An international study has identified two new genetic variants or loci that increase susceptibility to asthma. The findings, published in a special European Respiratory Society issue of The Lancet, add to the evidence that genes linked with signalling molecules (cytokines) involved in the functioning of the immune system are associated with the development of asthma, and suggest that a drug currently used to treat rheumatoid arthritis (RA) may be effective to treat asthma.
Despite numerous attempts to identify the specific genetic mechanisms responsible, the causes of asthma remain poorly understood. Recent genome-wide association studies (GWAS) have identified several candidate genes that have a moderate effect on the risk of asthma, but explain only a small fraction of the disease heritability suggesting that many more genetic variations have yet to be identified.
Manuel Ferreira from the Queensland Institute of Medical Research, Brisbane, Australia, led an international team to try and identify new genetic variations responsible for increasing the risk of asthma by expanding and combining existing asthma GWAS. By comparing the genomes of thousands of patients with asthma with those of non-asthmatics across several populations*, they identified two new genetic variants with a strong association with asthma risk, rs4129267 in the interleukin-6 receptor (IL6R) gene and rs7130588 on chromosome 11q13.5.
Interleukin 6 (IL-6) is a cytokine that has an important role in immunity and inflammation, and is involved in the pathogenesis of many diseases including RA. The rs4129267 risk variant increases the expression of the IL-6 receptor and so the authors suggest that drugs that block the receptor, such as tocilizumab, which is already licensed for treatment of RA, should be considered for clinical trials to prevent or reduce the airway inflammation associated with asthma.
The rs7130588 variant on chromosome 11q13.5 was found to be more common in atopic (allergic) asthma patients and, interestingly, was correlated with a nearby variant recently linked with atopic dermatitis. These results suggest that a gene in this region plays a role in the development of allergic sensitisation which increases the subsequent risk of developing allergic asthma.
The authors say: "At this stage it is unclear which gene underlies the association with 11q13.5. Given that no specific gene in this region has been directly implicated in allergic disease previously, further characterisation of this region of association is likely to discover novel molecular mechanisms involved in the causality of eczema, atopy, and asthma."
To date, no single genetic cause has been identified that accounts for more than 1% of the disease heritability. Results from this study confirm that asthma is a complex disease, with possibly a large number of genes of small effect each combining and interacting with environmental risk factors to influence whether a person is likely to develop asthma.
The authors conclude: "Our results are consistent with the contribution of hundreds or potentially thousands of variants with weak effects on asthma risk, which can be identified through larger GWAS as already shown with other diseases."
In a Comment, Kathleen Barnes from Johns Hopkins University, Baltimore, USA discusses the pros and cons of GWAS design and remarks: "Success in the validation of various candidates (and their pathways) that are already on the asthma shortlist of potential causal genes, and the biological insight to be gained from the novel findings in this report are grounds for optimism in the continuation of the GWAS approach. Combination of GWAS with next-generation technologies will undoubtedly further help to disentangle the molecular underpinnings of complex traits such as asthma."
Dr Manuel Ferreira, Queensland Institute of Medical Research, Brisbane, Australia. T) +61 7 3845 3552 E) manuel.ferreira@qimr.edu.au
Dr Kathleen Barnes, Johns Hopkins University, Baltimore, USA. E) kbarnes@jhmi.edu
Notes to Editors: * The authors began by analysing DNA samples from 2669 adults with asthma and 4528 non-asthmatics from Australia. Two specific genetic markers or SNPs emerged as significant and had not been previously connected to the disease. To prioritise additional SNPs for follow-up, results from the Australian study were then combined with those from the European GABRIEL consortium involving 12 475 asthmatics and 19 967 controls. Five additional SNPs were found significant by the meta-analysis and the associations with all seven genetic markers were tested for replication in a further four separate studies including over 25 000 independent samples from Australia, US, Finland and the Netherlands.
Journal
The Lancet