A sequence variant on 17q21 is associated with age at onset and severity of asthma

被引：124

作者：

Halapi, Eva

Gudbjartsson, Daniel F.

Jonsdottir, Gudrun M.

Bjornsdottir, Unnur S. ^{[2
]}

Thorleifsson, Gudmar

Helgadottir, Hafdis

Williams, Carolyn ^{[3
,4
,5
]}

Koppelman, Gerard H. ^{[6
]}

Heinzmann, Andrea ^{[7
]}

Boezen, H. Marike ^{[8
]}

Jonasdottir, Aslaug

Blondal, Thorarinn

Gudjonsson, Sigurjon A.

Jonasdottir, Adalbjorg

Thorlacius, Theodora

Henry, Amanda P. ^{[9
]}

Altmueller, Janine ^{[10
]}

Krueger, Marcus ^{[7
]}

Shin, Hyoung Doo ^{[11
,12
]}

Uh, Soo-Taek ^{[13
]}

Cheong, Hyun Sub ^{[12
]}

Jonsdottir, Brynja ^{[14
]}

Ludviksson, Bjorn R. ^{[2
,15
]}

Ludviksdottir, Dora ^{[16
]}

Gislason, David ^{[16
]}

Park, Choon-Sik ^{[17
]}

Deichmann, Klaus ^{[7
]}

Thompson, Philip J. ^{[3
,4
,5
]}

Wjst, Matthias ^{[18
,19
]}

Hall, Ian P. ^{[9
]}

Postma, Dirkje S. ^{[20
]}

Gislason, Thorarinn ^{[2
,16
]}

Kong, Augustine

Jonsdottir, Ingileif ^{[2
,15
]}

Thorsteinsdottir, Unnur ^{[1
,2
]}

Stefansson, Kari ^{[2
]}

机构：

[1] DeCODE Genet Inc, Populat Genom, IS-101 Reykjavik, Iceland

[2] Univ Iceland, Fac Med, Reykjavik, Iceland

[3] Lung Inst Western Australia, Nedlands, WA, Australia

[4] Western Australian Inst Med Res, Perth, WA, Australia

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

[6] Univ Groningen, Beatrix Childrens Hosp, Dept Pediat Pulmonol & Pediat Allergol, Univ Med Ctr Groningen, Groningen, Netherlands

[7] Univ Freiburg, Ctr Pediat & Adolescent Med, Freiburg, Germany

[8] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands

[9] Univ Nottingham Hosp, Queens Med Ctr, Div Therapeut, Nottingham NG7 2UH, England

[10] Univ Cologne, CCG, Cologne, Germany

[11] Sogang Univ, Dept Life Sci, Lab Genom Divers, Seoul, South Korea

[12] SNP Genet Inc, Dept Genet Epidemiol, Seoul, South Korea

[13] Soonchunhyang Univ, Seoul Hosp, Div Allergy & Resp Med, Seoul, South Korea

[14] Landspitali Univ Hosp, Dept Internal Med, Reykjavik, Iceland

[15] Landspitali Univ Hosp, Dept Immunol, Reykjavik, Iceland

[16] Landspitali Univ Hosp, Dept Allergy Resp Med & Sleep, Reykjavik, Iceland

[17] Soonchunhyang Univ, Bucheon Hosp, Div Allergy & Resp Med, Puchon, South Korea

[18] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Lung Biol & Dis, Neuherberg, Germany

[19] EURAC Res, Inst Med Genet, Bozen, Germany

[20] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, Groningen, Netherlands

来源：

EUROPEAN JOURNAL OF HUMAN GENETICS | 2010年 / 18卷 / 08期

关键词：

childhood asthma; single-nucleotide polymorphism; expression; ORMDL3; GSDMB; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY GENE; ORMDL3; EXPRESSION; ATOPIC DISEASES; CHILDHOOD; POLYMORPHISMS; POPULATION; FAMILIES; SEARCH; RISK;

D O I：

10.1038/ejhg.2010.38

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR=1.51, P=6.89. 10(-9)) and adolescence (age: 14-17 years OR=1.71, P=5.47. 10(-9)). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes. European Journal of Human Genetics (2010) 18, 902-908; doi:10.1038/ejhg.2010.38; published online 7 April 2010

引用

页码：902 / 908

页数：7

共 47 条

[1] Phenotypic and genetic heterogeneity in a genome-wide linkage study of asthma families [J].

Altmüller J. ;

Seidel C. ;

Lee Y.-A. ;

Loesgen S. ;

Bulle D. ;

Friedrichs F. ;

Jellouschek H. ;

Kelber J. ;

Keller A. ;

Schuster A. ;

Silbermann M. ;

Wahlen W. ;

Wolff P. ;

Schlenvoigt G. ;

Rüschendorf F. ;

Nürnberg P. ;

Wjst M. .

BMC Pulmonary Medicine, 5 (1)

[2] A common variant associated with prostate cancer in European and African populations [J].

Amundadottir, Laufey T. ;

Sulem, Patrick ;

Gudmundsson, Julius ;

Helgason, Agnar ;

Baker, Adam ;

Agnarsson, Bjarni A. ;

Sigurdsson, Asgeir ;

Benediktsdottir, Kristrun R. ;

Cazier, Jean-Baptiste ;

Sainz, Jesus ;

Jakobsdottir, Margret ;

Kostic, Jelena ;

Magnusdottir, Droplaug N. ;

Ghosh, Shyamali ;

Agnarsson, Kari ;

Birgisdottir, Birgitta ;

Le Roux, Louise ;

Olafsdottir, Adalheidur ;

Blondal, Thorarinn ;

Andresdottir, Margret ;

Gretarsdottir, Olafia Svandis ;

Bergthorsson, Jon T. ;

Gudbjartsson, Daniel ;

Gylfason, Arnaldur ;

Thorleifsson, Gudmar ;

Manolescu, Andrei ;

Kristjansson, Kristleifur ;

Geirsson, Gudmundur ;

Isaksson, Helgi ;

Douglas, Julie ;

Johansson, Jan-Erik ;

Balter, Katarina ;

Wiklund, Fredrik ;

Montie, James E. ;

Yu, Xiaoying ;

Suarez, Brian K. ;

Ober, Carole ;

Cooney, Kathleen A. ;

Gronberg, Henrik ;

Catalona, William J. ;

Einarsson, Gudmundur V. ;

Barkardottir, Rosa B. ;

Gulcher, Jeffrey R. ;

Kong, Augustine ;

Thorsteinsdottir, Unnur ;

Stefansson, Kari .

NATURE GENETICS, 2006, 38 (06) :652-658

[3]

[Anonymous], 2005, GLOB STRAT ASTHM MAN

[4] The costs of asthma [J].

Barnes, PJ ;

Jonsson, B ;

Klim, JB .

EUROPEAN RESPIRATORY JOURNAL, 1996, 9 (04) :636-642

[5] 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

[6] Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes [J].

Barrett, Jeffrey C. ;

Clayton, David G. ;

Concannon, Patrick ;

Akolkar, Beena ;

Cooper, Jason D. ;

Erlich, Henry A. ;

Julier, Cecile ;

Morahan, Grant ;

Nerup, Jorn ;

Nierras, Concepcion ;

Plagnol, Vincent ;

Pociot, Flemming ;

Schuilenburg, Helen ;

Smyth, Deborah J. ;

Stevens, Helen ;

Todd, John A. ;

Walker, Neil M. ;

Rich, Stephen S. .

NATURE GENETICS, 2009, 41 (06) :703-707

[7] Chromosome 17q21 Gene Variants Are Associated with Asthma and Exacerbations but Not Atopy in Early Childhood [J].

Bisgaard, Hans ;

Bonnelykke, Klaus ;

Sleiman, Patrick M. A. ;

Brasholt, Martin ;

Chawes, Bo ;

Kreiner-Moller, Eskil ;

Stage, Malene ;

Kim, Cecilia ;

Tavendale, Roger ;

Baty, Florent ;

Pipper, Christian Bressen ;

Palmer, Colin N. A. ;

Hakonarsson, Hakon .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2009, 179 (03) :179-185

[8] Effect of 17q21 Variants and Smoking Exposure in Early-Onset Asthma [J].

Bouzigon, Emmanuelle ;

Corda, Eve ;

Aschard, Hugues ;

Dizier, Marie-Helene ;

Boland, Anne ;

Bousquet, Jean ;

Chateigner, Nicolas ;

Gormand, Frederic ;

Just, Jocelyne ;

Le Moual, Nicole ;

Scheinmann, Pierre ;

Siroux, Valerie ;

Vervloet, Daniel ;

Zelenika, Diana ;

Pin, Isabelle ;

Kauffmann, Francine ;

Lathrop, Mark ;

Demenais, Florence .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 359 (19) :1985-1994

[9]

British Thoracic Society, 2003, Thorax, V58 Suppl 1, pi1

[10]

BRITTON J, 1994, EUR RESPIR J, V7, P881

← 1 2 3 4 5 →