Identification of IL6R and chromosome 11q13.5 as risk loci for asthma

被引：302

作者：

Ferreira, Manuel A. R. ^{[1
]}

Matheson, Melanie C. ^{[2
]}

Duffy, David L. ^{[1
]}

Marks, Guy B. ^{[3
]}

Hui, Jennie ^{[4
,5
,6
,7
]}

Le Souef, Peter ^{[8
]}

Danoy, Patrick ^{[9
]}

Baltic, Svetlana ^{[10
,11
]}

Nyholt, Dale R. ^{[1
]}

Jenkins, Mark ^{[2
]}

Hayden, Catherine ^{[8
]}

Willemsen, Gonneke ^{[12
]}

Ang, Wei ^{[13
]}

Kuokkanen, Mikko ^{[14
]}

Beilby, John ^{[4
,6
,7
]}

Cheah, Faang ^{[10
,11
]}

de Geus, Eco J. C. ^{[12
]}

Ramasamy, Adaikalavan ^{[15
]}

Vedantam, Sailaja ^{[16
,17
,18
]}

Salomaa, Veikko ^{[14
]}

Madden, Pamela A. ^{[19
]}

Heath, Andrew C. ^{[19
]}

Hopper, John L. ^{[2
]}

Visscher, Peter M. ^{[1
]}

Musk, Bill ^{[5
,7
,20
,21
]}

Leeder, Stephen R. ^{[22
]}

Jarvelin, Marjo-Riitta ^{[23
]}

Pennell, Craig ^{[13
]}

Boomsma, Dorret I. ^{[12
]}

Hirschhorn, Joel N. ^{[16
,17
,18
,24
]}

Walters, Haydn ^{[25
]}

Martin, Nicholas G. ^{[1
]}

James, Alan ^{[7
,21
,26
]}

Jones, Graham ^{[27
]}

Abramson, Michael J. ^{[28
]}

Robertson, Colin F. ^{[29
]}

Dharmage, Shyamali C. ^{[2
]}

Brown, Matthew A. ^{[9
]}

Montgomery, Grant W. ^{[1
]}

Thompson, Philip J. ^{[10
,11
]}

机构：

[1] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

[2] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia

[3] Univ Sydney, Woolcock Inst Med Res, Sydney, NSW 2006, Australia

[4] Univ Western Australia, PathW Lab Med Western Australia, Nedlands, WA 6009, Australia

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

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

[7] Sir Charles Gairdner Hosp, Busselton Populat Med Res Fdn, Perth, WA, Australia

[8] Princess Margaret Hosp Children, Sch Paediat & Child Hlth, Perth, WA, Australia

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

[10] Univ Western Australia, Lung Inst Western Australia, Perth, WA 6009, Australia

[11] Univ Western Australia, Ctr Asthma Allergy & Resp Res, Perth, WA 6009, Australia

[12] Vrije Univ Amsterdam, Dept Biol Psychol, EMGO & NCA Inst, Amsterdam, Netherlands

[13] Univ Western Australia, Sch Womens & Infants Hlth, Subiaco, WA, Australia

[14] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland

[15] Univ London Imperial Coll Sci Technol & Med, London, England

[16] Childrens Hosp, Div Genet, Boston, MA 02115 USA

[17] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[18] Broad Inst, Cambridge, MA USA

[19] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[20] Sir Charles Gairdner Hosp, Dept Resp Med, Perth, WA, Australia

[21] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA 6009, Australia

[22] Univ Sydney, Australian Hlth Policy Inst, Sydney, NSW 2006, Australia

[23] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England

[24] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[25] Menzies Res Inst, Hobart, Tas, Australia

[26] W Australian Sleep Disorders Res Inst, Dept Pulm Physiol, Nedlands, WA, Australia

[27] Univ Western Sydney, Penrith, NSW 1797, Australia

[28] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia

[29] Murdoch Childrens Res Inst, Melbourne, Vic, Australia

来源：

LANCET | 2011年 / 378卷 / 9795期

基金：

英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; GENETIC RISK; DISEASE; VARIANTS; ECZEMA; HERITABILITY; METAANALYSIS; EXPRESSION; PREDICTION; CHILDHOOD;

D O I：

10.1016/S0140-6736(11)60874-X

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. Methods We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26 475), and these were tested in an additional 25 358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Findings Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57 800): rs4129267 (OR 1.09, combined p=2.4x10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1.09, p=1.8x10(-8)) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1.33, p=7x10(-4)), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. Interpretation The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma.

引用

页码：1006 / 1014

页数：9

共 36 条

[1] Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].

Barrett, Jeffrey C. ;

Hansoul, Sarah ;

Nicolae, Dan L. ;

Cho, Judy H. ;

Duerr, Richard H. ;

Rioux, John D. ;

Brant, Steven R. ;

Silverberg, Mark S. ;

Taylor, Kent D. ;

Barmada, M. Michael ;

Bitton, Alain ;

Dassopoulos, Themistocles ;

Datta, Lisa Wu ;

Green, Todd ;

Griffiths, Anne M. ;

Kistner, Emily O. ;

Murtha, Michael T. ;

Regueiro, Miguel D. ;

Rotter, Jerome I. ;

Schumm, L. Philip ;

Steinhart, A. Hillary ;

Targan, Stephan R. ;

Xavier, Ramnik J. ;

Libioulle, Cecile ;

Sandor, Cynthia ;

Lathrop, Mark ;

Belaiche, Jacques ;

Dewit, Olivier ;

Gut, Ivo ;

Heath, Simon ;

Laukens, Debby ;

Mni, Myriam ;

Rutgeerts, Paul ;

Van Gossum, Andre ;

Zelenika, Diana ;

Franchimont, Denis ;

Hugot, Jean-Pierre ;

de Vos, Martine ;

Vermeire, Severine ;

Louis, Edouard ;

Cardon, Lon R. ;

Anderson, Carl A. ;

Drummond, Hazel ;

Nimmo, Elaine ;

Ahmad, Tariq ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Fisher, Sheila A. ;

Marchini, Jonathan ;

Ghori, Jilur .

NATURE GENETICS, 2008, 40 (08) :955-962

[2] Childhood eczema and asthma incidence and persistence: A cohort study from childhood to middle age [J].

Burgess, John A. ;

Dharmage, Shyamali C. ;

Byrnes, Graham B. ;

Matheson, Melanie C. ;

Gurrin, Lyle C. ;

Wharton, Cathryn L. ;

Johns, David P. ;

Abramson, Michael J. ;

Hopper, John L. ;

Waiters, E. Haydn .

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2008, 122 (02) :280-285

[3] Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene [J].

Capon, Francesca ;

Bijlmakers, Marie-Jose ;

Wolf, Natalie ;

Quaranta, Maria ;

Huffmeier, Ulrike ;

Allen, Michael ;

Timms, Kirsten ;

Abkevich, Victor ;

Gutin, Alexander ;

Smith, Rhodri ;

Warren, Richard B. ;

Young, Helen S. ;

Worthington, Jane ;

Burden, A. David ;

Griffiths, Christopher E. M. ;

Hayday, Adrian ;

Nestle, Frank O. ;

Reis, Andre ;

Lanchbury, Jerry ;

Barker, Jonathan N. ;

Trembath, Richard C. .

HUMAN MOLECULAR GENETICS, 2008, 17 (13) :1938-1945

[4] The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo [J].

Doganci, A ;

Eigenbrod, T ;

Krug, N ;

De Sanctis, GT ;

Hausding, M ;

Erpenbeck, VJ ;

Haddad, EB ;

Schmitt, E ;

Bopp, T ;

Kallen, KJ ;

Herz, U ;

Schmitt, S ;

Luft, C ;

Hecht, O ;

Hohlfeld, JM ;

Ito, H ;

Nishimoto, N ;

Yoshizaki, K ;

Kishimoto, T ;

Rose-John, S ;

Renz, H ;

Neurath, MF ;

Galle, PR ;

Finotto, S .

JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (02) :313-325

[5] A common variant on chromosome 11q13 is associated with atopic dermatitis [J].

Esparza-Gordillo, Jorge ;

Weidinger, Stephan ;

Foelster-Holst, Regina ;

Bauerfeind, Anja ;

Ruschendorf, Franz ;

Patone, Giannino ;

Rohde, Klaus ;

Marenholz, Ingo ;

Schulz, Florian ;

Kerscher, Tamara ;

Hubner, Norbert ;

Wahn, Ulrich ;

Schreiber, Stefan ;

Franke, Andre ;

Vogler, Rainer ;

Heath, Simon ;

Baurecht, Hansjoerg ;

Novak, Natalija ;

Rodriguez, Elke ;

Illig, Thomas ;

Lee-Kirsch, Min-Ae ;

Ciechanowicz, Andrzej ;

Kurek, Michael ;

Piskackova, Tereza ;

Macek, Milan ;

Lee, Young-Ae ;

Ruether, Andreas .

NATURE GENETICS, 2009, 41 (05) :596-601

[6] Harnessing the information contained within genome-wide association studies to improve individual prediction of complex disease risk [J].

Evans, David M. ;

Visscher, Peter M. ;

Wray, Naomi R. .

HUMAN MOLECULAR GENETICS, 2009, 18 (18) :3525-3531

[7] Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia [J].

Ferreira, Manuel A. R. ;

McRae, Allan F. ;

Medland, Sarah E. ;

Nyholt, Dale R. ;

Gordon, Scott D. ;

Wright, Margaret J. ;

Henders, Anjali K. ;

Madden, Pamela A. ;

Visscher, Peter M. ;

Wray, Naomi R. ;

Heath, Andrew C. ;

Montgomery, Grant W. ;

Duffy, David L. ;

Martin, Nicholas G. .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2011, 19 (04) :458-464

[8] Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci [J].

Franke, Andre ;

McGovern, Dermot P. B. ;

Barrett, Jeffrey C. ;

Wang, Kai ;

Radford-Smith, Graham L. ;

Ahmad, Tariq ;

Lees, Charlie W. ;

Balschun, Tobias ;

Lee, James ;

Roberts, Rebecca ;

Anderson, Carl A. ;

Bis, Joshua C. ;

Bumpstead, Suzanne ;

Ellinghaus, David ;

Festen, Eleonora M. ;

Georges, Michel ;

Green, Todd ;

Haritunians, Talin ;

Jostins, Luke ;

Latiano, Anna ;

Mathew, Christopher G. ;

Montgomery, Grant W. ;

Prescott, Natalie J. ;

Raychaudhuri, Soumya ;

Rotter, Jerome I. ;

Schumm, Philip ;

Sharma, Yashoda ;

Simms, Lisa A. ;

Taylor, Kent D. ;

Whiteman, David ;

Wijmenga, Cisca ;

Baldassano, Robert N. ;

Barclay, Murray ;

Bayless, Theodore M. ;

Brand, Stephan ;

Buening, Carsten ;

Cohen, Albert ;

Colombel, Jean-Frederick ;

Cottone, Mario ;

Stronati, Laura ;

Denson, Ted ;

De Vos, Martine ;

D'Inca, Renata ;

Dubinsky, Marla ;

Edwards, Cathryn ;

Florin, Tim ;

Franchimont, Denis ;

Gearry, Richard ;

Glas, Juergen ;

Van Gossum, Andre .

NATURE GENETICS, 2010, 42 (12) :1118-+

[9] Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction [J].

Gudbjartsson, Daniel F. ;

Bjornsdottir, Unnur S. ;

Halapi, Eva ;

Helgadottir, Anna ;

Sulem, Patrick ;

Jonsdottir, Gudrun M. ;

Thorleifsson, Gudmar ;

Helgadottir, Hafdis ;

Steinthorsdottir, Valgerdur ;

Stefansson, Hreinn ;

Williams, Carolyn ;

Hui, Jennie ;

Beilby, John ;

Warrington, Nicole M. ;

James, Alan ;

Palmer, Lyle J. ;

Koppelman, Gerard H. ;

Heinzmann, Andrea ;

Krueger, Marcus ;

Boezen, H. Marike ;

Wheatley, Amanda ;

Altmuller, Janine ;

Shin, Hyoung Doo ;

Uh, Soo-Taek ;

Cheong, Hyun Sub ;

Jonsdottir, Brynja ;

Gislason, David ;

Park, Choon-Sik ;

Rasmussen, Linda M. ;

Porsbjerg, Celeste ;

Hansen, Jakob W. ;

Backer, Vibeke ;

Werge, Thomas ;

Janson, Christer ;

Joensson, Ulla-Britt ;

Ng, Maggie C. Y. ;

Chan, Juliana ;

So, Wing Yee ;

Ma, Ronald ;

Shah, Svati H. ;

Granger, Christopher B. ;

Quyyumi, Arshed A. ;

Levey, Allan I. ;

Vaccarino, Viola ;

Reilly, Muredach P. ;

Rader, Daniel J. ;

Williams, Michael J. A. ;

van Rij, Andre M. ;

Jones, Gregory T. ;

Trabetti, Elisabetta .

NATURE GENETICS, 2009, 41 (03) :342-347

[10] Quantitative and functional impairment of pulmonary CD4+CD25hi regulatory T cells in pediatric asthma [J].

Hartl, Dominik ;

Koller, Barbara ;

Mehlhorn, Alexander T. ;

Reinhardt, Dietrich ;

Nicolai, Thomas ;

Schendel, Dolores J. ;

Griese, Matthias ;

Krauss-Etschmann, Susanne .

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2007, 119 (05) :1258-1266

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