TY - JOUR
T1 - Identification of IL6R and chromosome 11q13.5 as risk loci for asthma
AU - Ferreira, Manuel A. R.
AU - Matheson, Melanie C.
AU - Duffy, David L.
AU - Marks, Guy B.
AU - Hui, Jennie
AU - Le Souef, Peter
AU - Danoy, Patrick
AU - Baltic, Svetlana
AU - Nyholt, Dale R.
AU - Jenkins, Mark
AU - Hayden, Catherine
AU - Willemsen, Gonneke
AU - Ang, Wei
AU - Kuokkanen, Mikko
AU - Beilby, John
AU - Cheah, Faang
AU - De Geus, Eco J. C.
AU - Ramasamy, Adaikalavan
AU - Vedantam, Sailaja
AU - Salomaa, Veikko
AU - Madden, Pamela A.
AU - Heath, Andrew C.
AU - Hopper, John L.
AU - Visscher, Peter M.
AU - Musk, Bill
AU - Leeder, Stephen R.
AU - Jarvelin, Marjo-Riitta
AU - Pennell, Craig
AU - Boomsma, Doerret I.
AU - Hirschhorn, Joel N.
AU - Walters, Haydn
AU - Martin, Nicholas G.
AU - James, Alan
AU - Jones, Graham J.
AU - Abramson, Michael J.
AU - Robertson, Colin F.
AU - Dharmage, Shyamali C.
AU - Brown, Matthew A.
AU - Montgomery, Grant W.
AU - Thompson, Philip J.
PY - 2011
Y1 - 2011
N2 - 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. Funding: National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.
AB - 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. Funding: National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.
KW - allergic asthma
KW - chromosome
KW - gene replication
KW - genetic load
KW - interleukin 6 receptor
KW - leucine
UR - http://hdl.handle.net/1959.7/uws:16243
U2 - 10.1016/S0140-6736(11)60874-X
DO - 10.1016/S0140-6736(11)60874-X
M3 - Article
SN - 0140-6736
VL - 378
SP - 1006
EP - 1014
JO - The Lancet
JF - The Lancet
IS - 9795
ER -
