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

Ferreira, Manuel A. R., Matheson, Melanie C., Duffy, David L., Marks, Guy B., Hui, Jennie, Le Souef, Peter, Danoy, Patrick, Baltic, Svetlana, Nyholt, Dale R., Jenkins, Mark, Hayden, Catherine, Willemsen, Gonneke, Ang, Wei, Kuokkanen, Mikko, Beilby, John, Cheah, Faang, de Geus, Eco J.C., Ramasamy, Adaikalavan, Vedantam, Sailaka, Salomaa, Veikko, Madden, Pamela A., Heath, Andrew C., Hopper, John L., Visscher, Peter M., Musk, Bill, Leeder, Stephen R., Jarvelin, Marjo-Riitta, Pennell, Craig, Boomsma, Dorret I., Hirschhorn, Joel N., Walters, Haydn, Martin, Nicholas G., James, Alan, Jones, Graham, Abramson, Michael J., Robertson, Colin F., Dharmage, Shyamali C., Brown, Matthew A., Montgomery, Grant W., Thompson, Philip J. and for the Australian Asthma Genetics Consortium (2011) Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet, 378 9795: 1006-1014. doi:10.1016/S0140-6736(11)60874-X

Author Ferreira, Manuel A. R.
Matheson, Melanie C.
Duffy, David L.
Marks, Guy B.
Hui, Jennie
Le Souef, Peter
Danoy, Patrick
Baltic, Svetlana
Nyholt, Dale R.
Jenkins, Mark
Hayden, Catherine
Willemsen, Gonneke
Ang, Wei
Kuokkanen, Mikko
Beilby, John
Cheah, Faang
de Geus, Eco J.C.
Ramasamy, Adaikalavan
Vedantam, Sailaka
Salomaa, Veikko
Madden, Pamela A.
Heath, Andrew C.
Hopper, John L.
Visscher, Peter M.
Musk, Bill
Leeder, Stephen R.
Jarvelin, Marjo-Riitta
Pennell, Craig
Boomsma, Dorret I.
Hirschhorn, Joel N.
Walters, Haydn
Martin, Nicholas G.
James, Alan
Jones, Graham
Abramson, Michael J.
Robertson, Colin F.
Dharmage, Shyamali C.
Brown, Matthew A.
Montgomery, Grant W.
Thompson, Philip J.
for the Australian Asthma Genetics Consortium
Title Identification of IL6R and chromosome 11q13.5 as risk loci for asthma
Journal name Lancet   Check publisher's open access policy
ISSN 0140-6736
Publication date 2011-09
Sub-type Article (original research)
DOI 10.1016/S0140-6736(11)60874-X
Volume 378
Issue 9795
Start page 1006
End page 1014
Total pages 9
Place of publication London, England, U.K.
Publisher The Lancet Publishing Group
Collection year 2012
Language eng
Formatted abstract
We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. 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. 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. 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. National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix
Keyword Genome-Wide Association
Genetic Risk
Susceptibility Loci
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
UQ Diamantina Institute Publications
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