Identification of IL6R and chromosome 11q13.5 as risk loci for asthma
Open accessAbstract
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=2·4×10(-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 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.
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IL-6R is associated with asthma and atopic dermatitis.
“It was also reported that IL-6R is associated with asthma and atopic dermatitis (270, 271).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [270]
The Discussion reports an association between IL6R and asthma risk. It attributes the atopic dermatitis association to a different locus, chromosome 11q13.5, not to IL6R. Page numbers are not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSNPs in LRRC32 have been strongly associated with allergic rhinitis in three genome-wide association studies and with asthma, eczema, and other allergy-related comorbidities.
“SNPs in leucine-rich repeat-containing protein 32 (LRRC32) have been strongly associated with AR in 3 of the GWASs,486-488 and with asthma,487,489 eczema,488,490 and other allergy-related comorbidities.486,489,491”
From International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (2018) · cites this paper as [489]
In the GWAS by Ferreira et al., 11 variants were associated with the combined asthma phenotype and hay fever below the genome-wide significance level, with HLA-DQB1 as the top hit.
“In the GWAS by Ferreira et al.,489 11 variants were associated with the combined asthma phenotype and hay fever below the genome-wide significance level (HLA-DQB1 top hit).”
From International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (2018) · cites this paper as [489]
The Results describe a GWAS of asthma risk, but the passages found do not report an analysis of a combined asthma-and-hay-fever phenotype or 11 associated variants. The Results say HLA-DQ showed a consistent but non-significant effect for asthma; they do not identify HLA-DQB1 as the top hit for the claimed combined phenotype (searched: hay fever, HLA-DQB1, and 11 variants). (LLM, conf=0.76)
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References 36 · Cited by 381
- Authors
- Ferreira, M. A., Matheson, M. C., Duffy, D. L., Marks, G. B., Hui, J., Le Souëf, P., Danoy, P., Baltic, S., Nyholt, D. R., Jenkins, M., Hayden, C., Willemsen, G., Ang, W., Kuokkanen, M., Beilby, J., Cheah, F., de Geus, E. J., Ramasamy, A., Vedantam, S., Salomaa, V., Madden, P. A., Heath, A. C., Hopper, J. L., Visscher, P. M., Musk, B., Leeder, S. R., Jarvelin, M.-R., Pennell, C., Boomsma, D. I., Hirschhorn, J. N., Walters, H., Martin, N. G., James, A., Jones, G., Abramson, M. J., Robertson, C. F., Dharmage, S. C., Brown, M. A., Montgomery, G. W., & Thompson, P. J.
- Affiliations
- QIMR Berghofer Medical Research Institute (AU)
- The University of Melbourne (AU)
- The University of Sydney (AU)
- The University of Western Australia (AU)
- The University of Queensland (AU)
- Princess Margaret Hospital for Children (AU)
- Vrije Universiteit Amsterdam (NL)
- The Kids Research Institute Australia (AU)
- Finnish Institute for Health and Welfare (FI)
- Imperial College London (GB)
- Broad Institute (US)
- Washington University in St. Louis (US)
- Western Sydney University (AU)
- Monash University (AU)
- Murdoch Children's Research Institute (AU)
- ORCID
- Ferreira, Manuel AR
- Matheson, Melanie C
- Duffy, David L
- Marks, Guy B
- Hui, Jennie
- Baltic, Svetlana
- Nyholt, Dale R
- Jenkins, Mark
- Willemsen, Gonneke
- Kuokkanen, Mikko
- Beilby, John
- Ramasamy, Adaikalavan
- Vedantam, Sailaja
- Salomaa, Veikko
- Madden, Pamela A
- Heath, Andrew C
- Hopper, John L
- Visscher, Peter M
- Leeder, Stephen R
- Pennell, Craig
- Boomsma, Dorret I
- Hirschhorn, Joel N
- Martin, Nicholas G
- Abramson, Michael J
- Dharmage, Shyamali C
- Brown, Matthew A
- Montgomery, Grant W
- Thompson, Philip J
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 378
- Issue
- 9795
- Pages
- 1006-1014
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC3517659
- OpenAlex
- W2102687347
- Cited by
- 381
- References
- 36
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 17 · 2023: 13 · 2022: 20 · 2021: 17 · 2020: 21 · 2019: 33 · 2018: 41 · 2017: 35 · 2016: 32 · 2015: 37 · 2014: 30 · 2013: 32 · 2012: 30
- FWCI
- 21.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- QUT ePrints (Queensland University of Technology) (submittedVersion)
- Murdoch University Research Portal (submittedVersion)
- eCite Digital Repository (University of Tasmania) (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Health and Medical Research Council (613627)
- Topics
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Occupational exposure and asthma
- Keywords
- asthma, genetic susceptibility loci, IL-6 receptor, LRRC32, GARP, allergic asthma, allergen sensitization, polygenic risk, cytokine signaling, tocilizumab, Ndfip1, HLA-B, LPP, BACH2, asthma genetics, replication cohort, Gabriel
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Asthma, Child, Child, Preschool, Chromosomes, Human, Pair 11, Female, Humans, Hypersensitivity, Immediate, Male, Membrane Proteins, Middle Aged, Linkage Disequilibrium, Receptors, Interleukin-6, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Young Adult, Genetic Loci
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