Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

被引：212

作者：

Benyamin, Beben ^{[1
,2
]}

Esko, Tonu ^{[3
,4
,5
]}

Ried, Janina S. ^{[6
]}

Radhakrishnan, Aparna ^{[7
]}

Vermeulen, Sita H. ^{[8
,9
]}

Traglia, Michela ^{[10
,11
]}

Goegele, Martin ^{[12
]}

Anderson, Denise ^{[13
]}

Broer, Linda ^{[14
,15
]}

Podmore, Clara ^{[16
]}

Luan, Jian'an ^{[16
]}

Kutalik, Zoltan ^{[17
,18
]}

Sanna, Serena ^{[19
]}

van der Meer, Peter ^{[20
]}

Tanaka, Toshiko ^{[21
]}

Wang, Fudi ^{[22
]}

Westra, Harm-Jan ^{[23
]}

Franke, Lude ^{[23
]}

Mihailov, Evelin ^{[3
,24
]}

Milani, Lili ^{[3
]}

Haeldin, Jonas ^{[3
]}

Winkelmann, Juliane ^{[25
,26
,27
,28
,29
]}

Meitinger, Thomas ^{[28
,30
]}

Thiery, Joachim ^{[31
,32
]}

Peters, Annette ^{[33
,34
]}

Waldenberger, Melanie ^{[22
,34
]}

Rendon, Augusto ^{[7
,35
,36
]}

Jolley, Jennifer ^{[7
,35
]}

Sambrook, Jennifer ^{[7
,35
]}

Kiemeney, Lambertus A. ^{[37
]}

Sweep, Fred C. ^{[38
]}

Sala, Cinzia F. ^{[39
]}

Schwienbacher, Christine ^{[12
]}

Pichler, Irene ^{[12
]}

Hui, Jennie ^{[40
,41
,42
]}

Demirkan, Ayse ^{[43
]}

Isaacs, Aaron ^{[13
,44
]}

Amin, Najaf

Steri, Maristella ^{[19
]}

Waeber, Gerard ^{[45
]}

Verweij, Niek ^{[20
]}

Powell, Joseph E. ^{[46
]}

Nyholt, Dale R. ^{[2
]}

Heath, Andrew C. ^{[47
]}

Madden, Pamela A. F. ^{[47
]}

Visscher, Peter M. ^{[1
,46
]}

Wright, Margaret J. ^{[2
]}

Montgomery, Grant W. ^{[2
]}

Martin, Nicholas G. ^{[2
]}

Hernandez, Dena ^{[48
]}

机构：

[1] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia

[2] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia

[3] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia

[4] MIT, Broad Inst, Cambridge, MA 02141 USA

[5] Harvard Univ, Cambridge, MA 02141 USA

[6] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany

[7] Univ Cambridge, Dept Haematol, Cambridge CB2 0XY, England

[8] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6525 GA Nijmegen, Netherlands

[9] Radboud Univ Nijmegen, Med Ctr, Dept Genet, NL-6525 GA Nijmegen, Netherlands

[10] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy

[11] IRCCS Burlo Garofolo Trieste, Inst Maternal & Child Health, I-34137 Trieste, Italy

[12] European Acad Bolzano Bozen EURAC, Ctr Biomed, I-39100 Bolzano, Italy

[13] Univ Western Australia, Telethon Inst Child Hlth Res, Ctr Child Hlth Res, Perth, WA 6872, Australia

[14] Erasmus MC, Dept Epidemiol, Subdiv Genet Epidemiol, NL-3000 CA Rotterdam, Netherlands

[15] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands

[16] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England

[17] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1010 Lausanne, Switzerland

[18] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[19] CNR, IRGB, I-09042 Cagliari, Italy

[20] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands

[21] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA

[22] Zhejiang Univ, Sch Publ Hlth, Hangzhou 310058, Zhejiang, Peoples R China

[23] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

[24] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia

[25] Stanford Univ, Dept Neurol & Neurosc, Palo Alto, CA 94304 USA

[26] Stanford Univ, Ctr Sleep Sci & Med, Palo Alto, CA 94304 USA

[27] Tech Univ Munich, Klinikum Rechts Isar, Neurol Klin & Poliklin, D-81675 Munich, Germany

[28] Helmholtz Zentrum Munchen, Inst Humangenet, D-85764 Neuherberg, Germany

[29] Munich Cluster Syst Neurol SyNergy, D-81675 Munich, Germany

[30] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-81675 Munich, Germany

[31] Univ Klinikum Leipzig, Inst Lab Med Clin Chem & Mol Diagnost, D-04103 Leipzig, Germany

[32] Univ Leipzig, Fac Med, LIFE Res Ctr Civilizat Dis, D-04103 Leipzig, Germany

[33] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, D-85764 Neuherberg, Germany

[34] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany

[35] NHS Blood & Transplant, Cambridge, England

[36] MRC, Biostat Unit, Cambridge CB2 0SR, England

[37] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 GA Nijmegen, Netherlands

[38] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, Lab Genet Endocrine & Metab Dis LGEM, NL-6525 GA Nijmegen, Netherlands

[39] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy

[40] PathWest Lab Med WA, Nedlands, WA 6009, Australia

[41] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia

[42] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia

[43] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands

[44] Ctr Med Syst Biol, NL-2333 ZC Leiden, Netherlands

[45] Univ Lausanne, CHUV, Dept Med, CH-1011 Lausanne, Switzerland

[46] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld 4072, Australia

[47] Washington Univ, Dept Psychiat, St Louis, MO 63110 USA

[48] NIA, Neurogenet Lab, Bethesda, MD 20892 USA

[49] ASF, Geriatr Unit, I-50122 Florence, Italy

[50] ICIN Netherlands, Durrer Ctr Cardiogenet Res, Inst Heart, NL-3511 GC Utrecht, Netherlands

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

基金：

英国医学研究理事会;

关键词：

TRANSFERRIN RECEPTOR 2; GENOME-WIDE ASSOCIATION; FOAM CELL-FORMATION; HEREDITARY HEMOCHROMATOSIS; CIRCADIAN-RHYTHM; GENETIC-VARIANTS; COMMON VARIANTS; TOTAL MORTALITY; FERRITIN LEVELS; HFE;

D O I：

10.1038/ncomms5926

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P < 5 x 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

引用

页数：10

共 69 条

[1] Hemochromatosis and iron-overload screening in a racially diverse population
Adams, PC
Reboussin, DM
Barton, JC
McLaren, CE
Eckfeldt, JH
McLaren, GD
Dawkins, FW
Acton, RT
Harris, EL
Gordeuk, VR
Leiendecker-Foster, C
Speechley, M
Snively, BM
Holup, JL
Thomson, E
Sholinsky, P
Acton, RT
Barton, JC
Dixon, D
Rivers, CA
Tucker, D
Ware, JC
McLaren, CE
McLaren, GD
Anton-Culver, H
Baca, JA
Bent, TC
Brunner, LC
Dao, MM
Jorgensen, KS
Kuniyoshi, J
Le, HD
Masatsugu, MK
Meyskens, FL
Morohashi, D
Nguyen, HP
Panagon, SN
Phung, C
Raymundo, V
Ton, T
Walker, AP
Wenzel, LB
Ziogas, A
Adams, PC
Bloch, E
Chakrabarti, S
Fleischhauer, A
Harrison, H
Jia, K
Larson, S
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2005, 352 (17) : 1769 - 1778
[2] Interactions between hepatic iron and lipid metabolism with possible relevance to steatohepatitis
Ahmed, Umbreen
Latham, Patricia S.
Oates, Phillip S.
[J]. WORLD JOURNAL OF GASTROENTEROLOGY, 2012, 18 (34) : 4651 - 4658
[3] Iron-overload-related disease in HFE hereditary hemochromatosis
Allen, Katrina J.
Gurrin, Lyle C.
Constantine, Clare C.
Osborne, Nicholas J.
Delatycki, Martin B.
Nicoll, Amanda J.
McLaren, Christine E.
Bahlo, Melanie
Nisselle, Amy E.
Vulpe, Chris D.
Anderson, Gregory J.
Southey, Melissa C.
Giles, Graham G.
English, Dallas R.
Hopper, John L.
Olynyk, John K.
Powell, Lawrie W.
Gertig, Dorota M.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (03) : 221 - 230
[4] Common variants in TMPRSS6 are associated with iron status and erythrocyte volume
Benyamin, Beben
Ferreira, Manuel A. R.
Willemsen, Gonneke
Gordon, Scott
Middelberg, Rita P. S.
McEvoy, Brian P.
Hottenga, Jouke-Jan
Henders, Anjali K.
Campbell, Megan J.
Wallace, Leanne
Frazer, Ian H.
Heath, Andrew C.
de Geus, Eco J. C.
Nyholt, Dale R.
Visscher, Peter M.
Penninx, Brenda W.
Boomsma, Dorret I.
Martin, Nicholas G.
Montgomery, Grant W.
Whitfield, John B.
[J]. NATURE GENETICS, 2009, 41 (11) : 1173 - 1175
[5] Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA
Beutler, E
Felitti, VJ
Koziol, JA
Ho, NJ
Gelbart, T
[J]. LANCET, 2002, 359 (9302) : 211 - 218
[6] A Multi-Scale Model of Hepcidin Promoter Regulation Reveals Factors Controlling Systemic Iron Homeostasis
Casanovas, Guillem
Banerji, Anashua
d'Alessio, Flavia
Muckenthaler, Martina U.
Legewie, Stefan
[J]. PLOS COMPUTATIONAL BIOLOGY, 2014, 10 (01)
[7] Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma
Chambers, John C.
Zhang, Weihua
Sehmi, Joban
Li, Xinzhong
Wass, Mark N.
Van der Harst, Pim
Holm, Hilma
Sanna, Serena
Kavousi, Maryam
Baumeister, Sebastian E.
Coin, Lachlan J.
Deng, Guohong
Gieger, Christian
Heard-Costa, Nancy L.
Hottenga, Jouke-Jan
Kuehnel, Brigitte
Kumar, Vinod
Lagou, Vasiliki
Liang, Liming
Luan, Jian'an
Vidal, Pedro Marques
Leach, Irene Mateo
O'Reilly, Paul F.
Peden, John F.
Rahmioglu, Nilufer
Soininen, Pasi
Speliotes, Elizabeth K.
Yuan, Xin
Thorleifsson, Gudmar
Alizadeh, Behrooz Z.
Atwood, Larry D.
Borecki, Ingrid B.
Brown, Morris J.
Charoen, Pimphen
Cucca, Francesco
Das, Debashish
de Geus, Eco J. C.
Dixon, Anna L.
Doering, Angela
Ehret, Georg
Eyjolfsson, Gudmundur I.
Farrall, Martin
Forouhi, Nita G.
Friedrich, Nele
Goessling, Wolfram
Gudbjartsson, Daniel F.
Harris, Tamara B.
Hartikainen, Anna-Liisa
Heath, Simon
Hirschfield, Gideon M.
[J]. NATURE GENETICS, 2011, 43 (11) : 1131 - 1138
[8] Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels
Chambers, John C.
Zhang, Weihua
Li, Yun
Sehmi, Joban
Wass, Mark N.
Zabaneh, Delilah
Hoggart, Clive
Bayele, Henry
McCarthy, Mark I.
Peltonen, Leena
Freimer, Nelson B.
Srai, Surjit K.
Maxwell, Patrick H.
Sternberg, Michael J. E.
Ruokonen, Aimo
Abecasis, Goncalo
Jarvelin, Marjo-Riitta
Scott, James
Elliott, Paul
Kooner, Jaspal S.
[J]. NATURE GENETICS, 2009, 41 (11) : 1170 - 1172
[9] Iron and Immunity: Immunological Consequences of Iron Deficiency and Overload
Cherayil, Bobby J.
[J]. ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS, 2010, 58 (06) : 407 - 415
[10] Genetic and biochemical markers in patients with Alzheimer's disease support a concerted systemic iron homeostasis dysregulation
Crespo, Angela C.
Silva, Bruno
Marques, Liliana
Marcelino, Erica
Maruta, Carolina
Costa, Sonia
Timoteo, Angela
Vilares, Arminda
Couto, Frederico Simoes
Faustino, Paula
Correia, Ana Paula
Verdelho, Ana
Porto, Graca
Guerreiro, Manuela
Herrero, Ana
Costa, Cristina
de Mendonca, Alexandre
Costa, Luciana
Martins, Madalena
[J]. NEUROBIOLOGY OF AGING, 2014, 35 (04) : 777 - 785

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