• association;
  • asthma;
  • genetics;
  • gene–gene interaction;
  • haplotype;
  • multi-locus analysis;
  • pediatrics

Heinzmann A, Brugger M, Bierbaum S, Mailaparambil B, Kopp MV, Strauch K. Joint influences of Acidic-Mammalian-Chitinase with Interleukin-4 and Toll-like Receptor-10 with Interleukin-13 in the genetics of asthma. Pediatr Allergy Immunol 2010: 21: e679–e686. © 2010 John Wiley & Sons A/S

In the genetics of asthma, single genetic polymorphisms confer only a small individual risk factor. Haplotype-based association analyses, including joint analyses of several candidate genes, might therefore yield more convincing results than single-region statistics. We set out to test for joint influences of asthma genes previously identified in our study population that is acidic mammalian chitinase (AMCase), Toll-like receptor (TLR)-10, and the interleukins IL-4, IL-13, IL-8, and IL-15. In particular, we investigated whether haplotypes at two or three genes show stronger association with the trait than at a single gene alone. We genotyped 26 polymorphisms in 321 asthmatic children and 270 controls. Haplotype-based association analyses were performed by the program FAMHAP. Single-, two-, and three-gene analyses were conducted as well as conditional analyses for pairs of genes. In the two-region analyses, best evidence was found for a joint effect on asthma for AMCase and IL-4 (praw < 5 × 10−7) as well as AMCase and IL-13 (praw = 5 × 10−7). Besides, IL-13 and TLR-10 showed a stronger two-gene result (praw = 0.001607) than the respective single-gene analyses. Conditional analyses yielded similar results for these two-gene combinations and also revealed mutual additional effects for IL-13 and IL-4 (pstratified = 0.014831 and 0.001525, respectively). The most significant results demonstrate a joint effect of AMCase with IL-4 or IL-13 on the trait. Furthermore, additional mutual effects were seen for AMCase and IL-4 as well as for TLR-10 and IL-13. The corresponding pathways might therefore be of particular importance in the genetics of asthma. Further studies are needed to elucidate the functional importance of these gene–gene effects and their precise role in asthma pathogenesis.