A drug used today to treat rheumatoid arthritis might be effective in treating asthma symptoms after two genetic variants have been found to increase asthma susceptibility, researchers from the Queensland Institute of Medical Research, Brisbane, Australia and others from around the world reported in The Lancet. The scientists found that cytokines – genes associated with signalling molecules that are involved in how the immune system functions – are involved in the development of asthma.
The authors explained that the causes of asthma have for long been poorly understood, in spite of several attempts to locate the genetic variants. Some recent GWAS (genome-wide associated studies) have only managed to locate some candidate genes which appear to have a slight effect on asthma risk. They have not fully explained the heritability of asthma, which leads doctors and scientists to believe that many genetic variations are involved.
Manuel Ferreira and an international team of experts set out to determine what genetic variations might be responsible for higher asthma risk by carefully examining all current GWAS and expanding on them.
They compared the genomes of thousands of asthma patients with individuals who do not have asthma across several populations and identified two genetic mutations that were strongly linked to asthma risk.
The genetic variants were:
- rs4129267 in the interleukin-6 receptor (IL6R) gene, and
- rs7130588 on chromosome 11q13.5
Interleukin 6 (IL-6) is a cytokine. A cytokine is any substance that is secreted by some immune system cells that have an effect on other cells. Interferon, interleukin, and growth factors are examples of cytokines. Interleukin 6 (IL-6) plays a major role in immunity response and inflammation – it is involved in the way diseases develop (pathogenesis), including rheumatoid arthritis. The expression of the IL-6 receptor is increased by the rs4129267 risk variant. Consequently, the researchers believe that medications that inhibit the receptor should be tested in clinical trials to see how effective they are at reducing asthma-associated airway inflammation.
The drug tocilizumab is an example of a medication that blocks the receptor. It is already approved for rheumatoid arthritis treatment.
A high proportion of atopic (allergic) asthma patients were found to have the rs7130588 variant on chromosome 11q13.5. Interestingly, it was correlated with a nearby variant which has been recently associated with atopic dermatitis risk.
The authors believe that a gene in this region is involved in the development of allergic sensitisation, which raises allergic asthma risk.
The authors wrote:
“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 previou. sly, further characterisation of this region of association is likely to discover novel molecular mechanisms involved in the causality of eczema, atopy, and asthma.”
So far, no single genetic cause has been located which is responsible for over 1% of asthma heritability, the authors added. Their findings demonstrate that asthma is a complex condition, and most likely several genes of small effect combine and interact with environmental risk factors in driving asthma risk.
The scientists concluded:
“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.”
Kathleen Barnes, from Johns Hopkins University, Baltimore, USA, in a Comment in the same journal wrote:
“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 Christian Nordqvist