Objectives: Asthma is a heterogenous complex disorder caused by chronic inflammation of the airways. The key issue in genetic association studies of complex disorders is the identification of multiple low-risk genes that individually have little impact on the phenotype, but in combination account for the clinical manifestation of asthma. Since neurogenic inflammation is emerging as a candidate factor in the pathogenesis of asthma, the aim of the study was to investigate whether genetic variants of neurotrophin genes are associated with asthma disease severity or asthma-related phenotypes in a pediatric population.
Methods: We genotyped 27 polymorphisms located in neurotrophin genes, using TaqMan SNP genotyping assays or Polymerase Chain Reaction - Restriction Fragments Lengths Polymorphism (PCR-RFLP) in 200 children diagnosed with asthma and 226 controls. Interactions between 27 polymorphic loci and asthma-related phenotypes were determined using the Multifactor Dimensionality Reduction (MDR) method.
Results: In single marker analysis, we observed an association of MAP3K1 gene polymorphisms (rs702689 and rs889312) with asthma. We also observed that four Single Nucleotide Polymorphisms (SNPs) were associated with severe asthma. Analysis stratified by asthma-related phenotype revealed an association between atopy and NGFR (rs3785931), while BDNF (rs7124442), NTRK2 (rs1212171), NGFR (rs2072446), and FYN (rs3730353) variants were associated with increased exhaled nitric oxide (exNO). In addition, gene-gene interaction analysis revealed a significant epistatic interaction between MAPK (rs889312) and NGF (rs11102930) variants in asthma susceptibility.
Conclusions: Our results suggest that genetic variants of MAP3K1 and NGF genes involved in the regulation of neurogenic inflammation may contribute to asthma, possibly via enhanced NGF expression and MAPK signaling pathway activation.