michela Traglia, Clara Camaschella, Andres Metspalu, Tonu Esko, Christian Gieger, Janina Ried, Thomas Meitinger, Konrad Oexle, Juliane Winkelmann, Dorine Swinkels, Sita Vermeulen, Cornelia van Duijn, Linda Broer, John Beilby, Jennie Hui, Denise Anderson, Peter Visscher, Nick Martin, Irene Pichler, Fabiola Del Greco M, Martin Gögele, Christina M Lill, Lars Bertram, Chuong B Do, Nicholas Eriksson, Tatiana Foroud, Richard H Myers, PD GWAS Consortium, Michael Nalls, Margaux F Keller, International Parkinson's Disease Genomics Consortium, Wellcome Trust Case Control Consortium 2, Beben Benyamin, John B Whitfield, Genetics of Iron Status Consortium, Peter P Pramstaller, Andrew A Hicks, John R Thompson, Cosetta Minelli, Vincent Plagnol, Dena G Hernandez, Manu Sharma, Una-Marie Sheerin, Mohamad Saad, Javier Simón-Sánchez, Claudia Schulte, Suzanne Lesage, Sampath Arepalli, Roger Barker, Yoav Ben-Shlomo, Henk W Berendse, Daniela Berg, Kailash Bhatia, Rob M A de Bie, Alessandro Biffi, Bas Bloem, Zoltan Bochdanovits, Michael Bonin, Jose M Bras, Kathrin Brockmann, Janet Brooks, David J Burn, Gavin Charlesworth, Honglei Chen, Patrick F Chinnery, Sean Chong, Carl E Clarke, Mark R Cookson, J Mark Cooper, Jean Christophe Corvol, Carl Counsell, Philippe Damier, Jean-François Dartigues, Panos Deloukas, Günther Deuschl, David T Dexter, Karin D van Dijk, Allissa Dillman, Frank Durif, Alexandra Dürr, Sarah Edkins, Jonathan R Evans, Thomas Foltynie, Jianjun Gao, Michelle Gardner, J Raphael Gibbs, Alison Goate, Emma Gray, Rita Guerreiro, Clare Harris, Jacobus J van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Heiko Huber, Gavin Hudson, Sarah E Hunt, Thomas Illig, Jean-Charles Lambert, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Delia Lorenz, Alisdair McNeill, Catriona Moorby, Matthew Moore, Huw R Morris, Karen E Morrison, Ese Mudanohwo, Sean S O'Sullivan, Justin Pearson, Joel S Perlmutter, Pierre Pollak, Bart Post, Simon Potter, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Stephen Sawcer, Anthony Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Ellen Sidransky, Colin Smith, Chris C A Spencer, Joanna D Stockton, Amy Strange, Kevin Talbot, Carlie M Tanner, Avazeh Tashakkori-Ghanbaria, Daniah Trabzuni, Bryan J Traynor, André G Uitterlinden, Daan Velseboer, Marie Vidailhet, Robert Walker, Bart van de Warrenburg, Mirdhu Wickremaratchi, Nigel Williams, Caroline H Williams-Gray, Sophie Winder-Rhodes, Maria Martinez, John Hardy, Peter Heutink, Alexis Brice, Thomas Gasser, Andrew B Singleton, Nicholas W Wood, Peter Donnelly, Ines Barroso, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Peter Donnelly, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Ines Barroso, Panos Deloukas, Mark I McCarthy, Willem H Ouwehand, Aparna Radhakrishnan, Jennifer Sambrook, Daniela Toniolo, Michela Traglia, Clara Camaschella, Andres Metspalu, Tonu Esko, Christian Gieger, Janina Ried, Thomas Meitinger, Konrad Oexle, Juliane Winkelmann, Dorine Swinkels, Sita Vermeulen, Cornelia van Duijn, Linda Broer, John Beilby, Jennie Hui, Denise Anderson, Peter Visscher, Nick Martin

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 µg/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.

Conflict of interest statement

CM is a member of the Editorial Board of PLOS Medicine. NE and CBD are or have been employed by 23andMe and own stock options in the company. TF serves on Research Competitiveness Program for the American Association for the Advancement of Science; Study Sections, Review Panels, Board of Scientific Counselors for NIH; Scientific Advisory Board for University of Colorado; and the NIA's Long Life Family Study Observational Study Monitoring Board. All other authors have declared that no competing interests exist.

Figures

Figure 1. Graphical representation of the MR…
Figure 1. Graphical representation of the MR approach, with all estimates used to derive the final MR estimate.
*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.
Figure 2. Forest plot of the MR…
Figure 2. Forest plot of the MR estimates from the three instruments.
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.

References

    1. Crichton RR, Dexter DT, Ward RJ (2011) Brain iron metabolism and its perturbation in neurological diseases. J Neural Transm 118: 301–314.
    1. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5: 863–873.
    1. Dusek P, Jankovic J, Le W (2012) Iron dysregulation in movement disorders. Neurobiol Dis 46: 1–18.
    1. Forno LS (1996) Neuropathology of Parkinson's disease. J Neuropathol Exp Neurol 55: 259–272.
    1. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, et al. (1997) Alpha-synuclein in Lewy bodies. Nature 388: 839–840.
    1. Mariani S, Ventriglia M, Simonelli I, Donno S, Bucossi S, et al. (2013) Fe and Cu do not differ in Parkinson's disease: a replication study plus meta-analysis. Neurobiol Aging 34: 632–633.
    1. Davey Smith G, Ebrahim S (2005) What can mendelian randomisation tell us about modifiable behavioural and environmental exposures? BMJ 330: 1076–1079.
    1. Davey Smith G, Ebrahim S (2003) ‘Mendelian randomization’: Can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32: 1–22.
    1. Pierce BL, Ahsan H, Vanderweele TJ (2011) Power and instrument strength requirements for mendelian randomization studies using multiple genetic variants. Int J Epidemiol 40: 740–752.
    1. Palmer TM, Lawlor DA, Harbord RM, Sheehan NA, Tobias JH, et al. (2012) Using multiple genetic variants as instrumental variables for modifiable risk factors. Stats Methods Med Res 21: 223–242.
    1. Benyamin B, Ferreira MA, Willemsen G, Gordon S, Middelberg RP, et al. (2009) Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet 41: 1173–1175.
    1. Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, et al. (2012) Comprehensive research synopsis and systematic meta-analyses in parkinson's disease genetics: The PDGene database. PLoS Genet 8: e1002548 doi:
    1. Greco V, De Marco EV, Rocca FE, Annesi F, Civitelli D, et al. (2011) Association study between four polymorphisms in the HFE, TF and TFR genes and Parkinson's disease in southern Italy. Neurol Sci 32: 525–527.
    1. Halling J, Petersen MS, Grandjean P, Weihe P, Brosen K (2008) Genetic predisposition to parkinson's disease: CYP2D6 and HFE in the Faroe Islands. Pharmacogenet Genomics 18: 209–212.
    1. Guerreiro RJ, Bras JM, Santana I, Januario C, Santiago B, et al. (2006) Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a portuguese cohort. BMC Neurol 6: 24.
    1. Dekker MC, Giesbergen PC, Njajou OT, van Swieten JC, Hofman A, et al. (2003) Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism. Neurosci Lett 348: 117–119.
    1. Borie C, Gasparini F, Verpillat P, Bonnet AM, Agid Y, et al. (2002) Association study between iron-related genes polymorphisms and Parkinson's disease. J Neurol 249: 801–804.
    1. Buchanan DD, Silburn PA, Chalk JB, Le Couteur DG, Mellick GD (2002) The Cys282Tyr polymorphism in the HFE gene in Australian Parkinson's disease patients. Neurosci Lett 327: 91–94.
    1. Aamodt AH, Stovner LJ, Thorstensen K, Lydersen S, White LR, et al. (2007) Prevalence of haemochromatosis gene mutations in Parkinson's disease. J Neurol, Neurosurg Psychiatry 78: 315–317.
    1. Biasiotto G, Goldwurm S, Finazzi D, Tunesi S, Zecchinelli A, et al. (2008) HFE gene mutations in a population of Italian Parkinson's disease patients. Parkinsonism Relat Disord 14: 426–430.
    1. Akbas N, Hochstrasser H, Deplazes J, Tomiuk J, Bauer P, et al. (2006) Screening for mutations of the HFE gene in Parkinson's disease patients with hyperechogenicity of the substantia nigra. Neurosci Lett 407: 16–19.
    1. Pankratz N, Beecham GW, DeStefano AL, Dawson TM, Doheny KF, et al. (2012) Meta-analysis of Parkinson's disease: Identification of a novel locus, RIT2. Ann Neurol 71: 370–384.
    1. Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, et al. (2011) Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease. PLoS Genet 7: e1002141 doi:
    1. International Parkinson Disease Genomics Consortium (2011) Nalls MA, Plagnol V, Hernandez DG, Sharma M, et al. (2011) Imputation of sequence variants for identification of genetic risks for Parkinson's disease: A meta-analysis of genome-wide association studies. Lancet 377: 641–649.
    1. International Parkinson's Disease Genomics Consortium (IPDGC), Wellcome Trust Case Control Consortium 2 (WTCCC2) (2011) A two-stage meta-analysis identifies several new loci for Parkinson's disease. PLoS Genet 7: e1002142 doi:
    1. Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, et al. (2009) Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet 124: 593–605.
    1. Fung HC, Scholz S, Matarin M, Simon-Sanchez J, Hernandez D, et al. (2006) Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 5: 911–916.
    1. Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, et al. (2009) Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 41: 1308–1312.
    1. Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, et al. (2010) Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 74: 97–109.
    1. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, et al. (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet 42: 781–785.
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327: 557–560.
    1. D Didelez V, Meng S (2010) Assumptions of IV methods for observational epidemiology. Stat Sci 25: 22–40.
    1. Bautista LE, Smeeth L, Hingorani AD, Casas JP (2006) Estimation of bias in nongenetic observational studies using “mendelian triangulation”. Ann Epidemiol 16: 675–680.
    1. Thomas DC, Lawlor DA, Thompson JR (2007) Re: Estimation of bias in nongenetic observational studies using “mendelian triangulation” by Bautista et al. Ann Epidemiol 17: 511–513.
    1. Pierce BL, Ahsan H, Vanderweele TJ (2011) Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol 40: 740–752.
    1. Tanner CM, Goldman SM (1996) Epidemiology of Parkinson's disease. Neurol Clin 14: 317–335.
    1. Ritz B, Ascherio A, Checkoway H, Marder KS, Nelson LM, et al. (2007) Pooled analysis of tobacco use and risk of Parkinson disease. Arch Neurol 64: 990–997.
    1. Hernan MA, Takkouche B, Caamano-Isorna F, Gestal-Otero JJ (2002) A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease. Ann Neurol 52: 276–284.
    1. Linert W, Bridge MH, Huber M, Bjugstad KB, Grossman S, et al. (1999) In vitro and in vivo studies investigating possible antioxidant actions of nicotine: Relevance to Parkinson's and Alzheimer's diseases. Biochim Biophy Acta 1454: 143–152.
    1. Morck TA, Lynch SR, Cook JD (1983) Inhibition of food iron absorption by coffee. Am J Clin Nutr 37: 416–420.
    1. Zijp IM, Korver O, Tijburg LB (2000) Effect of tea and other dietary factors on iron absorption. Crit Rev Food Sci Nutr 40: 371–398.
    1. Kupershmidt L, Amit T, Bar-Am O, Youdim MB, Weinreb O (2012) Neuroprotection by the multitarget iron chelator M30 on age-related alterations in mice. Mech Ageing Dev 133: 267–274.
    1. Berg D, Roggendorf W, Schroder U, Klein R, Tatschner T, et al. (2002) Echogenicity of the substantia nigra: Association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol 59: 999–1005.
    1. Walter U, Witt R, Wolters A, Wittstock M, Benecke R (2012) Substantia nigra echogenicity in Parkinson's disease: Relation to serum iron and C-reactive protein. J Neural Transm 119: 53–57.
    1. Logroscino G, Chen H, Wing A, Ascherio A (2006) Blood donations, iron stores, and risk of Parkinson's disease. Mov Disord 21: 835–838.
    1. Savica R, Grossardt BR, Carlin JM, Icen M, Bower JH, et al. (2009) Anemia or low hemoglobin levels preceding Parkinson disease: a case-control study. Neurology 73: 1381–1387.
    1. Levenson CW, Cutler RG, Ladenheim B, Cadet JL, Hare J, et al. (2004) Role of dietary iron restriction in a mouse model of Parkinson's disease. Exp Neurol 190: 506–514.
    1. Miyake Y, Tanaka K, Fukushima W, Sasaki S, Kiyohara C, et al. (2011) Dietary intake of metals and risk of Parkinson's disease: a case-control study in Japan. J Neurol Sci 306: 98–102.
    1. Ramsey AJ, Hillas PJ, Fitzpatrick PF (1996) Characterization of the active site iron in tyrosine hydroxylase. Redox states of the iron. J Biol Chem 271: 24395–24400.
    1. Beard J, Erikson KM, Jones BC (2003) Neonatal iron deficiency results in irreversible changes in dopamine function in rats. J Nutr 133: 1174–1179.
    1. Levenson CW, Tassabehji NM (2004) Iron and ageing: an introduction to iron regulatory mechanisms. Ageing Res Rev 3: 251–263.
    1. Rhodes SL, Ritz B (2008) Genetics of iron regulation and the possible role of iron in Parkinson's disease. Neurobiol Dis 32: 183–195.
    1. Castiglioni E, Finazzi D, Goldwurm S, Pezzoli G, Forni G, et al. (2010) Analysis of nucleotide variations in genes of iron management in patients of Parkinson's disease and other movement disorders. Parkinsons Dis 2011: 827693.
    1. Castiglioni E, Finazzi D, Goldwurm S, Levi S, Pezzoli G, et al. (2010) Sequence variations in mitochondrial ferritin: Distribution in healthy controls and different types of patients. Genet Test Mol Biomarkers 14: 793–796.
    1. Ezquerra M, Campdelacreu J, Munoz E, Tolosa E (2005) Association study of the G258S transferrin gene polymorphism and Parkinson's disease in the Spanish population. J Neurol 252: 1269–1270.
    1. He Q, Du T, Yu X, Xie A, Song N, et al. (2011) DMT1 polymorphism and risk of Parkinson's disease. Neurosci Lett 501: 128–131.
    1. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, et al. (2003) The discovery of the new haemochromatosis gene. 1996. J Hepatol 38: 704–709.
    1. Du X, She E, Gelbart T, Truksa J, Lee P, et al. (2008) The serine protease TMPRSS6 is required to sense iron deficiency. Science 320: 1088–1092.
    1. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, et al. (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13: 399–408.
    1. Bradley LA, Johnson DD, Palomaki GE, Haddow JE, Robertson NH, et a (1998) Hereditary haemochromatosis mutation frequencies in the general population. J Med Screen 5: 34–36.
    1. Waheed A, Parkkila S, Zhou XY, Tomatsu S, Tsuchihashi Z, et al. (1997) Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci U S A 94: 12384–12389.
    1. Feder JN, Tsuchihashi Z, Irrinki A, Lee VK, Mapa FA, et al. (1997) The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. J Biol Chem 272: 14025–14028.
    1. Lebrón JA, Bennett MJ, Vaughn DE, Chirino AJ, Snow PM, et al. (1998) Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 93: 111–123.
    1. An P, Wu Q, Wang H, Guan Y, Mu M, et al. (2012) TMPRSS6, but not TF, TFR2 or BMP2 variants are associated with increased risk of iron-deficiency anemia. Hum Mol Genet 21: 2124–2131.
    1. Nai A, Pagani A, Silvestri L, Campostrini N, Corbella M, et al. (2011) TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals. Blood 118: 4459–4462.
    1. Fleiss JL (1993) The statistical basis of meta-analysis. Stat Methods Med Res 2: 121–145.
    1. Tamura T, Goldenberg RL, Hou J, Johnston KE, Cliver SP, Ramey SL, et al. (2002) Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age. J Ped 186: 458–463.
    1. Harbord RM, Didelez V, Palmer TM, Meng S, Sterne JA, et al. (2013) Severity of bias of a simple estimator of the causal odds ratio in mendelian randomization studies. Stat Med 32: 1246-1258.

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