Ερευνητικό υλικό ΕΚΠΑ

A Large-Scale, Consortium-Based Genomewide Association Study of Asthma

Αγγλικά

BACKGROUND
Susceptibility to asthma is influenced by genes and environment;
implicated genes may indicate pathways for therapeutic intervention.
Genetic risk factors may be useful in identifying subtypes of asthma and
determining whether intermediate phenotypes, such as elevation of the
total serum IgE level, are causally linked to disease.
METHODS
We carried out a genomewide association study by genotyping 10,365
persons with physician-diagnosed asthma and 16,110 unaffected persons,
all of whom were matched for ancestry. We used random-effects pooled
analysis to test for association in the overall study population and in
subgroups of subjects with childhood-onset asthma (defined as asthma
developing before 16 years of age), later-onset asthma, severe asthma,
and occupational asthma.
RESULTS
We observed associations of genomewide significance between asthma and
the following single-nucleotide polymorphisms: rs3771166 on chromosome
2, implicating IL1RL1/IL18R1 (P = 3x10(-9)); rs9273349 on chromosome 6,
implicating HLA-DQ (P = 7x10(-14)); rs1342326 on chromosome 9, flanking
IL33 (P = 9x10(-10)); rs744910 on chromosome 15 in SMAD3 (P = 4x10(-9));
and rs2284033 on chromosome 22 in IL2RB (P = 1.1x10(-8)). Association
with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to
childhood-onset disease (rs2305480, P = 6x10(-23)). Only HLA-DR showed a
significant genomewide association with the total serum IgE
concentration, and loci strongly associated with IgE levels were not
associated with asthma.
CONCLUSIONS
Asthma is genetically heterogeneous. A few common alleles are associated
with disease risk at all ages. Implicated genes suggest a role for
communication of epithelial damage to the adaptive immune system and
activation of airway inflammation. Variants at the ORMDL3/GSDMB locus
are associated only with childhood-onset disease. Elevation of total
serum IgE levels has a minor role in the development of asthma.

2010

Moffatt, Miriam F.
Gut, Ivo G.
Demenais, Florence
Strachan,
David P.
Bouzigon, Emmanuelle
Heath, Simon
von Mutius, Erika
and Farrall, Martin
Lathrop, Mark
Cookson, William O. C. M. and
Kumar, Ashish
Burney, Peter
Jarvis, Debbie
Wjst, Matthias
and Kogevinas, Manolis
Jogi, Rain
Janson, Christer
Franklin,
Karl A.
Omenaas, Ernst
Leynaert, Benedicte
Pin, Isabelle and
Heinrich, Joachim
Probst-Hensch, Nicole M.
Anto, Josep M. and
Sunyer, Jordi
Maldonado, Jose-Antonio
Martinez-Moratalla, Jesus
and Urrutia, Isabel
Payo, Felix
Kauffmann, Francine
Dizier,
Marie-Helene
Siroux, Valerie
Boznanski, Andrzej and
Braun-Fahrlaender, Charlotte
Genuneit, Jon
Glas, Juergen and
Horak, Elisabeth
Kabesch, Michael
Pillai, Sreekumar G. and
Helms, Peter J.
Carlsen, Karin
Carlsen, Kai-Hakon
Gerritsen,
Jorrit
Silverman, Michael
Sly, Peter
Tsanakas, John
Von
Berg, Andrea
Whyte, Moira
Blumenthal, Malcolm
Imboden, Medea
and Rochat, Thierry
Thun, Gian Andri
Gerbase, Margaret W. and
Curjuric, Ivan
Gaspoz, Jean-Michel
Liu, Lee-Jane S.
Wouters,
Inge M.
Sigsgaard, Torben
Heederik, Dick
Basinas, Ioannis
and Schlunssen, Vivi
Omland, Oyvind
Cullinan, Paul and
Vermeulen, Roel
Henderson, John
Granell, Raquel
McArdle,
Wendy L.
Smith, George Davey
James, Alan L.
Hui, Jennie and
Palmer, Lyle J.
Beilby, John
Musk, A. William
Laprise,
Catherine
Hudson, Thomas J.
Lemire, Mathieu
Daley, Denise
and Becker, Allan
Chan-Yeung, Moira
Sandford, Andrew and
Kozyrskyj, Anita L.
Pare, Peter
Ferguson, Alexander and
Dimich-Ward, Helen
Watson, Wade T.
Freidin, Maxim B. and
Bragina, Elena Iu.
Deev, Ivan A.
Deeva, Eugenia V. and
Kobyakova, Olga S.
Puzyrev, Valery P.
Ogorodova, Ludmila M. and
Khusnutdinova, Elza K.
Karunas, Alexandra S.
Fedorova, Yuliya Y.
and Hall, Ian P.
Sayers, Ian
Tobin, Martin D.
Wan, Yize I.
and Heaney, Liam G.
Al-Momani, Basima A. H.
Mansur, Adel H. and
Manney, Sarah
Thomson, Neil C.
Chaudhuri, Rekha
Brightling,
Christopher E.
Bafadhel, Mona
Singapuri, Amisha
Niven,
Robert
Simpson, Angela
Holloway, John W.
Howarth, Peter H.
and Polonikov, Alexey V.
Ivanov, Vladimir P.
Solodilova, Maria
A.
Melen, Erik
Pershagen, Goeran
Bergstroem, Anna
Kull,
Inger
Nyberg, Fredrik
Wickman, Magnus
Soderhall, Cilla and
Kere, Juha
Postma, Dirkje S.
Kerkhof, Marjan
Brunekreef,
Bert
Smit, Henriette A.
de Jongste, Johan C.
Wijga, Alet and
Aalberse, R. C.
Hoekstra, Maarten O.
Koppelman, Gerard H. and
Binia, Aristea
Chung, Kian Fan
Bhavsar, Pankaj
Chow,
Florence
Macedo, Patricia
Menzies-Gow, Andrew
van Stiphout,
Nicole
Bush, Andrew
Lee, Young-Ae
Esparza-Gordillo, Jorge
and Nickel, Renate
Wahn, Ulrich
Lau, Susanne
Marenholz, Ingo
and Haahtela, Tari
von Hertzen, Leena
Jousilahti, Pekka and
Laatikainen, Tiina
Makela, Mika J.
Vartiainen, Erkki and
Laitinen, Tarja
Balding, David J.
Peden, John F.
Corda, Eve
and Lechner, Doris
Besse, Celine
Zelenika, Diana
Boland,
Anne
Bacq, Delphine
Demonchy, Stephanie
Blanche, Helene and
Kamatani, Yoichiro
von Mutius, Erika
Farrall, Martin and
Lathrop, Mark
Cookson, William O. C. M.
GABRIEL Consortium

The New England journal of medicine

MASSACHUSETTS MEDICAL SOC

363

13

1211-1221

https://doi.org/10.1056/NEJMoa0906312

10.1056/NEJMoa0906312

https://pergamos.lib.uoa.gr/uoa/dl/object/3147033