Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
21907864
TITLE
Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.
ABSTRACT
BACKGROUND NlmCategory: BACKGROUND
We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease.
METHODS NlmCategory: 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 NlmCategory: RESULTS
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=2·4×10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10(-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=7×10(-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 NlmCategory: CONCLUSIONS
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.
FUNDING NlmCategory: BACKGROUND
National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.
Copyright 2011 Elsevier Ltd. All rights reserved.
DATE PUBLISHED
2011 Sep 10
HISTORY
PUBSTATUS PUBSTATUSDATE
entrez 2011/09/13 06:00
pubmed 2011/09/13 06:00
medline 2011/09/22 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Ferreira MA Ferreira Manuel A R MA The Queensland Institute of Medical Research, Brisbane, QLD, Australia. manuel.ferreira@qimr.edu.au
Matheson MC Matheson Melanie C MC
Duffy DL Duffy David L DL
Marks GB Marks Guy B GB
Hui J Hui Jennie J
Le Souëf P Le Souëf Peter P
Danoy P Danoy Patrick P
Baltic S Baltic Svetlana S
Nyholt DR Nyholt Dale R DR
Jenkins M Jenkins Mark M
Hayden C Hayden Catherine C
Willemsen G Willemsen Gonneke G
Ang W Ang Wei W
Kuokkanen M Kuokkanen Mikko M
Beilby J Beilby John J
Cheah F Cheah Faang F
de Geus EJ de Geus Eco J C EJ
Ramasamy A Ramasamy Adaikalavan A
Vedantam S Vedantam Sailaja S
Salomaa V Salomaa Veikko V
Madden PA Madden Pamela A PA
Heath AC Heath Andrew C AC
Hopper JL Hopper John L JL
Visscher PM Visscher Peter M PM
Musk B Musk Bill B
Leeder SR Leeder Stephen R SR
Jarvelin MR Jarvelin Marjo-Riitta MR
Pennell C Pennell Craig C
Boomsma DI Boomsma Dorret I DI
Hirschhorn JN Hirschhorn Joel N JN
Walters H Walters Haydn H
Martin NG Martin Nicholas G NG
James A James Alan A
Jones G Jones Graham G
Abramson MJ Abramson Michael J MJ
Robertson CF Robertson Colin F CF
Dharmage SC Dharmage Shyamali C SC
Brown MA Brown Matthew A MA
Montgomery GW Montgomery Grant W GW
Thompson PJ Thompson Philip J PJ
Australian Asthma Genetics Consortium
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Mészáros Désirée D
Roberts Mary M
Southey Melissa C MC
Tovey Euan R ER
Warrington Nicole M NM
Kattenberg Mathijs M
Palmer Lyle J LJ
Price Loren L
Wright Margaret J MJ
Gordon Scott D SD
Chung Li P LP
Henders Anjali K AK
Giles Graham G
Hottenga Jouke-Jan JJ
Thomas Paul S PS
Temple Suzanna S
Whitfield John B JB
Feather Ian I
Hartikainen Anna-Liisa AL
Haahtela Tari T
Laitinen Tarja T
Jousilahti Pekka P
Eriksson Johan G JG
Widen Elisabeth E
Raitakari Olli T OT
Lehtimäki Terho T
Kähönen Mika M
Viikari Jorma J
Palotie Aarno A
Gajdos Zofia K ZK
Lyon Helen N HN
O'Connor George T GT
Morrison Stephen S
Sly Peter D PD
Mitrpant Chalermchai C
Britton Warwick J WJ
John David D
Holt Pat G PG
Kemp Andrew S AS
JOURNAL
VOLUME: 378
ISSUE: 9795
TITLE: Lancet (London, England)
ISOABBREVIATION: Lancet
YEAR: 2011
MONTH: Sep
DAY: 10
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1474-547X
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Lancet
COUNTRY: England
ISSNLINKING: 0140-6736
NLMUNIQUEID: 2985213R
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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CommentIn Lancet. 2011 Sep 10;378(9795):967-8 21907849
GRANTS
GRANTID AGENCY COUNTRY
1RL1MH083268-01 NIMH NIH HHS United States
5R01HL087679-02 NHLBI NIH HHS United States
AA07535 NIAAA NIH HHS United States
AA07728 NIAAA NIH HHS United States
AA10248 NIAAA NIH HHS United States
AA11998 NIAAA NIH HHS United States
AA13320 NIAAA NIH HHS United States
AA13321 NIAAA NIH HHS United States
AA13326 NIAAA NIH HHS United States
AA14041 NIAAA NIH HHS United States
AA17688 NIAAA NIH HHS United States
DA12854 NIDA NIH HHS United States
G0500539 Medical Research Council United Kingdom
K05 AA017688 NIAAA NIH HHS United States
MH66206 NIMH NIH HHS United States
MOP-82893 Canadian Institutes of Health Research Canada
N01 HC025195 NHLBI NIH HHS United States
N01-HC-25195 NHLBI NIH HHS United States
N02 HL64278 NHLBI NIH HHS United States
N02-HL-6-4278 NHLBI NIH HHS United States
P50 AA011998 NIAAA NIH HHS United States
P60 AA011998 NIAAA NIH HHS United States
R01 AA007535 NIAAA NIH HHS United States
R01 AA010249 NIAAA NIH HHS United States
R01 AA013320 NIAAA NIH HHS United States
R01 AA013321 NIAAA NIH HHS United States
R01 AA013326 NIAAA NIH HHS United States
R01 AA014041 NIAAA NIH HHS United States
R01 DA012854 NIDA NIH HHS United States
R01 HD042157 NICHD NIH HHS United States
R01 HL087679 NHLBI NIH HHS United States
R01 MH066206 NIMH NIH HHS United States
R01D0042157-01A PHS HHS United States
R37 AA007728 NIAAA NIH HHS United States
R56 DA012854 NIDA NIH HHS United States
RL1 MH083268 NIMH NIH HHS United States
Department of Health United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adolescent
Adult
Aged
Aged, 80 and over
Asthma immunology
Child immunology
Child, Preschool immunology
Chromosomes, Human, Pair 11 genetics
Female genetics
Genetic Loci genetics
Genetic Predisposition to Disease genetics
Genome-Wide Association Study genetics
Humans genetics
Hypersensitivity, Immediate genetics
Linkage Disequilibrium genetics
Male genetics
Membrane Proteins genetics
Middle Aged genetics
Polymorphism, Single Nucleotide genetics
Receptors, Interleukin-6 genetics
Young Adult genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 LRRC32 protein, human
0 Membrane Proteins
0 Receptors, Interleukin-6
OTHER ID's
OTHERID SOURCE
NIHMS414524 NLM
PMC3517659 NLM