Interaction between variants in the interleukin-4 receptor α and interleukin-9 receptor genes in childhood wheezing: evidence from a birth cohort study


E. Melén, MD, Department of Occupational and Environmental Health, Norrbacka, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.


Background Several polymorphisms in the IL-4 receptor α (IL4RA) gene have been associated with asthma and atopy, but with variable success in different populations. Immunologic studies suggest that IL4RA may interact with other cytokines and receptors, and gene–gene interactions have also been observed with respect to asthma. Such interactions have been proposed to explain partly the difficulties in replicating association studies.

Methods Using the prospective birth cohort BAMSE, we examined eight single nucleotide polymorphisms (SNPs) and corresponding haplotypes in the IL4RA gene in relation to wheezing and sensitization up to age 4. We also evaluated potential interaction effects (departure from a multiplicative interaction model) between the IL4RA SNPs and four SNPs in the IL-9 receptor (IL9R) gene previously associated with childhood wheezing.

Results We found no main effect of the IL4RA SNPs alone and only weak associations to wheezing and sensitization when haplotypes were considered. Gene–gene interactions between several IL4RA and IL9R SNPs with regard to wheezing were observed (P=0.009), especially between IL4RA Q576R (rs1801275) and IL9R rs731476 (P=0.005). An interaction was also seen between IL4RA and IL9R haplotypes.

Conclusion Variants in the IL4RA gene alone may not exert any major influence on susceptibility to asthma-related diseases in childhood, but in combination with other genes, such as IL9R, IL4RA may be an important gene for disease susceptibility.