Published in a special European Respiratory Society issue of The Lancet, two new genetic variants or loci that increase susceptibility to asthma have been identified in an international investigation. These discoveries add to the evidence that genes connected with signaling molecules (cytokines) involved in the functioning of the immune system are linked with the development of asthma. This indicates that a medication which is used currently to treat rheumatoid arthritis (RA) might be successful to treat asthma.

Although there have been several attempts to detect the specific genetic mechanisms responsible for asthma, the causes are not very well understood. Several candidate genes have been identified in recent genome-wide association studies (GWAS), that have a moderate effect on the risk of asthma, however, this only explains a small segment of the disease heritability indicating that several more genetic variations have yet to be identified.

Expanding and combining existing asthma GWAS was carried out by Manuel Ferreira from the Queensland Institute of Medical Research, Brisbane, Australia, who led an international team, In order to try and identify new genetic variations responsible for increasing the risk of asthma. When they compared the genomes of thousands of patients with asthma with genomes of individuals who didn’t have asthma across several populations, they discovered two new genetic variants with a strong link 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 plays a crucial role in immunity and inflammation, and is involved in the pathogenesis of several diseases including rheumatoid arthritis. The rs4129267 risk variant increases the expression of the IL-6 receptor and therefore the researchers propose that medications that block the receptor, such as tocilizumab which for RA is already licensed for treatment, should be taken into consideration for clinical trials in order to prevent or reduce the airway inflammation linked with asthma.

The rs7130588 variant on chromosome 11q13.5 was discovered to be more common in asthma patients who are atopic (allergic), and was connected with a close variant which was recently associated with atopic dermatitis. Indicating that a gene in this area has an important role in the development of allergic sensitization, which increases the following risk of developing allergic asthma. The researchers explain:

“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 characterization of this region of association is likely to discover novel molecular mechanisms involved in the causality of eczema, atopy, and asthma.”

Up until now, not one genetic cause has been identified that accounts for over 1% of asthma heritability. Results from this investigation verify that the disease is complex, with potentially numerous genes of small effect each combining and interacting with environmental risk factors to effect whether an individual is likely to develop asthma.

They 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.”

Talking about the pros and cons of GWAS design, Kathleen Barnes from Johns Hopkins University, Baltimore, USA, comments:

“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.”

Written by Grace Rattue