Joint Influences of Acidic-Mammalian-Chitinase with Interleukin-4 and Toll-Like Receptor-10 with Interleukin-13 in the Genetics of Asthma

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 (p(raw) < 5 x 10(-7)) as well as AMCase and IL-13 (p(raw) = 5 x 10(-7)). Besides, IL-13 and TLR-10 showed a stronger two-gene result (p(raw) = 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 (p(stratified) = 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.