Consortium says findings support hypothesis that genetic dysregulation of cytokine signaling increases asthma risk.

Genome-wide association studies focused on asthma risk genes have identified a variation in the interleukin-6 receptor (IL6R) and alterations at another site on chromosome 11q13.5 near the leucine-rich repeat containing 32 genes (LRRC32, also known as GARP).

The Australian Asthma Genetics Consortium (AAGC) claims the IL6R finding adds weight to the existing hypothesis that a genetic dysregulation of cytokine signaling increases asthma risk. The results also point to the possibility that relevant drugs such as tocilizumab may be effectively used to treat asthma, perhaps in a genotype-dependent manner.

Lead AAGC investigator Manuel Ferreira, Ph.D., at the Queensland Institute of Medical Research, and colleagues, admit that at present it’s not clear which gene underlies the identified link between asthma and 11q13.5. However, they note, results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitization which, in turn, increases the risk of subsequent development of asthma. “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.”

The work in addition provided independent evidence supporting a link between four previously identified loci with asthma risk. The researchers report their studies in a special European Respiratory Society issue of The Lancet. The paper is titled “Identification of IL6R and chromosome 11q13.5 as risk loci for asthma.”

Dr. Ferreria et al started by conducting a GWAS in 2,669 physician-diagnosed asthmatics and over 4,000 controls from Australia. Seven loci were prioritized after combining the results with those from the GABRIEL consortium study in another 26,475 individuals. The seven loci were then evaluated in an additional 25,358 independent samples from four in-silico cohorts.

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. These were rs4129267 sited in the IL6R gene, and rs7130588 on chromosome 11q13.

The authors state there are multiple lines of animal model and clinical evidence suggesting that IL6R is the causal gene underlying their observed association with rs4129267: previous studies have shown rs4129267 is strongly associated with variation in serum concentrations of the soluble form of the IL-6 receptor (sIL-6R), and both serum and airway concentrations of sIL-6R are increased in asthma patients. This prior work, together with the AAGC results, “suggest that rs4129267, or a causal variant in linkage disequilibrium with it, increases the risk of development of asthma by upregulating protein concentrations of sIL-6R or membrane-bound IL-6R, or both, which in turn contributes to the development and maintenance of a Th2 immune response in the lung,” they conclude.

The 11q13.5 locus, meanwhile, is located near an SNP recently reported to associate with the immune-related disorders, Crohn disease and atopic dermatitis, the team continues. Significantly, the rs7927894 variant reported to associate with Crohn disease and atopic dermatitis was found to be in complete linkage disequilibrium with rs7130588 identified by the AAGC studies, and the two predisposing alleles—rs7927894:T and rs7130588:G—occur on the same haplotype. “This finding indicates that the same underlying causal variant is likely to explain the association between this locus and the three diseases,” they write.

Interestingly, the AAGC study found that rs7130588:G doesn’t seem to increase asthma risk in nonatopic individuals. This observation, combined with its link with atopic dermatitis, “collectively suggests that this allele directly increases the risk of allergic sensitisation and, if this develops, it increases the risk of subsequently developing asthma.” Moreover, they add, while their research was under review, a separate study was published reporting an association between 11a13.5 and asthma, and this also indicated that the effects were specific to allergic asthma.

The AAGC’s studies in addition supported previous evidence linking four other loci with asthma risk at the genome-wide significance. These are the ORMDL3 locus, IL18R1, IL33, and IL2R. Cconsistent but nonsignificant evidence for an association between the previously identified SNPs for HLADQ, and SMAD3 was found.These results suggest that they might represent true risk factors for asthma in the population we studied, but have an associated risk that is lower than originally reported,” the team remarks. Conversely, the Australian researchers’ studies found no supporting evidence for a link between two other previously identified gene variants, PDE4D2 or DENND1B3, and asthma.

What was highlighted by their analyses, however, was that at the causal level, the genetic component of asthma is likely to involve potentially hundreds or thousands of variants that individually only have a weak impact on disease risk. They found that quantitative genetic scores representing the combined effects of thousands of common SNPs that each had just a small influence on asthma risk in the GABRIEL study, were significantly associated with asthma case control status in the latest investigation. “These results thus suggest that many of these SNPs are either in high linkage disequilibrium with true causal variants that are common in the population but influence disease risk weakly, or they are in low linkage disequilibrium with causal variants that are rarer but increase disease risk more strongly.”

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